Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 541-15-1 | MDL No. : | MFCD00038747 |
Formula : | C7H15NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PHIQHXFUZVPYII-ZCFIWIBFSA-N |
M.W : | 161.20 | Pubchem ID : | 10917 |
Synonyms : |
(R)-Carnitine;Levocarnitine;Carnitine;ST-198;L-Cartin;Carnitor;R-Carnitine;(–)-Carnitine
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.86 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 39.13 |
TPSA : | 60.36 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) : | -7.88 cm/s |
Log Po/w (iLOGP) : | -2.37 |
Log Po/w (XLOGP3) : | -0.84 |
Log Po/w (WLOGP) : | -1.81 |
Log Po/w (MLOGP) : | -3.79 |
Log Po/w (SILICOS-IT) : | -0.8 |
Consensus Log Po/w : | -1.92 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.05 |
Solubility : | 145.0 mg/ml ; 0.899 mol/l |
Class : | Very soluble |
Log S (Ali) : | 0.05 |
Solubility : | 182.0 mg/ml ; 1.13 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.74 |
Solubility : | 29.1 mg/ml ; 0.18 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.94 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P362-P403+P233-P501 | 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 |
---|---|---|
88.6% | In ethanol; acetone; at 20 - 65℃;Resolution of enantiomers;Purification / work up; | A laboratory reactor is charged with 100g of carnitine and 300g of ethanol. The reactor is heated up to 65C and stirred until all carnitine has been dissolved. Afterwards the reactor temperature is set to 37C. At 37C seed crystals of pure L-carnitine are added. The reactor temperature is cooled down to 20C at a rate of -0.2K/min. At 20C 900g of acetone are added within 2 hours. Afterwards the suspension is cooled down to 10C. At 10C the solids are isolated and washed with acetone and dried at 55C and <100mbar. As a result, 86.1 g of a crystalline-white dry solid were obtained. The solid comprised 99.036% (w/w) of total carnitine. The enantiomeric purity was 99.60% (e.e.). The residual solvent content was 349 mg/kg ethanol and 386 mg/kg acetone. The total yield of L-carnitine was 88.6%. |
In methanol; acetone; at 10 - 50℃;Product distribution / selectivity; | Example 2A laboratory reactor is charged with 60.2 g of carnitine and 60 g of methanol. The reactor is heated up to 50 C. and stirred until all carnitine has been dissolved. Afterwards the reactor temperature is set to 25 C. At 25 C. 0.74 g of seed crystals of pure L-carnitine are added. The reactor temperature is cooled down to 20 C. at a rate of -0.2K/min. At 20 C. 180 g of acetone are added within 1 hour. Afterwards the suspension is cooled down to 10 C. within 50 min. The suspension is stirred at this temperature for another 30 min. Afterwards the solids are filtered via a Nutsch filter and washed twice with approximately 60 g of acetone and subsequently dried for 8 h at 55 C. and a pressure of 250 mbar.As a result, 45.78 g of a crystalline-white dry solid were obtained. The solid comprised 98.94% (w/w) of total carnitine. The enantiomeric purity was 99.78% (e.e.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.4% | Step 3 Preparation of L-carnitine L-3-cyano-2-hydroxypropyl trimethyl ammonium (27.5g) and 30% hydrochloric acid (40ml) was added in 205ml flask, heated at 70C?80C, and kept for 5 hours. After that, the excess hydrochloric acid was evaporated under reduced pressure at 70C, the residue was then cooled to 20C, added 20% ammonia (20g), cooled to 0C, the ammonium chloride was filtered off. Activated carbon (3g) was added to the mother liquor, decolored, desalted and evaporated to dryness under reduced pressure, then ethanol (50ml)was added , refluxed for 1 hour at 50C ? 80C, cooled to 20 C, acetone was dripped (125ml), filtrated and dried to give L-carnitine product (18.6g), yield 75.4%.Results: The experimental data of preparation L-carnitin from S-epichlorohydrin with different optical purity is listed in Table 4: The content of S-enantiomeric and R-enantiomeric of S-Epichlorohydrin having different optical purity is showed in FIG. 1-5. The HPLC of dextroisomer of L-carnitine is showed in FIG. 6-7. The data related to FIG.1-5 is listed in table 5-9: | |
75.4% | With hydrogenchloride; water; at 70 - 80℃; for 5h;Product distribution / selectivity; | L-3-cyano-2-hydroxypropyl trimethyl ammonium (27.5 g) and 30% hydrochloric acid (40 ml) was added in 205 ml flask, heated at 70 C.80 C., and kept for 5 hours. After that, the excess hydrochloric acid was evaporated under reduced pressure at 70 C., the residue was then cooled to 20 C., added 20% ammonia (20 g), cooled to 0 C., the ammonium chloride was filtered off. Activated carbon (3 g) was added to the mother liquor, decolored, desalted and evaporated to dryness under reduced pressure, then ethanol (50 ml)was added, refluxed for 1 hour at 50 C.80 C., cooled to 20 C., acetone was dripped (125 ml), filtrated and dried to give L-carnitine product (18.6 g), yield 75.4%. |
75.04% | With hydrogenchloride; water; at 80℃; for 5h; | Add 120 g of (R)-(-)-4-chloro-3-hydroxybutyronitrile and 240 g of ethanol solution prepared in Example 3 aboveIn a 500ml three-necked bottle,After stirring, a mixed solution is obtained,Slowly pass 101g of trimethylamine gas,Heated up to 50 C,Reaction for 4 hours,After the reaction is completed, water and unreacted trimethylamine are distilled off under negative pressure.White L-carnitine chloride after recrystallization from ethanol160.5g of nitrile solid,Yield was 84.99%.To the obtained L-carnitine nitrile was added 321 g of a 30% hydrochloric acid solution,Slowly warm up to 80C,5 hours reaction time,After the reaction is completed, adjust the pH of the reaction solution with ammonia water to 2 ~ 3, and then remove the water by vacuum distillation.The obtained crude product was recrystallized from ethanol,After purification by strong acid cation exchange resin (Amberlite IRA-402 (OH)) to remove chloride ions,And recrystallized from absolute ethanol,After vacuum drying, a white solid product was obtained.Structural analysis of the prepared product,1HNMR, 13CNMR;The infrared absorption spectra are similar to Figure 1, Figure 2, and Figure 3, respectively.It can be seen from the above spectrum that the product obtained is L-carnitine. In this example, 103.2 g of L-carnitine solid product was prepared.Yield: 75.04% |
5.8 g | With hydrogenchloride; In water; at 90℃; for 4h; | (4) 26.7 g (0.05 mol) of (R) -2-hydroxybutyronitrile quaternary ammonium salt IV was added into 150 mL of ethyl acetate, and 14.8 g (0.075 mol) of 30% aqueous solution of trimethylamine was added at 65 C for 6 hours , Cooled to below 5 C and filtered to give (R) -2-hydroxy-3-cyanopropyltrimethylammonium chloride as a white solid. It was added to 25mL concentrated hydrochloric acid, heated to 90 for 4 hours, the reaction was stopped, cooled to below 10 , suction filtration. The filtrate was neutralized to pH 3 with 30% sodium hydroxide solution and the water was removed by subtraction. To the concentrate, 90 mL of deionized water was added, dissolved, and chloride ion was removed by strongly basic anion exchange resin. After deionization, the solution was concentrated to dryness and recrystallized by adding 30 mL of a mixed solution of methanol and water (V / V = 9: 1) to obtain 6.2 g of L-carnitine in needle white crystals in a yield of 77%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | 100 g <strong>[541-15-1]L-carnitine</strong> and 180 g mono-chloracetic acid are filled in the equipment and heated up to 70 C. After complete melting the solution is cooled down to 30 C. 24g HCl gas are added to the reactor, the reaction is stirred for 1h at 50C. 213 g palmitoyl chloride are slowly dosed over 1 hour and the solution is heated up to 70C and stirred for 2 hours. 1000 g Acetone are added at room temperature. The solid is filter out and washed with 500 g Acetone and dried at 60C and 14 mbar overnight. The solid is recrystallized with 450g Acetone. 202.9 g palmitoyl-<strong>[541-15-1]L-carnitine</strong> hydrochloride is obtained (74% yield). Mp 164-184 C H-NMR (500 MHz, DMSO) delta 0.85 (t, 3 H); 1.22 (m, 24 H), 1.5 (m, 2 H), 2.3 (m, 2 H), 2.7 (d, 2 H), 3.1 (s, 9 H), 3.65 (d, 1 H), 3.85 (dd, 1 H), 5.45 (m, 1H) | |
With trifluoroacetic acid; at 60℃; for 2.5h; | (Synthesis of hexadecanoyl-<strong>[541-15-1]L-carnitine</strong> hydrochloride) A 500-ml four-necked flask equipped with a dropping funnel, a thermometer and a cooling tube was charged with <strong>[541-15-1]L-carnitine</strong> (1 mol) and trifluoroacetic acid (350 ml) , followed by heating at 60C with stirring to obtain a solution. To the resultant uniform reaction liquid, hexadecanoyl chloride (1.1 mol) was added dropwise from the dropping funnel over a period of 30 minutes. After completion of the dropwise addition, the reaction liquid was stirred at 60C for 2 hours. Thereafter, the trifluoroacetic acid was evaporated using an evaporator. The residue was dissolved in n-hexane (500 ml) , then combined with water (500 ml), and stirred for 30 minutes. The liquid mixture was combined with ethanol (500 ml) and methyl tert-butyl ether (500 ml) to perform extraction. The aqueous phase was collected and was combined with n-butanol (500 ml) and further with water (100 ml) to perform extraction. The n-butanol phase was separated and the solvent was evaporated to afford 201 g of a residue. The residue was purified by recrystallization in isopropanol to give 99% pure hexadecanoyl-<strong>[541-15-1]L-carnitine</strong> hydrochloride (0.3 mol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.3% | With acetic acid; In Isopropyl acetate; at 10 - 60℃; for 8h;Large scale; | 50<strong>[541-15-1]L-carnitine</strong> is added to the reaction kettle 1 kg, glacial acetic acid 3.8L, dropping acetyl chloride 0.6 kg, drop to finishes the elevation of temperature 50-60C, HPLC monitoring reaction levocarnitine content of less than 2%, cooling to room temperature, by adding isopropyl acetate 21L, -10 C crystallization 8 hours, filtering, drying, the white solid obtained 1.278 kg, yield 86%.10L in the reactor by adding 1.2 kg crude product, anhydrous ethanol 5L, heating to 45 C stirring dissolution, to take advantage of heat filtering, adding 2-butanone 12.5L and isopropyl acetate 12.5L, is slowly cooled to the room temperature, and then lower the temperature to -10 C stirring 8 hour, filtering, washing, vacuum drying to obtain the refined product about 1.035 kg, yield 86.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10 g | With water; potassium hydroxide; at 0℃;Green chemistry; | 15.0 g of ethyl (R)-(+)-4-bromo-3-hydroxybutanoate was added to a solution of 4.2 g of potassium hydroxide and 15.9 g ofan aqueous solution oftrimethylamine, and the mixture was stirred and cooled to 0 ± 5 C.The reaction mixture was completely distilled under reduced pressureto give a crude oil. An oil was obtained, 150 mL of deionized water was added, and 140 g of R-120H ion exchange resin was stirred in a 500 ml reaction flask.After filtration, the motherliquid was concentrated to give an oily substance, which was purified using 120 mL (ethanol/acetone = 1/2, volume ratio) solvent, filtered, and the filter cake wasdriedat 45 C under reduced pressure.10.0 g of L-carnitine inner salt was obtained (ee% was 99.64%, content was 98.3%, which was determined by the EP Pharmacopoeia test method). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.3 mg | With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dimethyl sulfoxide at 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.4% | With sodium hydroxide; In water; at -5 - 20℃; for 13h; | 250 g of purified water was added to a 1000 mL four-necked flask, and 13.5 g of sodium hydroxide was added, and the mixture was stirred to a solid solution. DownTo a temperature of -5 C, 65 g of 33% aqueous solution of trimethylamine was added dropwise, and the temperature was controlled to -5 C. Drop finished,To a solution of 35 g of ethyl (R) -4-chloro-3-hydroxybutyrate,Control temperature -5 C . Drop finished,The reaction was continued at -5 C for 1 hour and then allowed to warm to room temperature for 12 hours. Add concentrated hydrochloric acid to adjust the pH value 6, cationic resin column purification.Add the reaction solution control column under the flow rate ? 0.5L / hour, feeding finished, to the resin column by adding purified water, began to controlThe flow rate of the column is less than or equal to 0.5L / hour, and the pH of the column is 6. Add 5% -8% dilute ammonia water, control the column under the flow rate ?0.2L / hour, when the column under the discharge (pH 6.5-7.5) began to receive, pH> 8.5 to stop receiving. Add 3 g of injections to the concentrateCharcoal, refluxing for 30 minutes. Hot filter, the filtrate spin dry. The white solid L-carnitine product 30g, yield 88.4% |
