461-06-3

Usage

Originator

Flatistine,Sauba,France,1978

Uses

antihyperlipoproteinemic, gastric/ pancreatic secretion stimulant

Manufacturing Process

9.3 g of epichlorohydrin was added at a temperature of 40°-50°C under stirring to 9.6 g of trimethylamine hydrochloride dissolved in 10 cc of water. Continuing the reaction for an hour at the above temperature, the reaction product was concentrated under reduced pressure to obtain the crystals of 3- chloro-2-oxypropyl trimethyl ammonium chloride which were recrystallized with 25 cc of ethanol. The crystals obtained by concentrating the mother liquor were also recrystallized. The yield was 17.4 g (MP 190°C, yield 91.5%). This substance occurs as white, somewhat hygroscopic crystals and is readily soluble in water or alcohol, but insoluble in benzene, toluene, ether, acetone or chloroform.The result of analysis assuming (C6H15C10N)+Cl--calculated value: N, 7.45%; total Cl, 37.7%; Cl-, 18.88%. Observed value: N, 7.36%; total Cl, 37.54%; Cl-, 18.98%.18.8 g of 3-chloro-2-oxypropyl trimethyl ammonium chloride was dissolved in a mixed solvent composed of 19 cc of methanol and 1 cc of water. 5.1 g of sodium cyanide dissolved in 8 cc of water was dropped into the solution at 50°C under stirring. After dropping, the mixture was held at this temperature for 30 minutes under stirring. The reaction product was then neutralized with 6 N hydrochloric acid toward pH 5, and, after cooling, sodium chloride separated out and was filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was washed with small quantity of ethanol. Drying the residue, dissolving in hot methanol, filtering off insoluble matters, and cooling mother liquor, the crystals of 3-cyano-2-axypropyl trimethyl ammonium chloride which deposited out were filtered and dried. Yield 16.7 g [MP (decomposition) 220°-223°C, yield 93.4%].12.5 cc of concentrated hydrochloric acid was added to 17.9 g of 3-cyano-2- oxypropyl trimethyl ammonium chloride. Gradually heating the mixture on a water bath under stirring, so bringing the temperature up to 98°C at the end of about 3 hours, 9 cc of water was added. After cooling, free hydrochloric acid was neutralized with 3 cc of 6 N sodium hydroxide, and then by adding 1 g of active charcoal, the reaction product was decolorized and filtered. The filtrate was concentrated to almost dryness under reduced pressure. Then, this concentrate was, after washing with 10 cc of ethanol, dried. Yield 24.7 g.The dried product was dissolved in 46.5 cc of glacial acetic acid by heating on a boiling water bath. The insoluble matter is removed by filtering hot, and on cooling the mother liquor, crystals of carnitine hydrochloride separated out. The crystals were filtered, washed with 10 cc of ethanol, and dried. Recrystallizing 19.7 g of the crude carnitine with methanol, 17 g of the refined carnitine was obtained [MP 195°-198°C (decomposing point), yield 86%], The overall yield of the refined carnitine through whole steps was about 74%. Carnitine thus prepared was an odorless, white, crystalline powder, having a strong acid taste.

Therapeutic Function

Gastric stimulator, Pancreatic stimulator

Purification Methods

The S(L) isomer is levocarnitine, Vitamin B7. The R or S isomers crystallise from EtOH/Me2CO (hygroscopic). The R or S hydrochlorides crystallise from hot EtOH or EtOH/Et2O and have m 142o(dec). The RS-isomer crystallises from hot EtOH (hygroscopic). The RS hydrochloride crystallises in needles from hot EtOH and has m 196o(dec). [(±) Mazzetti & Lemmon J Org Chem 22 228 1957, Beilstein 4 H 513, 4 I 548, 4 II 937-8, 4 III 1632-5, 4 IV 3185.]

