CH648546A5 - PROCEDURE FOR THE PREPARATION OF CARNITINE ACID CHLORIDE. - Google Patents

PROCEDURE FOR THE PREPARATION OF CARNITINE ACID CHLORIDE. Download PDF

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Publication number
CH648546A5
CH648546A5 CH3884/82A CH388482A CH648546A5 CH 648546 A5 CH648546 A5 CH 648546A5 CH 3884/82 A CH3884/82 A CH 3884/82A CH 388482 A CH388482 A CH 388482A CH 648546 A5 CH648546 A5 CH 648546A5
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Prior art keywords
carnitine
acid chloride
chloride
preparation
hours
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CH3884/82A
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Italian (it)
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Maria Ornella Tinti
Carlo Bagolini
Emma Teresa Quaresima
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Sigma Tau Ind Farmaceuti
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Publication of CH648546A5 publication Critical patent/CH648546A5/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/115—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

La presente invenzione riguarda un procedimento per la preparazione del cloruro acido di D,L-carnitina, The present invention relates to a process for the preparation of the acid chloride of D, L-carnitine,

(CH3)3N-CH2-CH-CH2-COCl (CH3) 3N-CH2-CH-CH2-COCl

I THE

OH OH

Il cloruro acido di D,L-carnitina è un versatile intermedio per la preparazione di diversi derivati della carnitina, ad esempio di esteri ed ammidi, di cui sono note le applicazioni terapeutiche. The acid chloride of D, L-carnitine is a versatile intermediate for the preparation of various carnitine derivatives, for example esters and amides, whose therapeutic applications are known.

La carnitina, Carnitine,

(CH3)3N-CH2-CH-CH2-COOH (CH3) 3N-CH2-CH-CH2-COOH

i the

OH OH

contiene oltre alla funzione carbossilica anche la funzione ossidrilica che è notoriamente sensibile agli ambienti di reazione acidi. in addition to the carboxylic function it also contains the hydroxyl function which is known to be sensitive to acidic reaction environments.

Infatti è noto, ad esempio da Bull. Soc. Chim. Fr. (1960) 1196, che i ß-idrossi acidi ed i loro esteri eliminano molto facilmente in ambiente acido una molecola d'acqua formando dei composti insaturi. In Biochim. Biophys. Acta 137, 98-106 (1967) e 152, 559 (1968) si descrive la disidratazione della carnitina a caldo in ambiente acido. In J. Biol. Chem. 237/12, 3628 (1962) si descrive la formazione di crotonoilbetaina quale prodotto secondario per trattamento della carnitina a caldo in ambiente acido. In fact it is known, for example from Bull. Soc. Chim. Fr. (1960) 1196, that ß-hydroxy acids and their esters very easily eliminate a water molecule in an acid medium by forming unsaturated compounds. In Biochim. Biophys. Acta 137, 98-106 (1967) and 152, 559 (1968) describe the dehydration of hot carnitine in an acid medium. In J. Biol. Chem. 237/12, 3628 (1962) describes the formation of crotonoylbetaine as a secondary product for hot carnitine treatment in an acid medium.

Poiché la conversione di un acido carbossilico in cloruro acido avviene in condizioni acide, sarebbe logico attendersi che la clorurazione della carnitina non possa avvenire senza previa protezione del grappo ossidrilico, allo scopo di evitare la degradazione del prodotto di partenza e la formazione di sottoprodotti non desiderati. Ciò è pienamente confermato da quanto desumibile dalla tecnica nota. In J. Org. Chem. 43/20, 3972 (1978) si descrive la preparazione di cloruri acidi di acidi idrossisostituiti dopo previa protezione del gruppo ossidrilico. Più particolarmente, in J. Am. Chem. Soc. 95, 4016 (1973) si descrive la clorurazione del-Facido ß-idrossibutirrico (un ß-idrossiacido qual'è appunto la carnitina) dopo aver protetto il gruppo ossidrilico con un acetile. Since the conversion of a carboxylic acid into acid chloride takes place in acidic conditions, it would be logical to expect that carnitine chlorination cannot take place without prior protection of the hydroxyl group, in order to avoid degradation of the starting product and the formation of unwanted by-products . This is fully confirmed by what can be deduced from the prior art. In J. Org. Chem. 43/20, 3972 (1978) describes the preparation of acid chlorides of hydroxy-substituted acids after prior protection of the hydroxy group. More particularly, in J. Am. Chem. Soc. 95, 4016 (1973) describes the chlorination of the ß-hydroxybutyric acid (a ß-hydroxyacid such as carnitine) after protecting the hydroxy group with an acetyl.