75 - 89% | With sodium hydroxide; In water; at 0℃; for 3h;Product distribution / selectivity; | Sodium hydroxide (17.6 g, 0.44 mol, ca. 2 eq.) was dissolved in water (24O g). Aqueous tri- methylamine (25%, 61.3 g, ca. 1.2 eq.) was added with cooling. The resulting mixture was cooled to 0 0C and ethyl (lambda)-4-chloro-3-hydroxybutyrate (content 100%, 36 g, 0.216 mol) was added dropwise within 3 h to the stirred reaction mixture. After one additional hour at 0 0C the reaction mixture was warmed to +20 C and analyzed by HPLCYield: 80% L-carnitine <n="5"/>- A -Example 2 L-CarnitineThe procedure of Example 1 was repeated using 1.2 equivalents of sodium hydroxide and 2.5 equivalents of trimethylamine. L-Carnitine was obtained in essentially the same yield (81%).Example 3 L-CarnitineWater (1777 g), aqueous sodium hydroxide (50%, 203.7 g, 1.5 eq.) and aqueous trimethylamine (25%, 807 g, 2.0 eq.) were mixed and stirred at 0 C. Ethyl (R)-4-chloro-3-hydroxybutyrate (content 91.7%, 307.9 g) was added dropwise during 3 h and the procedure was continued as described in Example 1. Yield: 89% L-CarnitineExample 4L-Carnitine (continuous process)An aqueous solution of sodium hydroxide (3.9%) and trimethylamine (5.7%) was fed into the first stirred tank of a cascade of five 250 mL continuous stirred-tank reactors while ethyl (i?)-4-chloro-3-hydroxybutyrate was fed in equal amounts into the first four reactors. The mean residence time in each reactor was approx. 1 h and both trimethylamine and sodium hydroxide were used in an amount of 1.0 eq., based on the total amount of ethyl (lambda)-4-chloro-3-hydroxy- butyrate. The temperature of all reactors was maintained at 0 C. Once a steady state had been established, the yield of L-carnitine was 80-83%Comparative Example 1 L-CarnitineEthyl (/?)-4-chloro-3-hydroxybutyrate (content: 95.5%, 30.0 g, 0.172 mol) was stirred at O 0C while a mixture of trimethylamine (25% aqueous solution, 90.7 g, 0.383 mol), sodium hydroxide (content: 98.5%, 7.82 g, 0.193 mol) and deionized water (136 g) was added dropwise during 2 h. After an additional hour the L-carnitine content of the reaction mixture was determined by HPLC: 7.35%, corresponding to 70% yield. The reaction mixture was concentrated in vacuo and analyzed by 1H NMR. It was found to contain some gamma-hydroxycrotonic acid and an unidentified olefinic byproduct. <n="6"/>Example 5 L-CarnitineSodium hydroxide (156.1 g, 3.9 mol, 1.4 eq) was dissolved in water (370O g). Aqueous tri- methylamine (25%, 649.5 g, 1.0 eq) was added with cooling. The resulting mixture was cooled to 0C and ethyl (No.)-4-chloro-3-hydroxybutyrate (content 91.5%, 500.0 g, 2.75 mol) was added dropwise within 3 h to the stirred reaction mixture. After one additional hour at 0 C the reaction mixture was warmed to +20C and analyzed by HPLC. Yield: 85% L-CarnitineComparative Example 2 L-CarnitineIn a 250 mL reactor, ethyl (/?)-4-chloro-3 -hydro xybutyrate (content 94%, 12.00 g, 67.7 mmol) was stirred with water (75.04 g) and cooled to 0 C. Aqueous trimethylamine (25%, 17.71 g, 1.1 eq.) was added at once at 0 C, followed by dropwise addition of aqueous sodium hydroxide (25%, 15.30 g, 1.4 eq.) within 3 h. After another 1 h at 0 C the reaction mixture was allowed to warm to 20 C and analyzed by HPLC. Yield: 76% L-Carnitine (HPLC/IC)Comparative Example 3 L-CarnitineThe procedure of Comparative Example 2 was repeated with the exception that the aqueous sodium hydroxide was added at once, followed by dropwise addition of the aqueous trimethylamine within 3 h. Yield: 75% L-Carnitine (HPLC/IC)Comparative Example 4 L-CarnitineThe procedure of Comparative Example 2 was repeated with the exception that the aqueous trimethylamine and the aqueous sodium hydroxide were added separately but simultaneously within 3 h. Yield: 77% L-Carnitine (HPLC/IC) |
43% | Example 4: Preparation of L-carnitine (6); [56] 37 mL (0.156 mole) of an aqueous 30 wt/% trimethylamine solution was placed in10 g (0.06 mole) of ethyl (R)-4-chloro-3-hydroxybutyrate, and the mixture was heated and stirred at a temperature of 80 to 90 0C for 3 hours. The conversion (%) of the substrate was confirmed by gas chromatography. After the reaction was complete, unreacted trimethylamine was removed by distillation under reduced pressure. 70 mL of 10 % HCl was added to the resulting concentrated solution which was then heated and stirred at a temperature of 80 to 90 0C for 2 hours, concentrated by distillation under reduced pressure, and dissolved in a small amount of water, followed by elution on a column packed with an anion exchange resin (Amberlite IRA 410, OH"). The eluted fractions were combined, concentrated by distillation under reduced pressure, and recrystallized from small amounts of anhydrous ethanol and acetone to afford 4.15 g (yield: 43 %) of L-carnitine. The optical purity of the product was measured using a polarimeter. The result is as follows:[57] [alpha]25 = -30 (C=l, H O) |
8.9 g | With water; sodium hydroxide; at 0℃;Green chemistry; | 13.0 g of ethyl (R)-(+)-4-chloro-3-hydroxybutyrate was added to a 6 g aqueous solution of sodium hydroxide and 27 g of an aqueous solution of trimethylamineto the reaction flask, stirred, and cooled to 0 ± 5 C.The reaction mixture was completely distilled under reduced pressure until no fraction was obtained to obtain an oil, and 100 mL of deionized water was added, and 130 g of R-120H ion exchange resin was stirred in a 500 ml reaction flask.After filtration, the motherliquid wasconcentratedto an oily substance, and purified by a solvent of 150 mL (ethanol/acetone = 1/2, volume ratio), filtered, and the filter cake was dried under reduced pressure at 45 C.8.9 g of L-carnitine inner salt was obtained (ee% was 99.87%, content was 98.2%, which was determined by the EP Pharmacopoeia test method).Theactive enzyme was not detectedby the WOODmethod. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In N,N-dimethyl-formamide; at 125℃; for 8h; | A suspension of <strong>[541-15-1]L-carnitine</strong> inner salt (0.8051 g, 5.000 mmol) and benzyl bromide(0.72 mL, 6.00 mmol) in DMF (10 mL) was heated oil bath at 1250C (oil bath) under nitrogen for 8 h (solid of carnitine gradually dissolved). The solvent was removed by rotary evaporation and the residue was kept in vacuum (oil pump) for 1 h. The solid was washed with ethyl ether (2 x 5 mL). The remaining solid (1.50 g) was recrystallized from anhydrous acetonitrile to give <strong>[541-15-1]L-carnitine</strong> benzyl ester bromide (1.30 g, 3.91 mmol, 78%), mp 184-187C.IR(KBr) 3257, 3006, 1732, 1490, 1320, 1180, 1083, 958 cm'1. NMR: 1H (200 MHz, D2O) 7.44 (s, 5H C6H5), 5.19 (d, J= 2.9, 2H, CH2 benzyl), 4.76-4.58 (m, IH, CH), 3.50-3.39 (m, 2H, CH2N), 3.17 (s, 9H, N(CHa)3), 2.75-2.62 (m, 2H, CH2COO); 13C (50 MHz, D2O and acetonitrile as internal reference) 172.3, 135.9, 129.5, 129.3, 129.0, 70.1, 67.9, 63.3, 54.7, 40.7.MS (FAB, methanol) (positive) 252 (100%, M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In trifluoroacetic acid; at 22 - 55℃; | To a solution of 15-ethoxycarbonyl-3,3,14,14-tatramethylpentadecanoic acid (46) (1.31 g, 3.53 mmol) in SOCl2 (5 mL) was added DMF (one drop) and the mixture was heated to 6O0C for 2 h. Toluene (10 mL) was added and the solvents were evaporated. The residue was dried in vacuum (1 mm Hg) for 1 h and treated with solution of <strong>[541-15-1]L-carnitine</strong> (0.57 g, 3.53 mmol) in TFA (3.0 mL) at RT (22C).The mixture was kept at RT overnight and was then heated to 55C for 3 h. The reaction mixture was concentrated and the residue was dissolved in CH2Cl2 (50 mL). The solution was washed with water (10 mL), dried over molecular sieves (4A) in <n="43"/>the presence of charcoal, and evaporated. The residue was washed with heptane (2 x 10 mL), concentrated, and dried in vacuum. Purification by column chromatography (reverse-phase Cis-silica gel, EtOH-H2O, 3:1), dissolution in dichlorornethane, drying over molecular sieves (4A), and concentration in vacuo afforded 15-ethoxycarbonyl-3,3,14,14-tetramethylpentadecanoyl-L-caniitine(0.82 g, 41%) as a colorless, sticky oil.1HNMR (300 MHz, CD3OD/TMS): 5.60 (m, IH), 4.09 (q, J= 7.1 Hz5 2H), 3.86 (dd, J- 14.0, 8.2 Hz, IH), 3.70 (d, J- 14.0 Hz, IH), 3.19 (s, 9H), 2.76 (m, 2H), 2.29 (AB, J= 14.0 Hz, 2H), 2.18 (s, 2H), 1.29 (m, 23H), 1.01 (s, 6H), 0.98 (s, 6H).13CNMR (75 MHz, CD3OD): 173.86, 172.38, 172.24, 69.48, 66.09, 61.05, 54.49, 46.82, 46.49, 43.39, 37.96, 34.28, 34.17, 31.56, 30.78, 27.94, 27.71, 25.15, 14.72.HRMS (LSIMS, nba): CaIc For C29H56O6N (MH+): 514.4108, found: 514.4082.HPLC (Synergi Polar-RP, 4 mu, 4.6 x 250 mm, 1.0 mL/min, RI detection; 60% acetonitrile, 40% aqueous KH2PO4 (0.025 m5 pH 3); retention time 7.98 min): 88.0% pure.Elemental analysis for assumed hydrochloride salt (C2PHs6OeNCl): calc. C, 63.31; H, 10.26; N, 2.55; Cl, 6.44. Found: C, 54.70; H, 8.60; N, 2.13; Cl, 0.41. <n="44"/>Assignment of NMR resonances to specific protons/carbons: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With acetic anhydride; In nitric acid; | EXAMPLE 1 Preparation of (R)-3-nitriloxy-carnitine nitrate A solution of (R)-carnitine (20 g; e.e. >99%),) in 65% nitric acid (178 g), cooled to 0-5 C., is slowly added with 98% acetic anhydride (652.2 g) in the space of 12 h. On completing the addition, the mixture is brought back up to room temperature and maintained under stirring for a further 6 h and then diluted with isopropyl ether (0.6 l), with the formation, in the space of 1-2 h, of a white solid which is filtered, washed with isopropyl ether and dried to yield (R)-3-nitriloxy-carnitine nitrate (27.8 g; yield 83%), with a melting point of 125.5-127 C. and rotatory power [alpha]D25=-34.66, [alpha]D20=-36.7 (c=10%, H2O). 1H-NMR spectrum (D2O): delta 5.85-6.00 [m, 1H,-CH(ONO2)-]; 3.75-4.05 [m,2H,-CH2-N+(CH3)3)]; 3.25 [s,9H,N+(CH3)3)]; 2.85-3.20 [m, 2H,-CH2-COOH] in ppm. |
80 - 83% | With nitric acid; acetic anhydride; In water; at 0 - 20℃; for 5.5 - 18h; | EXAMPLE 1Preparation of (R)-3-Nitriloxy-carnitine Nitrate A solution of (R)-carnitine (20 g; e.e. >99%), in 65% nitric acid (178 g), cooled to 0-5 C., is slowly added to 98% acetic anhydride (652.2 g) in the space of 12 h. On completing the addition, the mixture is brought back up to room temperature and maintained under stirring for a further 6 h and then diluted with isopropyl ether (0.6 l), with the formation, in the space of 1-2 h, of a white solid which is filtered, washed with isopropyl ether and dried to yield (R)-3-nitriloxy-carnitine nitrate (27.8 g; yield 83%), with a melting point of 125.5-127 C. and rotatory power [alpha]D25=-34.66, [alpha]D20=-36.7 (c=10%, H2O). 1H-NMR spectrum (D2O): delta 5.85-6.00 [m, 1H, -CH(ONO2)-]; 3.75-4.05 [m, 2H, -CH2-N+(CH3)3)]; 3.25 [s,9H,N+(CH3)3)]; 2.85-3.20 [m, 2H, -CH2-COOH] in ppm. Elemental analysis: C 30.98; H 5.41; N 15.38.EXAMPLE 2Preparation of (R)-3-Nitriloxy-carnitine Nitrate A solution of (R)-carnitine (20 g; e.e. >99%) in 65% nitric acid (88 g), cooled to 5 C., is slowly added to 98% acetic anhydride (200 g) in the space of 2 h. On completing the addition, the mixture is maintained at 5-10 C. for 3.5 h. After a work-up similar to that in the previous example, (R)-3-nitriloxy-carnitine nitrate was obtained (26.8 g; yield 80%).EXAMPLE 3Preparation of (R)-3-Nitriloxy-carnitine Nitrate The preparation is done as in example 1, but, at the end of the reaction, most of the excess HNO3 and acetic acid is distilled off at reduced pressure (10 mm Hg). The residue is then precipitated by addition of ethyl acetate (0.4 l) to obtain (R)-3-nitriloxy-carnitine nitrate with comparable characteristics. |