InChI:InChI=1/C7H15NO3/c1-8(2,3)5-6(9)4-7(10)11/h6,9H,4-5H2,1-3H3

Upstream product

• 924-49-2 DL-4-amino-3-hydroxybutyric acid 
• 77-78-1 dimethyl sulfate 
• 74-88-4 methyl iodide 
• 18933-33-0 (R,S)-carnitinenitrile chloride 
• 75-50-3 trimethylamine 
• 101396-91-2 (S)-N-(3-chloro-2-hydroxypropyl)-N,N,N-trimethylammonium chloride 
• 638-07-3 ethyl (2-chloroaceto)acetate 
• 7440-06-4 platinum 
• 10488-68-3 methyl 4-chloro-3-hydroxybutanoate 
• 5261-99-4 (+/-)-carnitinamide chloride 
• 461-06-3 CARNITINE 
• 1116-95-6 (D)-(+)-carnitinenitrile chloride 
• 133039-09-5 Toluene-4-sulfonate((S)-3-carboxy-2-hydroxy-propyl)-trimethyl-ammonium; 
• 32224-01-4 (S)-4-bromo-3-hydroxy-butyric acid ethyl ester 

Downstream Products

• 14919-37-0 lauroylcarnitine chloride 
• 541-15-1 L-carnitine 
• 406-76-8 (S)-carnitin 
• 6865-14-1 hexadecanoylcarnitite hydrochloride 
• 107-43-7 betaine 
• 75-50-3 trimethylamine 
• 1239662-80-6 DL-carnitine benzyl ester bromide 
• 14548-19-7 (+)-Carnitin-aethylester 
• 6919-91-1 (+)-O-Lauroyl-carnitin 
• 6920-31-6 (+)-O-Isobutyryl-carnitin 
• 28330-02-1 palmitoyl carnitine chloride 
• 5469-16-9 (3S)-hydroxy-γ-butyrolactone 
• 5469-16-9 4-Hydroxy-dihydro-furan-2-on 

Relevant academic research and scientific papers

PROCESS FOR THE PRODUCTION OF CARNITINE BY CYCLOADDITION

The invention relates to a method for the production of L-carnitine, wherein a chiral β-lactone carnitine precursor is obtained by a [2+2] cycloaddition of ketene with an aldehyde X—CH2—CHO, wherein X is selected from Cl, Br, I and trimethylamine, in the presence of a chiral catalyst.

PROCESS FOR PRODUCTION OF BETAINE

According to the present invention, by using 4-halogeno-3-hydroxybutanamide as a substrate in quaternary amination reaction with trialkylamine which is an important step in betaine (such as carnitine) preparation processes, it becomes possible to reduce the production of crotonic acid derivatives (the major by-product) greatly compared to conventional processes. Consequently, it becomes possible to prepare a betaine, such as carnitine, at a high yield. The present invention also relates to a process for preparing a betaine represented by formula (1) below, comprising a step of quaternary aminating an amide represented by formula (2) below: wherein A1, A2 and A3 individually represent a C1-C20 hydrocarbon group which may have a substituent(s); and X1 is a halogen atom.

CARNITINE CONJUGATES AS DUAL PRODRUGS, METHODS OF PRODUCTION AND USES THEREOF

The present invention discloses novel dual prodrug compounds of formula (1), methods for their preparation and intermediates in their syntheses, formula (1): wherein A is a single bond, -0-, or -CH2-; m and n vary independently and are an integer from 1 to 15; p and q vary from 0 to an integer from 1 to 4; B is a single bond or -CR3R4; D is formula (2): or formula (3): and X is halogen; R1 to R4 are various substituents selected to optimize the physiochemical and biological properties such as, lipophilicity, bioavailability, and pharmacokinetics of compounds of Formula 1; and R1 and R2 or R3 and R4 may optionally be tethered together to form a 3- to 7-membered alicyclic ring. These compounds are useful for the treatment of various infections, metabolic, cardiovascular and neurological disorders.

An efficient, highly enantioenriched route to L-carnitine and α-lipoic acid via hydrolytic kinetic resolution

A general and practical approach for the synthesis of C-4 chiral building blocks using Jacobsen's hydrolytic kinetic resolution technique to resolve terminal epoxides and diols in high enantiomeric excess and excellent yields is described. The utilization of these building blocks for the synthesis of biologically important natural products L-carnitine and α-lipoic acid is illustrated. Georg Thieme Verlag Stuttgart.