È stato ora sorprendentemente provato che è possibile convertire D,L-carnitina in cloruro acido di D,L-carnitina con rese eccellenti, senza che si formino quantità industrialmente inaccettabili di sottoprodotti, in particolare di crotonoilbetaina, clorurando la D,L-carnitina senza previamente proteggere il gruppo ossidrilico (trasformandolo ad esempio in acetile come insegnato nella tecnica nota), purché vengano osservate certe condizioni operative critiche. It has now been surprisingly proven that it is possible to convert D, L-carnitine to acid chloride of D, L-carnitine with excellent yields, without industrially unacceptable quantities of by-products being produced, in particular crotonoylbetaine, by chlorinating D, L-carnitine without previously protect the hydroxy group (transforming it for example into acetyl as taught in the prior art), provided that certain critical operating conditions are observed.

Si è infatti trovato che il rapporto molare carnitina/agente clorurante, la temperatura di reazione ed il tempo di reazione sono i parametri critici influenti la conversione di D,L carnitina nel corrispondente cloruro acido e che i valori assunti da tali parametri devono rientrare in intervalli ben definiti. It has in fact been found that the carnitine / chlorinating agent molar ratio, the reaction temperature and the reaction time are the critical parameters influencing the conversion of D, L carnitine into the corresponding acid chloride and that the values assumed by these parameters must fall within ranges well defined.

In accordo all'invenzione, il procedimento per convertire carnitina nel cloruro acido di carnitina comprende lo stadio di: clorurare carnitina con un agente clorurante, preferibilmente scelto fra cloruro di tionile, diclorometiletere e 5 ossalilcloruro, a temperatura ambiente per tempi di reazione compresi fra circa 1,5 e 12 ore. According to the invention, the process for converting carnitine into carnitine acid chloride comprises the step of: chlorinating carnitine with a chlorinating agent, preferably selected from thionyl chloride, dichloromethyl ether and 5 oxalyl chloride, at room temperature for reaction times ranging from about 1.5 and 12 hours.

Quale agente clorurante si potrebbe usare anche il penta-cloruro di fosforo, che tuttavia non si fa preferire a causa dei tempi di reazione (1-3 giorni) nettamente superiori a io quelli sopraindicati. Phosphorus penta-chloride could also be used as a chlorinating agent, which, however, is not preferred due to the reaction times (1-3 days) clearly higher than those indicated above.

Preferibilmente, il rapporto molare carnitina/agente clorurante è compreso fra 1:1 e 1:3. Allo scopo di ottenere con alte rese la conversione della carnitina nel cloruro acido è essenziale che vengano rispettati la temperatura ed i ternis pi di reazione sopraindicati, scostamenti anche lievi provocando la formazione di sottoprodotti. Ad esempio, usando ossalilcloruro quale agente clorurante, con un tempo di reazione di 15 ore si ottiene la quasi totale degradazione della carnitina in cotonoilbetaina. Preferably, the carnitine / chlorinating agent molar ratio is between 1: 1 and 1: 3. In order to obtain the conversion of carnitine into acid chloride with high yields, it is essential that the above mentioned temperature and reaction ternis be respected, even slight deviations causing the formation of by-products. For example, using oxalyl chloride as a chlorinating agent, with a reaction time of 15 hours, the almost total degradation of carnitine into cotonoylbetaine is obtained.

20 Gli esempi non limitativi 1 e 2 che seguono illustrano il procedimento della presente invenzione. 20 The non-limiting examples 1 and 2 that follow illustrate the process of the present invention.