80% | With acetic anhydride; In nitric acid; | EXAMPLE 2 Preparation of (R)-3-nitriloxy-carnitine nitrate A solution of (R)-carnitine (20 g; e.e. >99%) in 65% nitric acid (88 g), cooled to 5 C., is slowly added with 98% acetic anhydride (200 g) in the space of 2 h. On completing the addition, the mixture is maintained at 5-10 C. for 3.5 h. After a work-up similar to that in the previous example, (R)-3-nitriloxy-carnitine nitrate was obtained (26.8 g; yield 80%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | In DMF (N,N-dimethyl-formamide); at 20℃; for 36h; | To a solution of 510 mg (0.86 mmol) of (E)-7-tert-butoxyiminomethyl- [20-0- (4-BROMO)-BUTYRYL-CAMPTOTHECIN] (2a) in 10 mL of anhydrous DMF [WERE ADDED 906 MG (5.6 MMOL, 6.5 EQ. ) OF L-CARNITINE INNER SALT. THE] mixture thus obtained was stirred at room temperature and sheltered from the light. After 16 h the reaction showed 40% conversion and 600 [MG (3.7 MMOL, 4.3 EQ. ) OF L-CARNITINE INNER SALT WERE THEN ADDED. AFTER] another 20 h the excess carnitine was eliminated after diluting the mixture with 15 mL of [CH2CI2,] with an aqueous washing (4 mL). The resulting organic phase was shaken with 10 mL of H20 to extract the product and eliminate the lipophilic impurities in [CH2CL2.] 161 mg (0.21 mmol, 24%) of a yellow solid were obtained (Tdec. = [189C).] Rf = 0.38 [(CH2CL2/CH3OH] 7: 3). MS (IS): M+ = 677.4 Elemental analysis: calculated: C 57.02, H 5.93, N 7.39 ; found: C 56. 98, H 5.92, N 7.38. (2% H20). [1H] NMR (300 MHz, DMSO, [8)] : 0.90-1. 00 (t, 3H, CH3), 1.50 (s, 9H, t- Bu), 1. [80-1.] 95 (quintet, 2H, [CH2),] 2.10-2. 20 (q, 2H, [CH2),] 2.60-2. 70 (t, 2H, [CH2),] 3.10 (s, 9H, NMes), 3.20-3. 40 (t, 4H, 2x [CH2),] 4.05-4. 15 (t, 2H, CH2), 4.35-4. 45 [(M,] 1H, CH), 5.30 (s, 2H, [CH2),] 5.50 (s, 2H, [CH2),] 7.10 (s, [1H,] CH), 7.70-7. 80 (t, [1H,] CH), 7.85-7. 95 (t, [1H,] CH), 8.15-8. 20 (d, 1H, CH), 8.55-8. 65 (d, 1H, CH), 9.30 (s, [1H,] CH). [13C] NMR (75.4 MHz, DMSO, [8)] : 8. 2; 24.4 ; 28. 0; 28.2 ; 30.5 ; 31.0 ; 53.3 ; 54.1 ; 62.9 ; 63.7 ; 67.0 ; 69.9 ; 76.6 ; 81.3 ; 95.3 ; 119.7, 125.0 ; 125.8 ; 127.3 ; 129.0 ; 130.4 ; 131.2 ; 132.6 ; 144.3 ; 146.0 ; 146.0 ; 149.4 ; 153.0 ; 157.1 ; 168.0 ; [170.] 7; 172.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.2% | With sodium hydrogencarbonate; In water; at 80℃; for 9h; | To a mixture of (S)-carnitine inner salt (100 g; 0.62 moles) in glacial CH3COOH (100 g) 100% HNO3 is added (117.2 g; 1.86 moles) keeping the temperature at 10 C. and in the space of 1 hour and 5 minutes. Then, the temperature was lowered to 0-5 C. and acetic anhydride was added (76 g; 0.744 moles) in 2 hours and 10 minutes. After keeping the reaction mixture cool (3-5 C.) for further 3 hours from the end of addition, the reaction mass was left at 5 C. overnight. The following morning, temperature was left to rise up to 19 C. and ethyl acetate was added (835 ml) to precipitate nitriloxy-carnitine nitrate. After stirring the suspension for 30', it was filtered washing with ethyl acetate (330 ml). The wet solid on the filter (164,6 g) was dissolved in water (760 ml) and NaHCO3 (94.53 g; 1.125 moles) was added to the solution. Temperature was kept at 80 C. for 9 hours, the solution was diluted with water (760 ml) and passed through IR 120 (H+) (1320 ml) with the purpose to block carnitine. After washing with water, to completely eliminate acidity, elution was made with 1N NH3 and the ammonia solution was concentrated and eliminated with an azeotrope with isobutyl alcohol, giving (R)-carnitine inner salt, having an enantiomeric excess higher than 98%, (70.8 g; yield 70.2%). |
With sodium hydrogencarbonate; In water; at 60 - 80℃; for 8 - 66h; | EXAMPLE 5Preparation of (R)-Carnitine A solution of (S)-3-nitriloxy-carnitine nitrate (1 g), obtained according to the process in example 4, in water (20 ml) is added to NaHCO3 (0.62 g) and heated to 60 C. for 66 h. The complete quantitative conversion of the starting product to (R)-carnitine nitrate is obtained, with e.e. >99%. The product thus obtained in aqueous solution was converted to the inner salt by treatment with ion-exchange resins; by subsequent concentration of the aqueous solution and crystallization, 0.8 g of (R)-carnitine was obtained with rotatory power [alpha]D25=-30.5 (c=10% H2O).EXAMPLE 6Preparation of (R)-Carnitine Operating as in example 5, but working at 80 C., the reaction is complete after 8 h. | |
With sodium hydrogencarbonate; In water; at 60℃; for 66h; | A solution of (S)-3-nitriloxy-carnitine nitrate (1 g), obtained according to the process in example 4, in water (20 ml) is added to NaHCO3 (0.62 g) and heated to 60 C. for 66 h. The complete quantitative conversion of the starting product to (R)-carnitine nitrate is obtained, with e.e. >99%. The product thus obtained in aqueous solution was converted to the inner salt by electrodialysis; by subsequent concentration of the aqueous solution and crystallization, 0.7 g of (R)-carnitine were obtained with rotatory power [alpha]D25=-30.1 (c=10% H2O). |
With potassium hydrogencarbonate; In water; at 80℃; for 8h; | Operating as in example 9, but distilling the crude product in the end to remove the nitric acid and most of the acetic acid, instead of precipitating (S)-nitriloxy-carnitine and adding KHCO3 (257 g) directly to the residue suitably diluted with H2O (3.3 l), the complete formation of (R)-carnitine nitrate is obtained by working for 8 h at 80 C. The product thus obtained in aqueous solution was converted to the inner salt by means of treatment with ion-exchange resins; by subsequent concentration of the aqueous solution and crystallisation, 82 g of (R)-carnitine were obtained with rotatory power [alpha]D25=-28.5 (c=10% H2O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; at 80℃; | A solution of (S)-3-nitriloxy-carnitine nitrate (1 g), obtained according to the process in example 4, in water (20 ml) is added to NaHCO3 (0.31 g) and heated to 45 C. After 48 h the formation of beta-lactone nitrate is noted. 1H-NMR (D2O)=5.25-5.35 (m, 1H), 3.98-3.86 (m, 3H), 3.55-3.45 (dd, 1H), 3.24 (s, 9H). By treating with an amount of 0.31 g of NaHCO3 and heating to 80 C., (R)-carnitine having an enantiomeric excess higher than 98% is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | To a suspension of 6.00 g (0.039 mol) of (S)-chlorosuccinic acid in 20 mL of anhydrous THF maintained at ?15 C. under nitrogen were added 58.5 mL (0.0585 mol) of a 1 M solution of borane in THF in 2 hours. After 20 hours at the same temperature, the mixture was treated with 5.5 mL of water and left to stir at room temperature for 3 hours. After the addition of 11 mL of 6M NaOH, the phases were separated. To the aqueous phase were added 7 mL of 40% Me3N in water and the solution was left to stir at room temperature for 3 hours. The solution was vacuum concentrated and the resulting solution brought to pH 5 with 37% HCl. By means of evaporation of this solution a solid was obtained which was extracted with 30 ml of MeOH. The solution obtained by filtration of the insoluble part was vacuum evaporated and dried. The crude product was purified on an ion-exchange column (Amberlite IR 120 form H+) by elution with 2% NH4OH. By means of evaporation of the fractions containing the pure product, 3.14 g (50%) of L-carnitine were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With borane-THF; at -15℃; for 22h; | To a suspension of 8.27 g (0.039 mol) of (S)-methanesulphonyloxysuccinic acid in 30 mL of anhydrous THF held at ?15 C. under nitrogen were added 58.5 mL (0.0585 mol) of a 1M solution of borane in THF in 2 hours. After 20 hours at the same temperature, the mixture was treated as described in Example 9 to obtain 2.51 g (40%) of L-carnitine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With lithium borohydride; at -15℃; for 22h; | To a suspension of 6.50 g (0.039 mol) of methyl (S)-2-chlorosuccinate in 30 mL of anhydrous DME held at -15 C. under nitrogen were added 0.87 g (0.040 mol) of 95% LiBH4 in portions in 2 hours. After 20 hours at the same temperature the mixture was treated as described in Example 9 above to obtain 3.45 g (55%) of L-carnitine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With lithium borohydride; at -15℃; for 22h; | To a suspension of 7.04 g (0.039 mol) of dimethyl (S)?2-chlorosuccinate in 30 mL of anhydrous DME held at ?15 C. under nitrogen, were added 0.69 g (0.030 mol) of 95% LiBH4 in portions in 2 hours. After 20 hours at the same temperature the mixture was treated as described in Example 9 to obtain 3.32 g (53%) of L-carnitine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.4% | To a vigorously stirred suspension of 6.13 g (0.162 mol) of NaBH4 in 18 mL of anhydrous THF, held at 0 C., were added 43.4 g (0.323 mol) of S-(?)chlorosuccinic anhydride in 90 mL of anhydrous THF. The suspension/solution was stirred for 8 hours at that temperature, then quenched with water, left to stir for one hour and then added with NaOH 4N in two portions, the first to bring the suspension to pH 7.5 and the second, after vacuum evaporating the organic solvent, to ensure total addition of 0.484 mol of NaOH (in all, 121 mL). To said solution were added 51 mL (0.337 mol) of a 40% aqueous solution of Me3N, and the whole was transferred into a closed vessel and held for 16 hours at 70 C. At the end of the reaction, the residual trimethylamine was eliminated by vacuum evaporation and then 80.75 mL (0.323 mol) of HCl 4N were added. [00101] The solution, containing L-carnitine inner salt, together with approximately 8% of impurities (mainly fumaric acid, maleic acid, hydroxycrotonic acid, D-carnitine) and sodium chloride, was desalted by electrodialysis and then vacuum dried. 38.5 g of a crude product were obtained which was crystallised with isobutylic alcohol to yield 31.4 g (60.4%) of pure L-carnitine inner salt. (ee?99.6%). [TABLE-US-00005] Elemental Analysis for: C7H15NO3 C % H % N % Calc. 52.16 9.38 8.69 Found 52.00 9.44 8.59 [?]D25 = ?31.1 (c = 1.0, H2O) 1H NMR (D2O, ?, p.p.m.): 4.57 (m, 1H, CHO); 3.41 (d, 2H, CH2COO); 3.24 (s, 9H, (CH3)3N); 2.45 (d, 2H, CH2N) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With sodium tetrahydroborate; at -15℃; for 22h; | To a solution of 7.39 g (0.039 mol) of (S)-2-chlorosuccinoyl-dichloride in 30 mL of anhydrous DME held at ?15 C. under nitrogen were added 0.74 g (0.0195 mol) of NaBH4 in portions in 2 hours. After 20 hours at the same temperature the mixture was treated as described in example 9 to obtain 2.83 g (45%) of L-carnitine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With phosphoric acid; In 2-methyl-propan-1-ol; water; at 40℃; | [00035] [C00004] [00036] 16.1 g (0.1 moles) of <strong>[541-15-1]L-carnitine</strong> inner salt were dissolved in 200 mL of water. To the resulting solution, 13.1 g (0.1 moles) and 7.5 mL of 85% phosphoric acid (0.1 moles) were added. Following complete dissolution, isobutanol was added and the resulting mixture was concentrated under vacuum at 40 C. The residue thus obtained was taken up with acetone and left under stirring for a few hours. The reaction product was crumbled and filtered under vacuum. [00037] The solid thus obtained was washed with acetone and dried in a thermostatic oven at 30 C. overnight. 33.2 g of the title compound were obtained as a white, crystalline, non-hygroscopic solid.[TABLE-US-00001] Yield95% m.p.150 C. (dec.) K.F.= 0.6% [alpha]20D = -15.1 (C = 1% H2O) pH3.2 (C = 0.5% H2O) Elementary analysis:C%H%N%Cl% Calculated:42.107.3415.109.56 Found:42.237.6315.629.32 [00038] NMR: D2O delta=5.5-5.4 (1H,m -CH-); 3.9 (2H,CH2-N-CH3); 3.8-3.5 (2H,m, N-CH2); 3.1 (9H,s, N-(CH3)3); 2.9 (3H,s, N-CH3); 2.7-2.5 (2H,m, -CH2-COOH); 2 (3H,s, COCH3).[TABLE-US-00002] HPLC: Column:Hypersil APS-2 (5 mum) 200 × 4.6Temperature:= 30 C.Mobile phase:CH3CN/H2O + 0.05M KH2PO4/CH3CN (65-35 v/v)pH:4.7 with H3PO4 Flow-rate0.7 mL/minAcetyl-<strong>[541-15-1]L-carnitine</strong>Rt = 8.5Creatine:Rt = 7.