Stabilization of polynucleotide complexes

Polynucleotide complexes are stabilized by adding a cryoprotectant compound and lyophilizing the resulting formulation. The lyophilized formulations are milled or sieved into a dry powder formulation which may be used to deliver the polynucleotide complex. Delivery of the polynucleotide to a desired cell tissue is accomplished by contacting the tissue with the powder to rehydrate it. In a preferred embodiment, a dry powder formulation is used to induce genetic modification of a patient's lung tissue.

Dialysis solutions containing water soluble vitamins and nutrients

The invention relates to methods and compositions for the prevention and treatment of vitamin and other nutrient deficiencies in hemodialysis and peritoneal dialysis patients. Patients are dialyzed with a dialysate solution comprising at least one vitamin.

Asymmetric synthesis of (S)-(+)-carnitine and analogs

A general asymmetric route to enantiomerically pure (S)-(+)-carnitine and analogs has been investigated that involves mono-addition of organometallic reagents to the lactone carbonyl group of (5R,6S)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin- 2-one and Lewis acid promoted stereoselective allylation of the resulting hemiacetals. The diastereomerically pure allyl oxazines thus obtained were readily converted into enantiomerically pure (S)-(+)-carnitine and two substituted analogs.

Retention and selectivity of teicoplanin stationary phases after copper complexation and isotopic exchange

Teicoplanin is a macrocyclic glycopeptide that is highly effective as a chiral selector for LC enantiomeric separations. Two possible interaction paths were investigated and related to solute retention and selectivity: (1) interactions with the only teicoplanin amine group and (2) role of hydrogen bonding interactions. Mobile phases containing 0.5 and 5 mM copper ions were used to try to block the amine group. In the presence of copper ions, it was found that the teicoplanin stationary phase has a decreased ability to separate most underivatized racemic amino acids. However, it maintained its ability to separate enantiomers that were not α - amino acids. It is established that there is little copper - teicoplanin complex formation. The effect of Cu2+ on the enantioseparation of some α - amino acids appears to be due to the fact that these solutes are good bidentate ligands and form complexes with copper ions in the mobile phase. Isotopic exchange with deuterium oxide was performed using acetonitrile - heavy water mobile phases. It was found that the retention times of all amino acids were lower with deuterated mobile phases. The retention times of polar or apolar molecules without amine groups were higher with deuterated mobiles phases. In all cases, the enantio-selectivity factors were unaffected by the deuterium exchange. It is proposed that the electrostatic interactions are decreased in the deuterated mobile phases and the solute-accessible stationary-phase volume is somewhat swollen by deuterium oxide. The balance of these effects is a decrease in the amino acid retention times and an increase in the apolar solute retention time. The enantio-selectivity factors of all of the molecules remain unchanged because all of the interactions are changed equally. We propose a new global quality criterion (the E factor) for comparing and evaluating enantiomeric separations.

Hydrolytically cleavable active ingredient derivative compounds, hair treatment compositions containing them and hair treatment methods

The new active ingredient derivative compounds have the formula (I) STR1 wherein R1, R2 and R3 are the same or different and are each an unsubstituted or substituted alkyl group, Y is an unsubstituted or substituted alkylene group, R is an active ingredient group which, prior to ester formation, has at least one OH group and A- is an anion. A process for making the compounds of formula (I) is described. Hair treatment compositions containing these compounds and methods of treating hair with these hair treatment compositions are also described.

Dry powder formulations of polynucleotide complexes

Polynucleotide complexes are stabilized by adding a cryoprotectant compound and lyophilizing the resulting formulation. The lyophilized formulations are milled or sieved into a dry powder formulation which may be used to deliver the polynucleotide complex. Delivery of the polynucleotide to a desired cell tissue is accomplished by contacting the tissue with the powder to rehydrate it. In a preferred embodiment, a dry powder formulation is used to transfer genetic information to the cells of the respiratory tract.