Esempio 1 (agente clorurante: cloniro di tionile) 2,25 cc (0,03 moli) di SOCl2 vennero aggiunti a 1,98 g 25 (0,01 moli) di D,L-carnitina cloruro. Dopo 1 ora la solubi-lizzazione era completa e dopo 1,5 ore la reazione poteva considerarsi finita. Si distillò il SOCl2 in eccesso e si lavò il residuo costituito dal cloruro acido di carnitina con etere etilico anidro. A scopo di controllo, si trasformò il cloruro 30 acido in estere metilico: si raffreddò a 0°C e si aggiunsero goccia a goccia 10 cc di metanolo anidro; quindi, si concentrò sotto vuoto a 35-40°C e si ottenne un grezzo gelatinoso che essiccato sotto vuoto solidificò rimanendo tuttavia molto igroscopico. Example 1 (chlorinating agent: thionyl cloniro) 2.25 cc (0.03 moles) of SOCl2 was added to 1.98 g 25 (0.01 moles) of D, L-carnitine chloride. After 1 hour the solubilization was complete and after 1.5 hours the reaction could be considered finished. The excess SOC1 was distilled and the residue consisting of the acid carnitine chloride was washed with anhydrous ethyl ether. For control purposes, the acid chloride 30 was transformed into methyl ester: it was cooled to 0 ° C and 10 cc of anhydrous methanol were added drop by drop; then, it was concentrated under vacuum at 35-40 ° C and a gelatinous crude was obtained which dried under vacuum solidified while remaining very hygroscopic.

35 35

T.L.C, cloroformio 55/Metanolo 35/H20 5/NH4OH 5 Spettro NMR Solvente D20 T.L.C, chloroform 55 / Methanol 35 / H20 5 / NH4OH 5 NMR spectrum Solvent D20

4,82 (lH,m,-CH-); 3,83 (3H,s,-OCHs); 3,55 (2H,d, -» « | N+CH2-); 4.82 (1H, m, -CH-); 3.83 (3H, s, -OCHs); 3.55 (2H, d, - »« | N + CH2-);

OH OH

3,30 (9H,s,-N+= 3.30 (9H, s, -N + =

CH3 CH3

-CH3); 2,73 (2H,d,-CH2CO-). ~CH3 CH3); 2.73 (2H, d, -CH2CO-). ~ CH3

Analisi elementare: Calcolato Elementary analysis: Calculated

50 50

C H N CI C H N CI

45,39 8,57 6,62 16,75 45.39 8.57 6.62 16.75

Trovato Found

43,99 8,54 6,09 16,92 43.99 8.54 6.09 16.92

K. F. ~ 4% K. F. ~ 4%

Esempio 2 (agente clorurante: diclorometiletere) 55 Si operò come nell'esempio precedente, tranne che in luogo del cloruro di tionile si impiegò diclorometiletere (1,78 cc; 0,02 moli). La miscela di reazione venne lasciata per una notte a temperatura ambiente. Si distillò il diclorometiletere in eccesso e si lavò il residuo con etere etilico 60 anidro. Il residuo risultò costituito da cloruro acido di carnitina. Example 2 (chlorinating agent: dichloromethyl ether) 55 The same procedure was used as in the previous example, with the exception of dichloromethyl ether (1.78 cc; 0.02 moles) was used instead of thionyl chloride. The reaction mixture was left overnight at room temperature. The excess dichloromethyl ether was distilled and the residue was washed with anhydrous ethyl ether 60. The residue was made up of carnitine acid chloride.

CH3 CH3

NMR CDSCN 8 3,33 (9H,s,CH3^N+-); 3,36-3,60 (4H,m,-* NMR CDSCN 8 3.33 (9H, s, CH3 ^ N + -); 3.36-3.60 (4H, m, - *

CH3 CH3

65 65

N+-CH2-, -CH2COCl); 4,40-4,90 (lH,m,-CH-) N + -CH2-, -CH2COCl); 4.40-4.90 (lH, m, -CH-)

OH OH

3 3

648546 648546

Dopo scambio con D20 i chemical shifts ritornavano ad avere gli stessi valori dello spettro NMR della carnitina. Il cloruro acido grzzo venne trasformato successivamente in estere metilico come precedentemente descritto. L'estere metilico della carnitina mostrava le caratteristiche chimico fisiche corrispondenti al prodotto precedentemente isolato. After exchange with D20 the chemical shifts returned to have the same values as the NMR spectrum of carnitine. The crude acid chloride was subsequently transformed into methyl ester as previously described. The methyl ester of carnitine showed the chemical-physical characteristics corresponding to the previously isolated product.