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In water; at 40℃; | [00042] [C00006] [00043] 20.3 g (0.1 moles) of acetyl L-carnitine inner salt were dissolved in 100 mL of distilled water and to the resulting solution 20.5 g (0.1 moles) of L-ornithine dihydrochloride were added under stirring. [00044] Following complete dissolution, the mixture was concentrated under vacuum at 40 C. in a rotary evaporator equipped with a water pump at 25 mm/Hg. Isobutanol was added to the concentrate and the resulting mixture was azeotropically distilled. The residue thus obtained was taken up with acetone and kept under mechanical stirring overnight. The mixture was distilled under vacuum with a Gooch filter, no4. [00045] The solid thus obtained was dried under vacuum in a thermostatic oven at 30 C. overnight. [00046] 38 g of the title compound were obtained as a white, crystalline, non-hygroscopic solid.[TABLE-US-00005] Yield:96% K.F:= 0.5 [alpha 20D = -5.7 (C = 1% H2O) pH3.2 (C = 1% H2O) Elementary analysis:C%H%N%Cl% Calculated:41.187.6810.2917.3 Found:41.278.0110.3317.1 [00047] NMR: D2O delta=5.5-5.4 (1H,m -CH-); 3.8-3.5 (2H,m, N-CH2); 3.7-3.6 (1H, t, CH2NH2); 3.1 (9H,s, N-(CH3)3); 3-2.9 (3H, t, N-CH2-NH2); 2.7-2.5 (2H,m, -CH2-COOH); 2(3H,s, CO-CH3); 1.9-1.8 (2H,q, CH2-CH); 1.7-1.5 (2H,m, CH2-CH2-CH2).[TABLE-US-00006] HPLC: Column:Hypersil APS-2 (5 mum) 200 × 4.6Temperature:= 30 C.Mobile phase:CH3CN/H2O + 0.05M KH2PO4/CH3CN (65-35 v/v)pH:4.7 with H3PO4 Flow-rate:0.7 mL/minAcetyl-L-carnitine:Rt = 8.5Ornithine:Rt = 12,58 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With CH3SO3H; In water; | EXAMPLE 3 Preparation of (R)-Carnitine To a mixture of (S)-mesyloxy carnitine methanesulfonate (13 g), prepared as in Angewandte Chemie Vol.33, N 20, 1994, p.2076, in H2O (0.26 L) having e.e. >99%, CH3SO3H (7.45 g) is added. After heating at 80 C. for 24h the mixture is cooled at r.t. and eluted on IRA 410 (OH-form)(0.25 L). The elude (0.75 L) is concentrated and the residue, crystallized by isobutyl alcohol, gives (R)-Carnitine with 94% e.e. (yield 66%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In water; | EXAMPLE 5 Preparation of (R)-carnitine A solution of (S)-3-nitriloxy-carnitine nitrate (1 g), obtained according to the process in example 4, in water (20 ml) is added with NaHCO3 (0.62 g) and heated to 60 C. for 66 h. The complete quantitative conversion of the starting product to (R)-carnitine nitrate is obtained, with e.e. >99%. The product thus obtained in aqueous solution was converted to the inner salt by treatment with ion-exchange resins; by subsequent concentration of the aqueous solution and crystallisation, 0.8 g of (R)-carnitine was obtained with rotatory power [alpha]D25=-30.5 (c=10% H2O). | |
With sodium hydrogencarbonate; In water; | EXAMPLE 7 Preparation of (R)-carnitine A solution of (S)-3-nitriloxy-carnitine nitrate (1 g), obtained according to the process in example 4, in water (20 ml) is added with NaHCO3 (0.62 g) and heated to 60 C. for 66 h. The complete quantitative conversion of the starting product to (R)-carnitine nitrate is obtained, with e.e. >99%. The product thus obtained in aqueous solution was converted to the inner salt by electrodialysis; by subsequent concentration of the aqueous solution and crystallisation, 0.7 g of (R)-carnitine were obtained with rotatory power [alpha]D25=-30.1 (c=10% H2O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In water; | Preparation of L-carnitine inner salt (7) from methanesulfonyl-D-carnitine chloride (5b). NaHCO3 (0.46g; 5.4 mmoles) was added to a solution of methanesulfonyl-D-carnitine chloride (1.5 g; 5.4 mmoles) in H2 O (25 mL) and the resulting solution was kept under stirring at room temperature for 20 hours. Further NaHCO3 (0.46; 5.4 mmoles) was then added and the solution was kept under stirring at room temperature for further 20 hours. | |
With sodium hydrogencarbonate; In water; | Preparation of L-carnitine inner salt (7) from methanesulfonyl-D-carnitine chloride (5b) . NaHCO3 (0.46g; 5.4 mmoles) was added to a solution of methanesulfonyl-D-carnitine chloride (1.5 g; 5.4 mmoles) in H2O (25 mL) and the resulting solution was kept under stirring at room temperature for 20 hours. Further NaHCO3 (0.46; 5.4 mmoles) was then added and the solution was kept under stirring at room temperature for further 20 hours. The title compound was isolated as previously described for the isolation of 7 from 6 b. L-carnitine is obtained from methanesulfonyl-D-carnitine through the formation of the lactone 6 , as evidenced by NMR, HPLC, IR and TLC analysis carried out on a sample obtained by lyophilizing a portion of the solution 20 hours following first NaHCO3 addition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In diethyl ether; trichloroacetic acid; | REFERENCE EXAMPLE 1 After a mixture of n-pentadecanoic acid (25 g, 103 mmol) and thionyl chloride (3.15 g, 26.5 mmol) was stirred for 3 hours at 75 to 80 C., a solution of <strong>[541-15-1]L-carnitine</strong> (4.27 g, 26.5 mmol) in 25 g of trichloroacetic acid was added at 60 C. The resulting mixture was stirred for 3 hours at 80 C. under argon atmosphere and then poured into stirred 100 ml of diethyl ether. The precipitates were collected by filtration, washed with diethyl ether and then dried to give 11.8 g of a crude desired product as a colorless solid. 11.8 g of the crude product was recrystallized from isopropanol to provide 9.38 g of (R)-(3-carboxy-2-pentadecanoyloxypropyl)trimethylammonium chloride as colorless needles. m.p.: 167 to 169 C. IR (Nujol) cm-1: 3020 to 2480, 1740, 1710 NMR (DMSO-d6) delta: 0.85 (3H, t, J=6.7Hz), 1.24 (22H, br s), 1.47 to 1.57 (2H, m), 2.23 to 2.40 (2H, m), 2.62 to 2.76 (2H, m), 3.12 (9H, s), 3.68 (1H, br d), 3.81 (1H, dd, J=14, 8.1Hz), 5.42 to 5.49 (1H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; nitrogen; hydrogen; trimethylamine; In methanol; ethanol; | EXAMPLE 1 Synthesis of L-Carnitine In a 200 ml-volume stainless steel autoclave whose atmosphere had been replaced with nitrogen were charged 31 g (0.2 mole) of methyl 4-chloroacetoacetate and 60 ml of methanol. To the mixture was added 168 mg (0.2 mmole) of Ru(OCOCH3)2 ((-)-BINAP), and the mixture was heated to 100 C. When the temperature reached 100 C., 100 kg/cm2 of hydrogen was introduced to the autoclave. The hydrogenation reaction completed in 15 minutes. After confirming disappearance of the starting material by gas chromatography, the methanol was removed by distillation. To the residue was added 150 ml of a 27 wt % aqueous solution of trimethylamine, followed by stirring at 70 C. for 1.5 hours and then at 90 C. for 30 minutes. Any unreacted trimethylamine was removed from the reaction mixture by distillation, and to the residue was added 15% by weight of a hydrochloric acid aqueous solution. The water was removed by distillation under reduced pressure, and ethanol was added to the residue to obtain 40 g of crude crystals of L-carnitine hydrochloride. Recrystallization from ethanol-acetone gave 18.1 g (46%) of L-carnitine hydrochloride having a melting point of 142 C. Optical Rotation: [alpha]23 -23 (c=4, H2 O). Next, some examples for synthesis of the intermediate optically active alcohol are given by reference to the following Examples 2 to 11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 4 An amount of 100 g of (3R)-4-chloro-3-hydroxybutyrylamide of L-tyrosine methylester is submitted to methanolysis under the same operating conditions as reported in Example 2. An amount is obtained of 20 g (70%) of (3R)-4-chloro-3-hydroxybutyric acid methylester with [alpha]D20 =-23 (c=1.5 in CHCL3). (3R)-4-Chloro-3-hydroxybutyric acid methylester is treated with trimethylamine and L-carnitine is obtained (yield 32%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | EXAMPLE 1 Preparation of L-carnitine <strong>[676-47-1]potassium succinate</strong> An amount of 16.12 g of L-carnitine inner salt is dissolved in 30 ml of water; 15.62 g of <strong>[676-47-1]potassium succinate</strong> dissolved in 10 ml of water are added, the mixture is stirred up to complete dissolution. The solution is submitted to freeze-drying, 31.7 g of L-carnitine <strong>[676-47-1]potassium succinate</strong> are obtained; the spectroscopic analyses confirm its structure. M.W.=317.388 C11 H20 NO7 K. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium hydroxide; In water; acetone; | Example 2 l-Carnitine phenoxyisobutyrate. 1.8 g (0.01 mols) of phenoxyisobutyric acid are dissolved in 8 ml of acetone. Separately, a solution of 1.6 g (0.01 mols) of l-Carnitine in 3 ml of H2O is added with 1 ml (0.01 mols) of 10N NaOH. The l-Carnitine solution is slowly poured into the phenoxyisobutyric acid solution. After stirring for about 5 minutes, the mixture is evaporated to nearly dryness under vacuum (rotatory evaporator) on 40C bath. The residue is taken up with about 80 ml of acetone and stirred for 20 minutes. The resulting white solid is filtered and dried under vacuum at 30C. 2.2 g of the title compound are obtained, yield = 60%. C10H11O3·C7H15NO3·Na |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; at 45℃; for 2h; | Example 6. Preparation of L-carnitine(7). Trimethylamine solution(2 eq.) was added to aqueous solution containing(R)-3,4-epoxybutyrate sodium salt or (R)-3,4-epoxybutyric acid prepared from Example 5 and stirred at 45 0C, for 2 hours . After purification of this solution using cation exchange resin(Amberite IR- 120), L-carnitine was obtained. The optical purity was analyzed by polarimeter(ATAGO Inc., Model AP-100).[63] [alpha]2 D= -30 (C=I, H2O) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; at 45℃; for 2h; | Example 6. Preparation of L-carnitine(7). Trimethylamine solution(2 eq.) was added to aqueous solution containing(R)-3,4-epoxybutyrate sodium salt or (R)-3,4-epoxybutyric acid prepared from Example 5 and stirred at 45 0C, for 2 hours . After purification of this solution using cation exchange resin(Amberite IR- 120), L-carnitine was obtained. The optical purity was analyzed by polarimeter(ATAGO Inc., Model AP-100).[63] [alpha]2 D= -30 (C=I, H2O) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 90% | In water; for 2h; | EXAMPLE 5; Preparation of <strong>[541-15-1]L-carnitine</strong> calcium acetate. A mixture of calcium acetate (0.5 g, 0.003 mol) and <strong>[541-15-1]L-carnitine</strong> (0.5 g, 0.003 mol) was dissolved in water (15 mL) and stirred for 2 hours. The clear and colorless solution was concentrated at reduced pressure at bath temperatures that were less than about 70 C. to a white solid. The solid, <strong>[541-15-1]L-carnitine</strong> calcium acetate, was obtained in greater than 90% yield and had a melting point of 166-167 C., with decomposition and evolution of trimethylamine. (The melting point of <strong>[541-15-1]L-carnitine</strong> was 186-190 C.) The solid was not hygroscopic. The solid had no objectionable taste. The 1H-Nuclear Magnetic Resonance (1H-NMR) spectrum (FIG. 1) is consistent with the structure of the salt and shows the presence of <strong>[541-15-1]L-carnitine</strong> and acetate in a molar ratio of approximately 1:2. (Calcium is not detected by 1H-NMR.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 90% | In methanol; water; at 20℃; for 4.25h; | EXAMPLE 6; Preparation of <strong>[541-15-1]L-Carnitine</strong> calcium butyrate. <strong>[541-15-1]L-Carnitine</strong> (0.5 g, 0.003 mol) and butyric acid (0.54 g, 0.006 mol) were added to 5 mL of water and 1 mL of methanol. To the resulting solution was added calcium hydroxide (0.22 g, 0.003 mol). The resulting slurry clarified during 15 minutes of stirring at room temperature. After continued stirring at room temperature for four hr, the solution was filtered, and the filtrate was concentrated to dryness under vacuum at bath temperatures that were less than about 70 C. The solid, <strong>[541-15-1]L-carnitine</strong> calcium butyrate, was obtained in greater than 90% yield and had a melting point of 97.6 C., with decomposition and evolution of trimethylamine. (The melting point of <strong>[541-15-1]L-carnitine</strong> was 186-190 C. Butyric acid is a liquid.) The solid was not hygroscopic. The solid had no objectionable taste but had a somewhat bitter aftertaste. The 1H-NMR spectrum (FIG. 2) is consistent with the structure of the salt and shows the presence of <strong>[541-15-1]L-carnitine</strong> and butyrate in a molar ratio of approximately 1:2. (Calcium is not detected by 1H-NMR.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 90% | In water; for 0.25h; | EXAMPLE 7 Preparation of <strong>[541-15-1]L-carnitine</strong> calcium propionate. <strong>[541-15-1]L-Carnitine</strong> calcium propionate was prepared by combining <strong>[541-15-1]L-carnitine</strong> (0.5 g. 0.003 mol) and calcium propionate (0.55 g, 0.003 mol) in about 4 mL of water. When dissolution was complete, the clear and colorless solution that results was stirred for about 15 minutes and then concentrated to dryness under vacuum, using a water bath that was maintained at less than about 70 C. <strong>[541-15-1]L-Carnitine</strong> calcium propionate, a white solid that is not hygroscopic, was obtained in greater than 90% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; at 20 - 80℃; for 3.5h; | EXAMPLE 2 Attempted preparation of <strong>[541-15-1]L-carnitine</strong> calcium succinate. A mixture of calcium succinate (0.85 g, 0.003 mol) and <strong>[541-15-1]L-carnitine</strong> (0.5 g, 0.003 mol) was dissolved in water (5 mL) and stirred at room temperature for 30 minutes. Dissolution was incomplete, and the reaction temperature was raised to 80 C. Stirring was continued at the higher temperature for 3 hr. The resulting solution was cooled to room temperature and filtered, and the filtrate was concentrated at reduced pressure to a white solid. On exposure to the atmosphere, the solid absorbed water and became "sticky." In other words, <strong>[541-15-1]L-carnitine</strong> calcium succinate was found to be hygroscopic. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.4% | To the reaction completed solution in Example 12 (16.37 g; containing 2.59 g of Car-amide), 36% aqueous HCl (4.01 g; 39.6 mmol) was added and the reaction was started at 80C. After 8 hr, the conversion rate of Car-amide reached 100% and the reaction was completed. After neutralization of the system with aqueous NaOH, (L)-Car and CB in the reaction solution were quantitatively determined. As a result, it was found that 2.11 g of (L)-Car (yield 99.4%) and 0.001 g of CB (yield 0.05%) were produced. A part of this aqueous solution was taken, dried and subjected to measurement of the optical purity of Car. As a result, the optical purity was found to be 94.5% ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
~ 100% | In water; at 20℃;pH ~ 4; | According to one embodiment, 96.7 grams (0.6 mole) of <strong>[541-15-1]L-carnitine</strong> inner salt (C7H15NO3, molecular weight 161.20) was added to a 50% aqueous solution (having a pH value < 1) of 66.0 grams (0.1 mole) phytic acid and stirred at room temperature resulting in an exothermic reaction. According to one embodiment, 96.7 grams (0.6 mole) of <strong>[541-15-1]L-carnitine</strong> inner salt (C7H15NO3, molecular weight 161.20) was added to a 50% aqueous solution (having a pH value < 1) of 66.0 grams (0.1 mole) phytic acid and was stirred at room temperature for about 15 minutes to create a solution. According to one embodiment, the solution (having a pH value of about 4) was further stirred 20n minutes. According to one embodiment, the solution was concentrated on an evaporator under a vacuum at 500C. According to one embodiment, the residue was repeatedly (3 times) taken up using anhydrous ethanol under a vacuum to dry the solution as much as possible. According to one embodiment, the residue is further dried in a vacuum oven at 500C to obtain 166.2 grams of white solid powder with an almost quantitative yield (i.e., the white solid powder contains 2% H2O). According to one embodiment, this white solid powder has a melting point of 121-125 degrees Celsius (dec), is odorless (i.e., it does not have the unpleasant fishy smell of <strong>[541-15-1]L-carnitine</strong> inner salt that is usually generated by the decomposition of <strong>[541-15-1]L-carnitine</strong> inner salt to emit amine), and has a pH value of 4 (c=1% HhO), 1HNMR (D2O ppm) delta = 4.89, 4.46, and 4.24 (6H, m, CH-O-P), 4.64 (6H, m, CJH-OH), 3.45 (12H, m, CH2N), 3.20 (54H, s, NCH3), 2.59 (12H, m. CH2COOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In ethanol; | Example 2. Z,-carnitine acetylsalicylateI-Carnitine (1.61 g, 10 mmol) and acetylsalicylic acid (1.8O g, 10 mmol) were dissolved in ethanol (20 ml) and the solution concentrated in vacuo at about 40 0C till syrup consistence that on cooling crystallizes. The crystalline mass was triturated with acetone (50 ml), filtered, washed with acetone and dried in vacuo at room temperature. The yield of colorless crystals with m.p. 90-94 0C was 3.17 g (93%). The substance is water soluble, stable at ambient conditions.1H NMR spectrum (D2O, TMS) delta: 2.32 (3H, s, COCH3); 2.53 (2H, d, J = 6.6 Hz, CH2COO"); 3.18 (9H, s, Me3N); 3.38-3.45 (2H, m, CH2N); 4.59 (IH, quint., J = 6.1 Hz, CHOH); 7.15 (IH, dd, J = 1.1 and 8.1 Hz, H-3); 7.37 (IH, ddd, J = 1.1, 7.6 and 7.6 Hz, H-5); 7.56 (IH, ddd, J = 1.8, 7.8 and 7.8 Hz, H-4); 7.79 ppm (IH, dd, J =1.8 and 7.8 Hz, H-6).C16H23NO7. Calculated, %: C 56.30; H 6.79; N 4.10.Found: %: C 55.67; H 6.85; N 4.12.The new salt is characterized by X-ray powder pattern (Cu K11 - radiation) having peaks at 2Theta-angles 5.09, 12.62, 13.48, 13.84, 15.04, 17.82, 19.15, 19.77, 21.84, 22.56, 23.33, 23.92, 24.40, 25.17, 25.43, 26.14, 27.24, 29.50, 30.36 +/- 0.2.Structure of the new salt is confirmed by means of X-ray single crystal structure analysis (below). Crystals are monoclinic, cell parameters at experiment temperature T = - 85 0C are: a = 13.1342(6) A, b = 7.6396(3) A, c = 17.737(1) A, beta = 104.535(2), cell volume V = 1722.8(2) A3, space group P2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
~ 100% | In water; at 20℃; for 0.583333h; | Preparation of <strong>[541-15-1]L-Carnitine</strong> Phytate In a 6:1 Mole Ratio <strong>[541-15-1]L-Carnitine</strong> Phytate (in a 6:1 mole ratio) (C48H108N6O42P6, molecular weight 1627.24) is represented by the formula shown by Formula (I).According to one embodiment, 96.7 grams (0.6 mole) of <strong>[541-15-1]L-carnitine</strong> inner salt (C7H15NO3, molecular weight 161.20) was added to a 50% aqueous solution (having a pH value <1) of 66.0 grams (0.1 mole) phytic acid and stirred at room temperature resulting in an exothermic reaction. According to one embodiment, 96.7 grams (0.6 mole) of <strong>[541-15-1]L-carnitine</strong> inner salt (C7H15NO3, molecular weight 161.20) was added to a 50% aqueous solution (having a pH value <1) of 66.0 grams (0.1 mole) phytic acid and was stirred at room temperature for about 15 minutes to create a solution. According to one embodiment, the solution (having a pH value of about 4) was further stirred 20 minutes. According to one embodiment, the solution was concentrated on an evaporator under a vacuum at 50 C. According to one embodiment, the residue was repeatedly (3 times) taken up using anhydrous ethanol under a vacuum to dry the solution as much as possible. According to one embodiment, the residue is further dried in a vacuum oven at 50 C. to obtain 166.2 grams of white solid powder with an almost quantitative yield (i.e., the white solid powder contains 2% H2O). According to one embodiment, this white solid powder has a melting point of 121-125 degrees Celsius (dec.), is odorless (i.e., it does not have the unpleasant fishy smell of <strong>[541-15-1]L-carnitine</strong> inner salt that is usually generated by the decomposition of <strong>[541-15-1]L-carnitine</strong> inner salt to emit amine), and has a pH value of 4 (c=1% H2O), 1HNMR (D2O ppm) delta=4.89, 4.46, and 4.24 (6H, m, CH-O-P), 4.64 (6H, m, CH-OH), 3.45 (12H, m, CH2N), 3.20 (54H, s, NCH3), 2.59 (12H, m, CH2COOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 20℃; for 5h; | Example 2Preparation of Retinyl O-Carnitinoylglycolate BromideCarnitine inner salt (0.65 g, 4 mmol) was suspended in dimethylformamide (3 mL). Retinyl bromoacetate (1.628 g; 4 mmol) in dimethyl formamide (2 mL) was added dropwise. The mixture was stirred at room temperature for 5 hours to afford >99% conversion of retinyl bromoacetate to the ester according to HPLC analysis. The mixture was filtered and concentrated in vacuo to give 2.2 g of a yellow, very hygroscopic solid. 1H NMR (Hydrogen-1-Nuclear Magnetic Resonance) (CDCl3) delta (ppm): 6.67 (dd, 1H, J=15.0, 11.4 Hz), 6.27 (d, 1H, J=15.0 Hz), 6.3-6.0 (m, 3H), 5.57 (t, 1H, J=7.2 Hz), 4.9-4.7 (m, 2H), 4.68 (d, 2H, J=2.4 Hz), 3.9-3.7 (m, 2H), 3.45 (br s, 9H), 3.0-2.8 (m, 4H), 2.02 (t, 2H, J=6.6 Hz), 1.96 (s, 3H), 1.89 (s, 3H), 1.71 (s, 3H), 1.65-1.55 (m, 2H), 1.5-1.4 (m, 2H), 1.02 (s, 6H).HPLC (4.6×150 mm Zorbax SB-C8 column [Agilent], 3.5mu thickness, 95:5 methanol:water (containing 0.1% trifluoroacetic acid) for 10 min, detection at 325 nm): tR 2.0 min (retinyl O-carnitinoylglycolate bromide); tR 5.1 min (retinyl bromoacetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With dmap; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.5% | With tetrafluoroboric acid; In water; for 0.166667h; | <strong>[541-15-1]L-Carnitine</strong> inner salt (0.32 g, 2 103 mol) was dissolved in a0.9 M solution of HBF4 in water (3.33 mL, 3 103 mol, 1.5 eq).After 10 min under stirring, the solution was taken to drynessunder vacuum with a gentle heating, leaving a dense oil whichdid not solidify by adding different solvents (acetone, methanoletc.) neither by prolonged stay under vacuum with dehydratingagents (K2CO3, P2O5): 0.4 g (1 103 mol, yield 82.5%).1H NMR in acetone-d6: 2.62 (m, 2H, CH2COOH), 3.40 (s, 9H,Me3N), 3.60 (m, 2H, CH2N), 4.75 (m, 1H, CHOH) ppm.19F NMR in acetone-d6: 150.5 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.3% | 4. Production of Propionyl-l-Carnitine Nitrate with Catalyst [0062] In a reflux flask, <strong>[541-15-1]L-carnitine</strong> base (0.1 moles) and propionic anhydride (0.15 moles), a trace of pyridine, KOH (0.1 moles), and a small amount of pyridine were added. The compounds were gently refluxed for an hour at about 80 C. to produce propionyl-<strong>[541-15-1]L-carnitine</strong> free base and potassium propionate precipitate, which is formed from the propionic acid produced by the reaction react with KOH. Potassium propionate is filtered out of the solution. The isolated propionyl-<strong>[541-15-1]L-carnitine</strong> free base is reacted with nitric acid at a reaction temperature of about 30 C. for 2 hours to produce propionyl-<strong>[541-15-1]L-carnitine</strong> nitrate. The reaction is dried under vacuum to result in pure propionyl-<strong>[541-15-1]L-carnitine</strong> nitrate crystals. The reaction produced 25.2 g of propionyl-<strong>[541-15-1]L-carnitine</strong> nitrate (90.3% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