Gli esempi A e B che seguono servono ad illustrare l'assoluta criticità delle condizioni operative indicate allo scopo di ottenere il cloruro acido di carnitina. Examples A and B below serve to illustrate the absolute criticality of the operating conditions indicated for the purpose of obtaining carnitine acid chloride.

Esempio A Example A

(mancata osservanza dell'appropriata temperatura di reazione) (failure to observe the appropriate reaction temperature)

Una miscela di carnitina e cloruro di tionile nel rapporto molare 1:1 venne mantenuta sotto agitazione a 50°C. Vennero fatti dei prelievi ai tempi successivi di 0,5 ore, 1 ora, 1,5 ore. I campioni prelevati vennero esaminati mediante TLC (cloroformio 55/CH3OH 35/ H20 5/ NH4OH 5') dopo diluizione con metanolo per trasformare l'eventuale cloruro acido in estere metilico. A mixture of carnitine and thionyl chloride in the molar ratio 1: 1 was kept under stirring at 50 ° C. Withdrawals were made in the following times of 0.5 hours, 1 hour, 1.5 hours. The samples taken were examined by TLC (chloroform 55 / CH3OH 35 / H20 5 / NH4OH 5 ') after dilution with methanol to transform any acid chloride into methyl ester.

Dopo 0,5 ore si notò la presenza di carnitina e estere metilico di carnitina. Rf 0,4-0,8 rispettivamente. After 0.5 hours the presence of carnitine and carnitine methyl ester was noted. Rf 0.4-0.8 respectively.

Dopo 1 ora si cominciò a formare crotonoilbetaina più carnitina e estere metilico di carnitina Rf 0,2-0,4-0,8 rispettivamente. After 1 hour, crotonoylbetaine plus carnitine and methyl ester of carnitine Rf 0.2-0.4-0.8 began to form respectively.

Dopo 1,5 ore si notò la presenza di crotonoilbetaina più altri prodotti di degradazione non identificabili. After 1.5 hours, the presence of crotonoylbetaine plus other unidentifiable degradation products was noted.

Esempio B Example B

(mancata osservanza dell'appropriato tempo di reazione) (failure to observe the appropriate reaction time)

Cloruro di tionile (2,3 cc; 0,03 moli) venne aggiunto a s carnitina cloruro (1,98 g; 0,01 moli) e la risultante miscela di reazione venne mantenuta a temperatura ambiente sotto agitazione per 24 ore. Il cloruro di tionile in eccesso venne distillato e il residuo grezzo venne lavato con etere etilico anidro con ottenimento di un solido avente punto di fusione io 217-218°C. Thionyl chloride (2.3 cc; 0.03 moles) was added to s carnitine chloride (1.98 g; 0.01 moles) and the resulting reaction mixture was kept at room temperature under stirring for 24 hours. The excess thionyl chloride was distilled and the crude residue was washed with anhydrous ethyl ether to obtain a solid having a melting point of 217-218 ° C.

T.L.C, cloroformio 55/ Metanolo 35/ H20 5/ NH4OH 5/ Rf 0,2. T.L.C, chloroform 55 / Methanol 35 / H20 5 / NH4OH 5 / Rf 0.2.