177 g | 2. Production of Acetyl-<strong>[541-15-1]L-Carnitine</strong> Nitrate: Version 2 [0057] Acetic acid (200 g) was added to a reaction vessel where it was stirred with <strong>[541-15-1]L-carnitine</strong> (130 g) until <strong>[541-15-1]L-carnitine</strong> was completely dissolved. Acetic anhydride (166 g) was then added to the reaction vessel followed by heating the reaction vessel to 30 C. Acetic anhydride and <strong>[541-15-1]L-carnitine</strong> were allowed to reaction for 3 hours to produce acetyl-<strong>[541-15-1]L-carnitine</strong> free base and acetic acid. Once the reaction was completed, acetic acid was removed from the reaction vessel by distillation under a vacuum (-0.09 Mpa) at a temperature below 30 C. The temperature of the reaction vessel was raised to 40 C., and acetone (260 g) was added to the reaction vessel and stirred for about half an hour. The reaction vessel was cooled to below 5 C. to allow the acetyl-<strong>[541-15-1]L-carnitine</strong> free base to crystallize. The reaction vessel was maintained at temperatures between 0 C. to 5 C. for two hours. The acetyl-<strong>[541-15-1]L-carnitine</strong> free base crystals were isolated by filtration, and then washed with acetone. The acetyl-<strong>[541-15-1]L-carnitine</strong> free base crystals were then dried in a vacuum (-0.09 Mpa) at 80 C. The reaction retrieved 147 g of acetyl-<strong>[541-15-1]L-carnitine</strong> free base, which was a yield of 89.2%. [0058] To make acetyl-<strong>[541-15-1]L-carnitine</strong> nitrate salts, the prepared acetyl <strong>[541-15-1]L-carnitine</strong> free base (147 g) was dissolved in a reaction vessel with acetic acid (220 g) by stirring. After the acetyl-<strong>[541-15-1]L-carnitine</strong> free base was completely dissolved, reaction vessel was heated to 30 C. and nitric acid (105 g) was added to the reaction vessel. The temperature of the reaction vessel was then warmed to 30 C. The nitric acid and the acetyl-<strong>[541-15-1]L-carnitine</strong> free base were allowed to react at 30 C. for 2 hours before the produced acetic acid was removed by distillation in a vacuum (-0.09 Mpa) at a temperature about 30 C. Acetone (294 g) was added and thoroughly stirred with the content of the reaction vessel at 30 C. The temperature of the reaction vessel was then cooled to below 5 C. to crystallize the acetyl-<strong>[541-15-1]L-carnitine</strong> nitrate. The reaction vessel was maintained at between 0 C. to 5 C. for 2 hours before the acetyl-<strong>[541-15-1]L-carnitine</strong> nitrate crystals were isolated by filtration and washed with acetone. The acetyl-<strong>[541-15-1]L-carnitine</strong> nitrate crystals were dried in a vacuum (-0.09 Mpa) at 70 C. The reaction produced 177 g of acetyl-<strong>[541-15-1]L-carnitine</strong> nitrate (92.4% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | A solution of AgBF4 (0.103g, 5.3·10-4mol, 1eq) in 3mL of H2O was added dropwise under stirring to a suspension of [PtCl2(1,2-DACH)] (0.100g, 2.6·10-4mol) in 20mL of H2O. After ten minutes a solution of l-carnitine inner salt (0.085g, 5.3·10-4mol, 2eq) in 3mL of water was also added. The mixture was kept under stirring for 24h and then subject to centrifugation to remove AgCl. The remaining solution is then taken to dryness giving a cream solid (0.200g, MW 805.3gmol-1, 2.5·10-4mol, yield 94%), soluble in H2O and DMSO. Complex 4 found (% calculated for C20H44B2F8N4O6Pt): C 29.90 (29.83), H 5.58 (5.51) and N 7.01 (6.96). 1H NMR (300MHz D2O, 25C) delta=1.0-1.1 (4H), 1.4 (2H), 1.9 (2H), (bm, 8H, DACH), 2.2-2.25 (bm, 2H, DACH+2d, 4H, CH2COO), 3.05 (s, 18H, Me3N+), 3.25 (m, 4H, CH2N), 4.4 (bm, 2H, CHOH). 1H NMR (300MHz DMSO-d6, 25C) delta=1.03, 1.2, 1.5, 1.9, 2, 2.25 (bm, 10H, DACH), 1.95 (bm, 4H, CH2COO), 3.1 (s, 18H, Me3N+), 3.2 (m, 4H, CH2N), 4.2 (bm, 2H, CHOH), 7.7 (bs, 1H, OH) ppm. MS-ESI: observed m/z 718.27, (718.11 calculated for C20H44BF4N4O6Pt (M+)) and 315.6 (M2+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Complex [PtCl(l-carnitine-O)(1,2-DACH)]BF4, 5 Complex 5 was prepared as above described for complex 4, using 1 eq of AgBF4 (0.051 g, 2.6 · 10-4 mol) and 1 eq of l-carnitine inner salt (0.042 g, 2.6 · 10-4 mol). The product was obtained as a crystalline pale yellow solid (0.143 g, MW 592.7 g mol-1, 2.4 · 10-4 mol, yield 92%), soluble in water and DMSO. Complex 5 found (% calculated for C13H29BClF4N3O3Pt): C 26.33 (26.34), H 5.12 (4.93) and N 7.15 (7.09). 1H NMR (300 MHz D2O, 25 C) delta = 0.9-1.2 (4H), 1.44 (2H), 1.9 (2H), (bm, 8H, DACH), 2.3 (bm, 2H, DACH + 2d, 2H CH2COO), 3.1 (s, 9H, Me3N+), 3.3 (m, 2H, CH2N), 4.4 (bm, 1H, CHO) ppm. Unchanged over 30 h. 1H NMR (300 MHz DMSO-d6, 25 C) delta = 1.0, 1.2, 1.4 (bm, 6H, DACH), 2.0 (bm, 4H DACH + 2H, CH2COO), 3.1 (s, 9H, Me3N+), 3.2 (m, 2H, CH2N), 4.2 (bm, 1H, CHO), 5-6 (bm, NH2 DACH), 7.1 (bs, 1H, OH) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.4% | With triethylamine; In dichloromethane; at 0 - 5℃; for 12h; | Equipped with a mechanical stirrer and thermometer, a three-necked flask was filled with 100 g of <strong>[541-15-1]L-carnitine</strong> zwitterion (0.62 mol, 1 eq), dichloromethane 3 liters, and 188.2 g of triethylamine (1.86 mol, 3.0 eq). Stirring down to 0 ~ 5C. 97.34 g of acetyl chloride (1.24 mol, 2.0 eq) was added dropwise. After dropping, the reaction was carried out at 0 to 5C for 12 hours then filtered. The filter cake was washed with dichloromethane to obtain crude acetyl-<strong>[541-15-1]L-carnitine</strong>. This was dissolved in an appropriate amount of ethanol. Stirring dissolved. The solid was then precipitated by the addition of acetone and filtered. The filter cake was washed with acetone. Vacuum drying to obtain refined products 90 grams, yield 71.4%, purity 99.6%. Nuclear magnetic resonance spectrum shown in Figure 1. The mass spectrum is shown in Figure 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 125℃; for 4h; | <strong>[541-15-1]L-carnitine</strong> 3mmol (about 484mg), 3.6mmol of brominated section was added to about 25ml DMF whipped all hook, heated to125 C, the reaction was stirred for 4 hours under reduced pressure to remove the solvent DMF and unreacted benzyl bromide, <strong>[541-15-1]L-carnitine</strong> benzylester. Stearic acid 3mmol, was added about 15ml of dichloromethane was stirred and dissolved, oxalyl chloride was added dropwise 3.6mmol, stirring conditionsThe reaction 0.5h, the solvent was removed by distillation under reduced pressure methylene chloride and unreacted oxalyl chloride, stearic acid chloride. Obtained above<strong>[541-15-1]L-carnitine</strong> benzyl ester and stearic acid chloride was added about 25ml of acetonitrile was stirred evenly, heated to 45 C, the reaction was stirred for 24h, under reduced pressure to remove acetonitrile, methylene chloride: methanol = 19: 1 mobile phase The column was separated to give stearoyl-L-botulinumAlkali benzyl ester. The stearyl-<strong>[541-15-1]L-carnitine</strong> benzyl ester obtained above was dissolved in 25 ml of methanol, stirred well, added with 10% palladium on carbonAgent 0.2g, heated to 30 C, the reaction under H2 protection conditions 5h, the reaction was filtered to remove palladium carbon under reduced pressure distillation conditionsRemove the solvent methanol, namely stearoyl-<strong>[541-15-1]L-carnitine</strong>. | |
In N,N-dimethyl-formamide; at 125℃; for 4h; | <strong>[541-15-1]L-carnitine</strong> 6 mmol (about 968 mg),Benzyl bromide 7.2mmol addedStir in about 30 ml of DMF,Heat to 125C,4 hours under stirring,Vacuum distillation to remove solvent DMFWith unreacted benzyl bromide,This gives <strong>[541-15-1]L-carnitine</strong> benzyl ester (Compound A).<strong>[541-15-1]L-carnitine</strong> benzyl ester to be obtained (A)3 mmol (about 756 mg) and succinic anhydride 3.3 mmol (about 330 mg) are addedIn anhydrous dichloromethane,Heat to 40C,The reaction was stirred overnight.The solvent dichloromethane is removed under distillation under reduced pressure.Residue mixed solvent of ether and dichloromethane (1:2)Wash three times,The yellow sticky residue is compound (B).Compound (B) 1 mmol (about 352 mg)With carbodiimide type activating reagent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)1.1mmol (about 210mg) addedDichloromethane,The reaction is activated in an ice bath for 2 hours.Then add polyethylene glycol stearate 1mmol (about 2.5g)And catalyst 4-dimethylaminopyridine (DMAP)0.3mmol (about 36.6mg),Continue for 48 hours under nitrogen protection at 40C.Dichloromethane is removed under reduced pressureUsing dichloromethane:methanol = 40:1 mobile phase for column separation,Compound (C) is obtained.The obtained compound (C) 1gDissolve in methanol and stir well.Add 10% palladium on carbon reducing agent (about 0.1g),Heat to 25-35C,Reaction under H2 protection conditions for 6 hours,The reaction solution was filtered to remove palladium carbon,The solvent methanol is removed under distillation under reduced pressure.That is, the target compound (D) is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; In tetrahydrofuran; at 0 - 20℃; | With a thermometer, stir,The outer bath of the four bottles first add 30g (0.186mol)(R) -carnitine, followed by addition of 300 ml of tetrahydrofuran,Outer bath ice water cooling is 0-10 ,17.7 g (0.468 mol) of (2.5 eq) of sodium borohydride was added portionwise,Plus finished, back to room temperature reaction,After the reaction,A 16.8 g water quenching reaction was added,The tetrahydrofuran and water were distilled off under reduced pressure,Then add 300 ml of ethyl acetate,Stir, filter,The purity of the product in the filtrate was 87.9%The filtrate is used directly for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.6 g | With hydrogenchloride; lithium hydroxide; In tetrahydrofuran; at 23 - 85℃;pH 2 - 3; | 25.8 g of intermediate III was added to a 250 ml three-necked flask100 ml of tetrahydrofuran,Mechanical agitation,Add lithium hydroxide7g,The reaction was stirred at room temperature (23 C)TLC detection of intermediate disappeared,Keep low temperature slowly dripping0.1Mol of HClSolution to pH value of 2 to 3, after the drop is completed, the temperature to 80 ~ 85 reaction 5 ~ 6h, filter, filter cake organic solvent washing,Using 10 times the volume of water dissolved, through the strong base type anion exchange resin column to remove chloride ions, the column after the use of concentratedThe crystallization reagent is subjected to recrystallization,That white crystal is15.6gL-carnitine.The recrystallization reagent consists of ethanol and water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; | A powder mixture of 3.51g of zoledronic acid and 1.95 g of L-carnitine were slurried overnight in 50 mL of isopropanol. The filtered and dried solids were stored in a screw cap vial for subsequent analysis. The material was characterized by PXRD and is shown in FIG 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; at 55 - 60℃; | bOg of L-carnitine is dried in a vacuum oven at 80 - 90 C for 2-3 days or in a phosphorous pentoxide chamber for 5 -7 days. Once dry the material is weighed and a slurry is created at 1 g/mL in deionized water. One molar equivalent of concentrated HCI is added and the solid is dissolved. The solution is heated on a hotplate open at 55 - 60 C in a shallow container for 5 - 8 hours until very viscous and then placed in an oven at the same temperature for 12-16 hours until a stiff layer exists or nucleation is visible. The material is then further dried with a vacuum oven at 80 - 90 C for 2- 3 days until the solid is opaque white and easily flaking off the container. The particulate material was gathered and stored in a desiccator with phosphorus pentoxide for subsequent analysis. The material was characterized by proton NMR, 500 MHz, Methanol, 6 2.57 (dd, 1H); 3.25 (s, 9H); 3.48 (m, 3H); 4.58 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 16h; | 10292] A suspension of (R)-2-amino-3-(((R)-3-amino-2- ((4Z,7Z,1OZ,13Z,1 6Z, 19Z)-docosa-4,7,10,13,1 6, 19-hexae- namido)-3-oxopropyl)disulfanyl)-3-methylbutanoic acid (9.3 mmol) in methanol (30 mE) was cooled in an ice bath and iN aqueous NaOH (25 mmol) was added. This was followed by the addition of di-tert-butyl dicarbonate (3.12 g, 14 mmol). The resulting reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was then acidified with HC1 (aq) to a pH of about 5. The resulting mixture was extracted with EtOAc (3x100 mE). The combined organic layers were washed with and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient elution, methanol:CH2C12*=1 .5%.