15 NMR D20 S 7,2-6,2 (2H,m,-CH=CH-); 4,2 (2H,d, -» 15 NMR D20 S 7.2-6.2 (2H, m, -CH = CH-); 4.2 (2H, d, - "

CH3 CH3

N+-CH2-); 3,2 (9H,s,CH3^N+-). N + -CH2-); 3.2 (9H, s, CH3 ^ N + -).

ch3 ch3

20 20

Come risulta da TLC e dallo spettro NMR in queste condizioni di reazione non si è formato il cloruro acido di carnitina ma è avvenuta una disidratazione con formazione di crotonoilbetaina As shown by TLC and the NMR spectrum in these reaction conditions carnitine acid chloride was not formed but dehydration with crotonoylbetaine formation occurred

25 25

ch3 ch3

CH35=N+-CH2-CH=CH-COOH CH35 = N + -CH2-CH = CH-COOH

ch3 ci- ch3 ci-

Claims (2)

648546 2 RIVENDICAZIONI648546 2 CLAIMS 1. Procedimento per produrre cloruro acido di carnitina comprendente lo stadio di clorurare carnitina con un agente clorurante scelto fra cloruro di tionile, diclorometiletere e ossalilcloruro, a temperatura ambiente, per tempi di reazione compresi fra circa 1,5 ore e 12 ore. 1. A process for producing carnitine acid chloride comprising the step of chlorinating carnitine with a chlorinating agent selected from thionyl chloride, dichloromethyl ether and oxalyl chloride, at room temperature, for reaction times of between about 1.5 hours and 12 hours. 2. Procedimento secondo la rivendicazione precedente, in cui il rapporto molare carnitina/agente clorurante è compreso fra 1:1 e 1:3. Method according to the preceding claim, wherein the carnitine / chlorinating agent molar ratio is between 1: 1 and 1: 3.
CH3884/82A 1981-07-03 1982-06-24 PROCEDURE FOR THE PREPARATION OF CARNITINE ACID CHLORIDE. CH648546A5 (en)

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IT48817/81A IT1171360B (en) 1981-07-03 1981-07-03 PROCEDURE FOR THE PREPARATION OF CARNITINE ACID CHLORIDE

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ID=11268676

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CH (1) CH648546A5 (en)
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FR (1) FR2510559B1 (en)
GB (1) GB2101133B (en)
GR (1) GR76546B (en)
IE (1) IE53279B1 (en)
IL (1) IL66251A0 (en)
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IT1190358B (en) * 1985-05-24 1988-02-16 Sclavo Spa PROCEDURE FOR THE PREPARATION OF L-CARNITINA

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3940439A (en) * 1973-11-14 1976-02-24 G. D. Searle & Co. Acid chloride synthesis
IT1116037B (en) * 1979-04-23 1986-02-10 Sigma Tau Ind Farmaceuti ACIL CARNITINE ESTERS AND AMIDS THEIR PREPARATION PROCEDURES AND THERAPEUTIC USE
DE2943433A1 (en) * 1979-10-26 1981-05-07 Bayer Ag, 5090 Leverkusen METHOD FOR PRODUCING CARBONIC ACID HALOGENIDES

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KR840000475A (en) 1984-02-22
DE3224666C2 (en) 1991-01-24
IE821524L (en) 1983-01-03
JPH0244300B2 (en) 1990-10-03
GR76546B (en) 1984-08-10
BE893713A (en) 1982-10-18
DK295482A (en) 1983-01-04
SE8204117D0 (en) 1982-07-02
DE3224666A1 (en) 1983-01-20
IT1171360B (en) 1987-06-10
NL189666C (en) 1993-06-16
AT390057B (en) 1990-03-12
JPS5815943A (en) 1983-01-29
IL66251A0 (en) 1982-11-30
DK154425C (en) 1989-04-10
SE448724B (en) 1987-03-16
IE53279B1 (en) 1988-09-28
IT8148817A0 (en) 1981-07-03
DK154425B (en) 1988-11-14
FR2510559A1 (en) 1983-02-04
SE8204117L (en) 1983-01-04
NL189666B (en) 1993-01-18
FR2510559B1 (en) 1986-05-09
ES8304064A1 (en) 1983-03-01
GB2101133A (en) 1983-01-12
GB2101133B (en) 1985-08-14
ES513658A0 (en) 1983-03-01
LU84244A1 (en) 1983-01-20
CA1186332A (en) 1985-04-30
ATA257382A (en) 1989-08-15
KR860001886B1 (en) 1986-10-24
NL8202677A (en) 1983-02-01

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