-2.2%) to afford (R)-3-----(((R)-3-amino-2- ((4Z,7Z,1OZ,13Z,1 6Z, 19Z)-docosa-4,7,10,13,1 6, 19-hexae- namido)-3-oxopropyl)disulfanyl)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (4.5 g, 53% yield). This material (3.8 g, 5.6 mmol) was taken up in CH2C12 (30 mE) and 2-aminopropane-1,3-diol (0.51 g, 5.6 mmol) was added at room temperature, followed by HATU (2.6 g, 6.7 mmol) and DIEA (7.5 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. The following day, the mixture was diluted with CH2C12, washed with H20 and brine, dried over anhydrous Na2SO4 and concentrated underreduced pressure to afford tert-butyl ((R)-3-(((R)-3-amino- 2-((4Z,7Z,1OZ, 13Z,1 6Z, 19Z)-docosa-4,7,10,13,1 6,19- hexaenamido)-3-oxopropyl)disulfanyl)-1 -((1 ,3-dihydroxy- propan-2-yl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (5.6 mmol, -100% yield). This material was used for the next step without further purification. tert-butyl ((R)-3- (((R)-3-Amino-2-((4Z,7Z, 1OZ, 1 3Z, 1 6Z, 1 9Z)-docosa-4,7, 10,13,16,1 9-hexaenamido)-3-oxopropyl)disulfanyl)- 1 -((1, 3-dihydroxypropan-2-yl)amino)-3-methyl-1 -oxobutan-2-yl) carbamate (5.6 mmol) was treated with 4 N HC1-dioxane (5 mE) at room temperature for 1 h and then concentrated under reduced pressure to afford the 130C-deprotected intermediate. This material (4.2 g, 5.6 mmol) taken up in CH2C12 (20 mE) and E-camitine (0.91 g, 5.6 mmol) was added at room temperature, followed by HATU (2.6 g, 6.7 mmol) and DIEA (8 mmol). The resulting reaction mixture was stirredroom temperature for 16 hours. The following day, the reaction mixture was concentrated under reduced pressure and the resulting crude product was purified by preparative HPEC to afford 4-((3-(((R)-3-amino-2-((4Z,7Z, 1 OZ, 13Z,6Z, 1 9Z)-docosa-4,7, 10,13,16,1 9-hexaenamido)-3-oxopro- pyl)disulfanyl)- 1 -((1 ,3-dihydroxypropan-2-yl)amino)-3- methyl-i -oxobutan-2-yl)amino)-2-hydroxy-N,N,N- trimethyl-4-oxobutan- 1 -aminium (850 mg, 19% yield) as a white solid. MS, calculated for C40H58N507S2: 794.46; found 795 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.6% | With sodium hydroxide; for 10h;Reflux; | In the reactor, compound (II) (225.5 g, 1.0 mol) and a 5% sodium hydroxide solution (1800 g) were added, followed by heating to reflux for 10 hours with stirring, and after completion of the reaction, L-carnitine was obtained. The crude alkali solution is treated with a cation exchange resin to remove impurities, and an aqueous solution of L-carnitine is obtained. The obtained pale white solid is recrystallized from anhydrous ethanol and dried in vacuo to give a white solid. ), 131.4 g, and a yield of about 81.6%. [a]200 = -30.9, after the ^: test its quality indicators are in line with the requirements of the United States Pharmacopoeia 1 ^ (28) version. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap for 12h; | 3 Example 3 azelaic anhydrideL-carnitine reaction,Add N,N-4-dimethylaminopyridine,The reaction solvent is anhydrous tetrahydrofuran, dichloromethane, cyclohexane or dimethylformamide.The reaction temperature is from 0 ° C to the boiling point of the solvent, preferably from 20 to 60 ° C.After 12 hours of reaction time,Adding didanosine and dicyclohexylcarbodiimide,After an ice bath reaction for 1 hour, the reaction solution was allowed to warm to room temperature and the reaction was continued for 24 hours.After the reaction is finished, suction filtration,The N,N-dimethylformamide in the filtrate was distilled off under reduced pressure.The residue was dissolved in ethyl acetate, and then washed with distilled water, saturated sodium hydrogen carbonate and brine.The ethyl acetate layer was collected, dried over sodium sulfate, and the mixture was combined with silica gel and evaporated to dryness.The solid was separated on a silica gel column eluting with ethyl acetate and petroleum ether to afford (V). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.8 g | With water; sodium hydroxide; at 0℃;Green chemistry; | 27.0 g of (R)-(+)-4-bromo-3-hydroxybutyrate butyl ester was added to an aqueous solution of 5.0 g of sodium hydroxide and 28.0 g ofan aqueous solution oftrimethylamine, and the mixture was stirred and cooled to 0 ± 5 C.The reaction mixture was completely distilled under reduced pressureto give a crude oil. An oil was obtained, and 250 mL of deionized water was added, and 280 g of R-120H ion exchange resin was stirred in a 1000 ml reaction flask.After filtration, themother liquid was concentrated to give an oily substance, which was purified using a solvent of 240 mL (ethanol/acetone = 1/2, volume ratio), filtered, and the filter cake wasdried underreduced pressure at 60 C.11.8 g of L-carnitine inner salt was obtained (ee% was 99.80%, content was 99.0%, which was determined by the EP Pharmacopoeia test method). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.2 g | With water; sodium hydroxide; at 0℃;Green chemistry; | 14.0 g of (R)-(+)-4-chloro-3-hydroxybutyric acid isopropyl ester was addedto a reaction flask of6.5 g of sodium hydroxide and 31 g ofan aqueous solution oftrimethylamine, stirred, and cooled to 0 ± 5 C.The reaction mixture was completely distilled under reduced pressureto give a crude material. An oil was obtained, 120 mL of deionized water was added, and 140 g of R-120H ion exchange resin was stirred in a 500 ml reaction flask.After filtration, the motherliquid was concentrated to give an oily substance, which was purified using a solvent of 130 mL (ethanol/acetone = 1/2, volume ratio), filtered, and the filter cake wasdriedat 45 C under reduced pressure.9.2 g of L-carnitine inner salt was obtained (ee% was 99.74%, content was 97.8%, which was based on the EP Pharmacopoeia test method).Theactive enzyme was not detectedby theWOOD method. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.2 g | With water; potassium hydroxide; at 0℃;Green chemistry; | 9.5 g of methyl (R)-(+)-4-chloro-3-hydroxybutanoate was added to 3 g of an aqueous solution of potassium hydroxide and 21 g of an aqueous solution of trimethylamine, and the mixture was stirred and cooled to 0 ± 5 C.The reaction mixture was completely distilled under reduced pressure until no fraction was obtained to obtain an oil, 100 mL of deionized water was added, and 90 g of R-120H ion exchange resin was stirred in a 500 ml reaction flask.After filtration, the motherliquid wasconcentratedto an oily substance, which was purified by using a solvent of 80 mL (ethanol/acetone = 1/2, volume ratio), filtered, and the filter cake was dried under reduced pressure at 45 C.To givethe 8.2g L-carnitine inner salt (ee% 99.52% 98.7% content, EP pharmacopoeia tests to date). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In n-heptane; at 20℃; for 15h; | To a round-bottomed flask equipped with magnetic stirring containing a mixture of CBD (300 mg, 0.954 mmol, 98.8% a/a HPLC) and <strong>[541-15-1]L-carnitine</strong> (307 mg, 1 .908 mmol, 2 eq.), was added heptane (3 mL). The resulting mixture was seeded with cocrystal Form Ill and stirred at room temperature for 15 hours. The suspension was filtered through a sinter funnel (porosity n3) and washed with 2 x 1 .0 mL of heptane. After drying under vacuumat room temperature, cocrystal Form Ill was obtained as a white solid (483 mg, 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In water; acetone; for 5h;Reflux; | To a mixture of L-carnitine (20.6 g, 128 mmol) and Orotic acid (19.9 g, 128 mmol) was added a mixed solvent of 200 ml of acetone and 20 ml of distilled water and refluxed for 5 hours. The reaction solution was slowly cooled to 20 to 25 . The resulting white crystals were filtered and dried at room temperature for 24 hours to obtain white crystals of L-carnitine oroate (39.0 g, 96%). Its XRD spectrum and DSC spectrum are shown in Figures 1 and 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In water; isopropyl alcohol; at 20 - 25℃; for 2h; | <strong>[541-15-1]L-Carnitine</strong> (20.0 g, 124 mmol) and 1,5-naphthalenedisulfonic acid (22.5 g, 62 mmol) were added to a mixed solvent of 220 ml of acetone and 22 ml of distilled water, and the mixture was stirred at 20 to 25 C for 2 hours. 200 ml of acetone was added and the reaction solution was slowly cooled to 0 & lt; 0 & gt; C.The resulting white crystal was filtered and dried at 40 under vacuum for 24 hours to obtain white crystalline <strong>[541-15-1]L-carnitine</strong> 1,5-naphthalenedisulfonate (36 g, 95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Fumaric acid (13.9 g, 120 mmol) was added to a mixed solvent of 200 ml of acetone and 20 ml of distilled water, and the mixture was stirred at 50 to 60 C for 30 minutes. Carnitine (20 g, 124 mmol) was added to the mixed solution, and the mixture was stirred for 30 minutes. The reaction solution was slowly cooled to 20 to 25 C and further stirred for 2 hours. The reaction solution was gradually cooled to 0 deg. C, and the resulting white crystal was filtered and dried under vacuum at 40 deg. C for 24 hours to obtain white crystalline <strong>[541-15-1]L-carnitine</strong> fumarate (28.9, 87%). Its XRD spectrum and DSC spectrum are shown in Fig. 3 and Fig. 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.1 g | With potassium chloride; water; at 95℃; for 2h; | L-camitine (inner salt) 1.5 g (9.3 mmol) is mixed with potassium chloride 0.69g (9.3 mmol) in 6 mL of water (deionized). The solution is stirred at 95C for 2 hours in a round bottom flask. After reaction is complete maltodextrin 2.1 g is added and stirred for 5 minutes. Water is removed via roto evaporation and the semi -dry mixture is placed in a vacuum oven at 50C for 8 hours to yield 2.1 g of a dry semi crystalline solid powder product in 50% concentrate mp C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.18 g | With water; calcium chloride; at 95℃; for 2h; | L-camitine (inner salt) 3.5 g (21.7 mmol) is mixed with calcium chloride 0.8lg (10.8 mmol) in 6 mL of water (deionized). The solution is stirred at 95C for 2 hours in a round bottom flask. After reaction is complete maltodextrin 4.3 g is added and stirred for 5 minutes. Water is removed via roto evaporation and the semi -dry mixture is placed in a vacuum oven at 50C for 8 hours to yield 3.18 g of a dry semi crystalline solid powder product in 50% concentrate mp C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.8 g | With water; at 95℃; for 2h; | L-camitine (inner salt) 4.0 g (24.8 mmol) is mixed with fumaric acid l.44g ( 12.4 mmol) in 10 mL of water (deionized). The solution is stirred at 95C for 2 hours in a round bottom flask. After reaction is complete maltodextrin 5.5 g is added and stirred for 5 minutes. Water is removed via roto evaporation and the semi -dry mixture is placed in a vacuum oven at 50C for 8 hours to yield 8.8 g of a dry semi crystalline solid powder product in 50% concentrate mp C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.2 g | With water; at 95℃; for 2h; | L-camitine (inner salt) 4.0 g (24.8 mmol) is mixed with succinic acid l.46g (12.4 mmol) in 10 mL of water (deionized). The solution is stirred at 95C for 2 hours in a round bottom flask. After reaction is complete maltodextrin 5.5 g is added and stirred for 5 minutes. Water is removed via roto evaporation and the semi -dry mixture is placed in a vacuum oven at 50C for 8 hours to yield 8.2 g of a dry semi crystalline solid powder product in 50% concentrate mp C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.3% | With triethylamine; In methanol; at 45℃; for 10h; | 120 g of fluorene-fluorene-4-chloro-3-hydroxybutyronitrile and 200 g of hydrochloric acid prepared in the above Example 3 were added to 500 mlIn a three-necked bottle,After stirring, a mixed solution is obtained,Slowly warm up to 75C,6 hours of reaction,After the reaction is completed, the water is distilled off under negative pressure.Then filtered out the by-product ammonium chloride,133g of light yellow transparent liquid was obtained,(R) --4-chloro-3-hydroxybutyric acid,Yield was 95.64%.To the obtained (R) -fluorene-4-chloro-3-hydroxybutyric acid was added 200 g of methanol and 101 g of trimethylamine was slowly passed in.gas,Heated up to 45C,Reaction for 10 hours,Stop reaction.After the reaction is completed, adjust the pH of the reaction solution to pH 2 ~ 3 with hydrochloric acid.The solvent methanol was distilled off under reduced pressure,The obtained crude product was recrystallized from methanol,After being purified and dechlorinated by strong acid cation exchange resin (Amberlite IRA-402 (OH)),And recrystallized from absolute ethanol,After vacuum drying, a white solid product was obtained.Structural analysis of the prepared product,In this example, 132 g of L-carnitine solid product was prepared with a yield of 85.30%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.3 g | With sodium hydroxide; In water; at 0℃; for 1h; | Go to step 1 at 0C An aqueous solution of sodium hydroxide and TMA (19.1 g of NaOH and 22.5 g of TMA dissolved in 300 ml of water) was added to the residue,After incubation for 1 hour,The temperature was then raised to room temperature for 1 hour, and the reaction was followed by HPLC. The content of L-carnitine was 88.5% (normalized method).The reaction solution was concentrated to recover TMA, and the concentrated residue was added to deionized water (200 mL), and dissolved into a clear and transparent solution. The solution was added to an electrodialysis tank, and the salt was removed by dialysis according to the method of electrodialysis. ,Take 50g of the concentrated material and dissolve it in 200ml of absolute ethanol, heat up to 65 C, heat and reflux until all are dissolved, then cool to 40 C, add 0.5g of L-carnitine seeds, stir, and slowly cool the temperature to 20 C (decrease rate) 0.5 / min),Keep the temperature at 20 C, slowly add 450ml of acetone (2ml / min) at 20 C. After the addition, cool down to 10 C, stir and crystallize for 1 hour, filter, and wash the filter cake with 20mL of acetone.The filter cake was dried under vacuum to obtain 43.5 g (87%) of L-carnitine.After analysis of the product, the L-carnitine content was 99.6%, the product ee% was 99.3%, and the solvent residue met the requirements. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In water; at 10℃; for 0.166667h; | A 100 mL 3 N RBF fitted with a water condenser and internal thermometer was charged with NaMN (0.300 g, 0.894mmol, 1 eq) and 30 ml of distilled deionized water and mixed to form a solution, a faint suspension is also acceptable. This solution was cooled using an ice/water bath to bring the internal temperature below 10 C. To this solution was then added dropwise 8.77 ml of 0.1M L- Carnitine solution (0.98 eq) in distilled deionized water slowly so as to prevent the temperature from increasing, all the suspension goes into solution. The resulting solution was stirred for 10 minutes. After this addition the pH was ~ 3.2.The flask was then removed and the colorless solution decanted into a 100 ml 1 N RBF and frozen using liquid nitrogen. While the flask was frozen it was connected to the freeze dryer. Once dried the product is rendered as a colorless to faint yellow solid. Yield :0.32l.2 g (72% ) Melting point: 92 C (degradation, corrected) 146 C Outgassing Analytical data. 1H-NMR (400 MHz, D2O) d = 9.36 (s, 1H), 9.26 (d, 1H), 8.98 (d, 1H), 8.26 (dd, 1H), 6.24 (d, 1H), 4.65 (m, 1H), 4.56 (t, 1H), 4.47 (dd, 1H), 4.33 (dq, 1H), 4.19 (dq, 1H), 3.50 (m, 2H), 3.25 (s, 9H), 2.60-2.70 (m, 2H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | In water; at 10℃; for 0.166667h; | A 100 mL 3 N RBF fitted with a water condenser and internal thermometer was charged with NaMN (0.250 g, 0.298 mmol, 1 eq) and 25ml of distilled deionized water and mixed to form a solution, a faint suspension is also fine. This solution was cooled using an ice/water bath to bring the internal temperature below 10 C. To this solution was then added dropwise 14.76 ml of 0.1M <strong>[541-15-1]L-Carnitine</strong> solution (1.98 eq) in distilled deionized water slowly so as to prevent the temperature from increasing, all the suspension goes into solution. The resulting solution was stirred for 10 minutes. After this addition the pH was ~ 3.3-3.9. The flask was then removed and the colorless solution decanted into a 100 ml 1 N RBF and frozen using liquid nitrogen. While the flask was frozen it was connected to the freeze dryer. Once dried the product is rendered as a colorless to faint yellow solid. Yield: 238.9 mg (49 % after transfer)Analytical data. -NMR (400 MHz, D2O) d = 9.35 (s, 1H), 9.25 (d, 1H), 8.95 (d, 1H), 8.25 (dd, 1H), 6.23 (d, 1H), 4.65 (m, 3H), 4.55 (t, 1H), 4.48 (d7, 1H), 4.33 (dq, 1H), 4.18 (dq, 1H), 3.48 (m, 4H), 3.24 (s, 18H), 2.56 (d, 4H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In water; at 10℃; for 0.166667h; | A 50 mL 3 N RBF fitted with a water condenser and internal thermometer was charged with NMN (0.250 g, 0.748mmol, 1 eq) and 25ml of distilled deionized water and mixed to form a solution. This solution was cooled using an ice/water bath to bring the internal temperature below 10 C. To this solution was then added dropwise 7.33 ml of 0.1M L- Camitine solution (0.98 eq) in distilled deionized water slowly so as to prevent the temperature from increasing, all the suspension goes into solution. The resulting solution was stirred for 10 minutes. After this addition the pH was ~ 4.4. The flask was then removed and the colorless solution decanted into a 100 ml 1 N RBF and frozen using liquid nitrogen. While the flask was frozen it was connected to the freeze dryer. Once dried the product is rendered as a colorless to faint yellow solid. Yield: 249.4 mg (67 %) Melting point: 68-99 C (degradation, corrected) outgassing at 136 C Analytical data. 1H-NMR (400 MHz, D20) d = 9.50 (s, 1H), 9.31 (d, 1H), 9.02 (d, 1H), 8.33 (dd, 1H), 6.25 (d, 1H), 4.68 (p, 1H), 4.60 (m, 2H), 4.48 (dd, 1H), 4.33 (dq, 1H), 4.18 (dq, 1H), 3.45 (m, 2 H), 3.25 (s, 9H), 2.48 (m, 2H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In water; for 0.166667h;pH Ca. 3.3 - 3.9;Cooling with ice; | [00142] A 50 mL 1 N RBF fitted with a water condenser was charged with Nicotinic acid(0.200 g, 1.62 mmol, 1 eq) and 10 ml of distilled deionized water and mixed to form a solution. This solution was cooled using an ice/water bath. To this solution was then added L- carnitine in one portion (0.262 g, 1.62 mmol, 1.0 eq). The solution was allowed to stir for 10 minutes. After this addition the pH was ~ 3.3 -3.9. The flask was then removed and the colorless solution frozen using liquid nitrogen. While the flask was frozen it was connected to the freeze dryer. Once dried the product is rendered as a colorless hygroscopic solid. Yield: 478.6 mg (quantitative) Melting point: 75.6-78.4 C (melted on loading into capillary) Analytical data. -NMR (400 MHz, D20) d = 9.10 (s, 1H), 8.79 (m, 2H), 7.98 (t, 1H), 4.61 (p, 1H), 3.44 (m, 2H), 3.24 (s, 9H), 2.51 (d, 2H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In acetonitrile at 80℃; for 16h; | 2.1. Synthesis of compounds General procedure: General procedure for the synthesis of Betaine and L-Carnitine alkyl ester bromides - (2-alkyloxy-2-oxoethyl)-trimethylammonium bromide (B1-B6) and (4-alkyloxy-2-hydroxy-4-oxobutyl)-trimethylammonium bromide (C1-C6) were synthesized via the O alkylation reaction of betaine or L-carnitine with the appropriate1-bromoalkane (CnH2n+1Br with n = 8, 10, 12, 14, 16, 18) according to the protocol described by Häckl et al. [41] and Niemczk et al. [37] with slight modification. Briefly, betaine or L-carnitine (20 mmol), the 1-bromoalkane (25 mmol) and 15 mL of acetonitrile were added in a flask of 100 mL and stirred at 80 C for 16 h (B1-B2and C1-C2), 24 h (B3-B4 and C3-C4), or 72 h (B5-B6 and C5-C6).Diethyl ether was added to the final mixture to precipitate the desired product and eliminate unreacted 1-bromoalkane. Solid precipitates were filtered under vacuum, washed with diethylether and dried in vacuo, to afford white solids products. All synthetized compounds have been characterized by 1H and 13C NMR and FTIR analysis and all the spectra are given in the Supporting Information (Figs. S1-S12 for 1H and 13C NMR and Figs. S13-S24for FTIR). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In acetonitrile at 80℃; for 72h; | 2.1. Synthesis of compounds General procedure: General procedure for the synthesis of Betaine and L-Carnitine alkyl ester bromides - (2-alkyloxy-2-oxoethyl)-trimethylammonium bromide (B1-B6) and (4-alkyloxy-2-hydroxy-4-oxobutyl)-trimethylammonium bromide (C1-C6) were synthesized via the O alkylation reaction of betaine or L-carnitine with the appropriate1-bromoalkane (CnH2n+1Br with n = 8, 10, 12, 14, 16, 18) according to the protocol described by Häckl et al. [41] and Niemczk et al. [37] with slight modification. Briefly, betaine or L-carnitine (20 mmol), the 1-bromoalkane (25 mmol) and 15 mL of acetonitrile were added in a flask of 100 mL and stirred at 80 C for 16 h (B1-B2and C1-C2), 24 h (B3-B4 and C3-C4), or 72 h (B5-B6 and C5-C6).Diethyl ether was added to the final mixture to precipitate the desired product and eliminate unreacted 1-bromoalkane. Solid precipitates were filtered under vacuum, washed with diethylether and dried in vacuo, to afford white solids products. All synthetized compounds have been characterized by 1H and 13C NMR and FTIR analysis and all the spectra are given in the Supporting Information (Figs. S1-S12 for 1H and 13C NMR and Figs. S13-S24for FTIR). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In ethanol; water at 35℃; for 0.25h; | L-Carnitine and 2-hydroxy-6-pentadecylbenzoic acid are dissolved in a water/ethanol mixture in a 25 ml_ three-necked round-bottomed flask, with magnetic stirring. The reaction medium is heated at about 35°C on a water bath for 15 minutes. The solvents are evaporated off on a rotavapor and the product is then dried in a desiccator. The desired compound is obtained in a yield of 88% and a mass of 3.9 g. The NMR analyses confirm the expected structure. The melting point of the compound obtained is 63°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: 0.5 h / 24 °C 1.2: 4 h / 24 °C 2.1: hydrogenchloride / water / Sealed tube; Darkness |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.8% | With triethylamine In water monomer at 0 - 25℃; for 0.0666667h; Flow reactor; | 1.2-11.2 (2) Preparation of L-carnitine (Compound A) in a continuous flow tubular reactor, as shown in Figure 2 Preparation of material C: trimethylamine (20mol, 5910g) dissolved in purified water, preparation of 20% aqueous solution of trimethylamine, placed in raw material tank C; Preparation material D: Compound C (10mol, 1300g) placed in raw material tank D, standby; By changing the flow rate to control the molar ratio of Compound C and Compound B, the molar ratio of compound C and Compound B is 1:2, and the materialSC and D are transported together to a continuous flow tube reactor, reacted for 60s at 0 °C, and then heated up to 25 °C, and the continuous reaction is 180s, and the ring-opening reaction occurs; the heat exchange medium is ethylene glycol or a mixture of water and ethylene glycol; After the end of the reaction, the excess unreacted trimethylamine was removed by reduced pressure distillation, and then the pH of concentrated hydrochloric acid was adjusted to 5 to 6 dropwise, and then the crystals were purified to give a white crystal of 15.9g and a yield of 98.8%. the total yield of the two-step reaction was 95.7%, and the purity of l-carnitine was 99.6%. |
90.3% | at 0 - 25℃; for 14h; | 1.2; 2.2; 3.2; 4.2; 5.2; 6.2; 7.2; 8.2; 9.2; 10.2; 11.2; 12.2; 13.2; 14.2; 15.2; 16.2; 17.2; 18.2; 19.2; 20.2; 21.2; 22.2 (2) Preparation of L-carnitine (Compound A) Under the condition of 0 , the aqueous solution of 20% trimethylamine (0.2 mol, 59.1 g) was slowly added dropwise to compound C (0.1 mol, 13.0 g), the temperature was controlled to 0 , the reaction was stirred for 1 hour, and then the temperature was raised to 25 The stirring was continued at °C, and the reaction was carried out for 14 hours. After the reaction, excess unreacted trimethylamine was distilled off under reduced pressure, and concentrated hydrochloric acid was added dropwise to adjust the pH to 5 to 6, followed by crystallization and purification to obtain 15.5 g of white crystal L-carnitine (the theoretical value was 16.1 g, and the yield was 96.3 g). %). The overall yield of the two-step reaction was 90.3%, and the purity of L-carnitine was 99.3%. |
Tags: 541-15-1 synthesis path| 541-15-1 SDS| 541-15-1 COA| 541-15-1 purity| 541-15-1 application| 541-15-1 NMR| 541-15-1 COA| 541-15-1 structure
A1466618[ 126827-79-0 ]
(R)-3-Hydroxy-4-(tris(methyl-d3)ammonio)butanoate
Reason: Stable Isotope
[ 542-06-3 ]
4-(Dimethylamino)-3-hydroxybutanoic acid
Similarity: 1.00
[ 7013-07-2 ]
(R)-4-Amino-3-hydroxybutanoic acid
Similarity: 0.81
[ 7013-05-0 ]
(S)-4-Amino-3-hydroxybutanoic acid
Similarity: 0.81
[ 924-49-2 ]
4-Amino-3-hydroxybutanoic acid
Similarity: 0.81
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.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :