WO2014009964A1 - Procédé d'enrichissement énantiomerique de 2', 6'-pipécoloxylidide - Google Patents

Procédé d'enrichissement énantiomerique de 2', 6'-pipécoloxylidide Download PDF

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Publication number
WO2014009964A1
WO2014009964A1 PCT/IN2012/000575 IN2012000575W WO2014009964A1 WO 2014009964 A1 WO2014009964 A1 WO 2014009964A1 IN 2012000575 W IN2012000575 W IN 2012000575W WO 2014009964 A1 WO2014009964 A1 WO 2014009964A1
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formula
carbon atoms
pipecoloxylidide
mixture
alkyl containing
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PCT/IN2012/000575
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English (en)
Inventor
Mahesh Bhagoji Dalvi
Rajesh Shashikant Kenny
Pradeep Kisan Tarade
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Neon Laboratories Limited
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Publication of WO2014009964A1 publication Critical patent/WO2014009964A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a novel process for enantiomeric enrichment of 2', 6'- pipecoloxylidide using a chiral carbamoyl benzoic acid (hereafter referred to as CCBA).
  • CCBA chiral carbamoyl benzoic acid
  • the invention further relates to a novel process for synthesis of CCBA and alkylation of 2 ' ,6 ' -pipecoloxylidide.
  • R' is methyl (mepivacaine), propyl (d/l-ropivacaine) or butyl (bupivacaine) are local anaesthetics.
  • Biological studies reveal that the (S)-enantiomers of bupivacaine and ropivacaine exhibit lower cardiotoxicity than the corresponding racemates while possessing the same anaesthetic activity and are therefore more advantageous for clinical purpose.
  • levobupivacaine Compared to bupivacaine, levobupivacaine has a longer duration of action. It is approximately 13 percent less potent (by molarity) than racemic bupivacaine.
  • (S)-2',6'-pipecoloxylidide of formula (IV) is a valuable intermediate for the preparation of (S)-isomer of N-propylpipecolic acid-2',6'-xylidide (ropivacaine), (S) isomer of mepivacaine and (S)-isomer of N-butylpipecolic acid-2',6'-xylidide (levobupivacaine).
  • Levobupivacaine and its preparation have been disclosed for the first time in the patent No. GB 1 180712.
  • the process includes following steps: resolving dl-2',6'-pipecoloxylidide using 0,0-dibenzoyl-d-tartaric acid; reacting resulting mixture of diastereoisomeric 0,0-dibenzoyl-d-tartrate salts with boiling acetone; separating acetone-insoluble dexti -2',6'-pipecoloxylidide salt; and isolating levo-2',6'- pipecoloxylidide salt from the acetone solution.
  • the process is intricate and provides levo-2',6'-pipecoloxylidide in lower yield. Further the process includes isolating the product from hot acetone i.e. it is a plain method for laboratories which could not be used for production in the plant.
  • J. Med. Chem. Volume 14, issue 9, pages 891 to 892 (1971) describes optical resolution method to obtain a single enantiomer of mepivacaine and levobupivacaine.
  • the process includes following steps: treatment of 2',6'-pipecoloxylidide with dibenzoyl-L-tartaric acid monohydrate; addition of isopropanol to separate isopropanol-insoluble enantiomer; and isolation of the desired enantiomer.
  • Acta. Chem. Scand. B41, pages 757 to 761 (1987) discloses resolution of 2', 6'- pipecoloxylidide using (-)-0,0'-dibenzoyl-L-tartaric acid in a mixture of isopropanol and water.
  • the combination of isopropanol and water gave a crystallization system resulting in only 48% isolation yield of desired diastereomeric salt.
  • (-)-0,0'-dibenzoyl-L- tartaric acid is a costly reagent.
  • the U.S. Patent No. 5959112 discloses optical resolution of 2', 6' -pipecoloxylidide using L-(-)-dibenzoyl tartaric acid or L-(-)-ditoluoyl tartaric acid in presence of acetone, water and sodium hydroxide.
  • enantiomeric purity of the product is not mentioned in the patent.
  • the PCT publication WO2009044404 discloses enantiomeric separation of 2 ',6'- pipecoloxylidide using L-(-)-dibenzoyl tartaric acid in non-ketonic etheric solvents such as water-soluble cyclic ethers (e.g. tetrahydrofuran or 1,4-dioxane).
  • non-ketonic etheric solvents such as water-soluble cyclic ethers (e.g. tetrahydrofuran or 1,4-dioxane).
  • the process provides (S)-2',6'-pipecoloxylidide in 99.2% enantiomeric purity but in relatively low yield.
  • L-(-)-dibenzoyl tartaric acid and L-(-)-ditoluoyl tartaric acid are the only reagents used for resolution of 2',6'-pipecoloxylidide and the resolution is efficiently carried out only in isopropanol.
  • the main drawback of theses resolving agents is that their recovery and reuse are not feasible due to their solubility in water.
  • Helvetica Chimica Acta, volume 52, Issue 1, pages 329 - 333 (1969) discloses use of enantiomorphs of N-(l-phenylethyl)succinamic acid and N-(l -phenylethyl)phthalamic acid for optical resolution of (l -phenylethyl)amine, 2-aminobutane-l -ol, threo-l-(4- nitrophenyl)-2-aminopropane-l, 3-diol and l-phenyl-2-aminopropane.
  • U.S. patent No. 3576854 discloses resolution of 1 -phenyl -2-aminopropane, 2- aminobutanol, threo-l-(4-nitrophenyl)-2-aminopropane-l, 3-diol and (1- phenylethyl)amine using enantiomorphs of N-(l-phenylethyl)succinamic acid and N-(l- phenylethyl)phthalamic acid.
  • the present invention is based on the surprising discovery that hardly any literature discloses use of CCBA for optical resolution of xylidide compounds. Due to limited use, availability of CCBA is also restricted. Therefore to make the process more economical it is essential to synthesise CCBA.
  • An object of the invention is to overcome or ameliorate atleast one disadvantage of the prior art or to provide a useful alternative.
  • Another object of the invention is to provide a novel process for enantiomeric enrichment of 2',6'-pipecoloxylidide to provide (S)-enantiomer which is an intermediate of ropivacaine and levobupivacaine, in high yield and high enantiomeric purity.
  • Yet another object of the invention is to provide a commercially viable and industrially applicable enantiomeric separation process which enables easy recovery of the resolving reagent.
  • Yet another object of the invention is to provide a novel and concise process for preparation of CCBA, which eliminates the necessity of hazardous substances.
  • the object of the invention is to convert (S)-2',6'-pipecoloxylidide, which is obtained by the present method, into highly pure ropivacaine and levobupivacaine having desirable pharmacological activity, broad safety margins, without toxicity or unfavourable side effects.
  • Chiral carbamoyl benzoic acid as used according to the invention is selected from N-substituted amidic acids of formula (lie).
  • N-substituted amidic acids of the present invention encompasses N-((R)-1- phenylethyl)phthalamic acid; N-((S)-l-phenylethyl)succinamic acid and N-((R)-1- phenylethyl)maleinamic acid.
  • the present invention provides novel intermediates formed in the enantiomeric enrichment process of 2',6'-pipecoloxylidide.
  • the invention provides a novel process for synthesis of N-substituted amidic acids and alkylation of 2',6'-pipecoloxylidide resulting in ropivacaine, bupivacaine and levobupivacaine.
  • any of the words 'having', 'including', 'includes', 'comprising' and 'comprises' mean 'including without limitations' and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
  • Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose illustration rather than limitation of the invention as set forth the appended claims.
  • the present invention provides a novel process for enantiomeric enrichment of 2',6'-pipecoloxylidide.
  • the process comprises: reacting a mixture of enantiomer of 2',6'-pipecoloxylidide of formula (I) with CCBA in presence of a solvent.
  • the enantiomeric enrichment of 2',6'-pipecoloxylidide is carried out by reacting a mixture of enantiomers of 2',6'-pipecoloxylidide of formula (I) with CCBA of formula (II) in presence of a solvent to provide a mixture of chiral salts of formula (Ilia); and isolating a salt of formula (Hlb) from the salt mixture of formula (Ilia).
  • R is phenyl, phenyl substituted by halogen or alkyl containing 1 to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms; and R' is alkyl containing 1 to 5 carbon atoms.
  • the enantiomeric enrichment of 2',6'-pipecoloxylidide is carried out by reacting a mixture of enantiomers of 2',6'-pipecoloxylidide of formula (I) with CCBA of formula (Ila) in presence of a solvent to provide a mixture of chirai salts of formula (IIIc); and isolating a salt of formula (Hid) e of formula (IIIc).
  • R is phenyl, phenyl substituted by halogen or alkyl containing 1 to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms; and R' is alkyl containing 1 to 5 carbon atoms.
  • R is phenyl and R' is methyl.
  • the solvent used in the process of enantiomeric enrichment is a polar solvent selected from the group consisting of alcohol, nitrile, ester, ketone or mixture thereof.
  • the preferred solvents for enantiomeric enrichment are selected from isopropanol, acetone, ethyl acetate or acetonitrile.
  • the process of enantiomeric enrichment may be carried out at suitable temperature.
  • the reaction is carried out at 0 to 80°C.
  • the preferred temperature is 30 to 70°C.
  • the most preferred range of temperature is 55 to 65°C.
  • the reaction normally completes in 1 to 10 hours, preferably within 2 to 3 hours.
  • the CCBA is conveniently used in an amount, relative to 2',6'-pipecoloxylidide of formula (I) in a range between 0.25 to 1.5 equivalents.
  • the preferred amount of CCBA is 0.5 to 1.0 equivalent.
  • the process of enantiomeric enrichment of 2',6'-pipecoloxylidide of formula (I) further comprises releasing (S)-2',6'-pipecoloxylidide of formula (IV) from the 2', 6'- pipecoloxylidide-amide chiral salt of formula (Illb) or (Hid) using a base.
  • the base which may be used for releasing (S)-2',6'-pipecoloxylidide of formula (IV) is organic or inorganic.
  • organic base include tertiary amines such as trialkyl amine.
  • inorganic base include ammonia, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate and mixture thereof.
  • the alkali metal carbonates are selected from sodium carbonate and potassium carbonate.
  • the alkali metal bicarbonates are selected from sodium bicarbonate and potassium bicarbonate.
  • the alkaline earth metal carbonates are selected from calcium carbonate and magnesium carbonate. Examples of alkaline earth metal bicarbonate include calcium bicarbonate and magnesium bicarbonate.
  • the preferred base for releasing (S)-2',6'-pipecoloxylidide of formula (IV) from the 2',6'-pipecoloxylidide-amide chiral salt of formula (III) or (Ilia) is sodium carbonate.
  • (S)-2',6'-pipecoloxylidide prepared according to prior art processes contains extraneous compounds or impurities that can come from any source.
  • the impurities can be in the form of unreacted starting materials, by-products of the reaction, products of side reactions or degradation products.
  • (S)-2',6'-pipecoloxylidide containing impurities can lead to impure ropivacaine, levobupivacaine or their salts. Impurities in ropivacaine, levobupivacaine or their salts are undesired and might even be harmful to a patient being administered with a dosage form containing the same. Therefore known processes for preparation of (S)-2',6'-pipecoloxylidide need a step of purification, making the process expensive.
  • the process of the invention provides highly pure (S)-2',6'-pipecoloxylidide with more than 99% enantiomeric purity, and can be alkylated directly avoiding the step of purification. Hence the process is quite economical
  • the present invention provides novel intermediates of formula (Illb), (Hid), (Hie) and (Illf) formed in the process of enantiomeric enrichment of 2',6'- pipecoloxylidide.
  • R is phenyl, phenyl substituted by halogen or alkyl containing 1 to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms; and R' is alkyl containing 1 to 5 carbon atoms; formed in the enantiomer enrichment process of 2',6'-pipecoloxylidide of formula (I).
  • the salts of formula (Illb), (Hid), (Hie) and (Illf) are further processed to recover CCBA.
  • the present invention describes a novel method for preparation of N-substituted amidic acids of formula (He) or enantiomers thereof;
  • R is phenyl, phenyl substituted by halogen or alkyl containing 1 to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms;
  • R' is alkyl containing 1 to 5 carbon atoms; and
  • R is phenyl, phenyl substituted by halogen or alkyl containing 1 to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms; and R' is alkyl containing 1 to 5 carbon atoms.
  • R is phenyl and R' is methyl.
  • the polar aprotic solvents used for preparation of N-substituted amidic acids are selected from carboxylic acid ester, ketone, halogenated hydrocarbon or mixture thereof.
  • the preferred solvent is ethyl acetate, acetone, ethyl methyl ketone, methyl isobutyl ketone, dichloromethane, chloroform or mixture thereof.
  • the most preferred polar aprotic solvent for the reaction is ethyl acetate.
  • the amine of formula (V) is conveniently used in an amount, relative to anhydride, preferably in a range between 0.5 to 2.0 equivalents, more preferably 0.7 to 1.5 equivalents.
  • the most preferred quantity of the amine of formula (V) is 1.0 equivalent.
  • the reaction is carried out at 25 to 120°C, more preferably at 40 to 100°C.
  • the most preferred temperature for the reaction is 60 to 90°C.
  • the reaction normally completes in 0.25 to 3 hours, more preferably 0.5 to 2.0 hours, most preferably 1.0 to 1.5 hours.
  • the process provides N-substituted amidic acids with required optical purity, avoiding need for further purification. Hence the method is economical. As the process is carried out in non-toxic solvent, it is non-hazardous.
  • (R)-2',6'-pipecoloxylidide obtained from hydrolysis of the salts of formula (Hie) and (Hit) is racemized.
  • the racemic 2',6'-pipecoloxylidide is either alkylated to provide bupivacaine or mepivacaine; or resolved using CCBA.
  • the present invention provides a novel process for preparing alkylated 2',6'-pipecoloxylidides or acid addition salt thereof.
  • the process comprises reacting 2',6'-pipecoloxylidide or its enantiomer with alkylating reagent using a base in presence of aromatic solvent; and optionally reacting the resulting product with acid.
  • the solvent used for alkylation is selected from toluene, tetralene, o-xylene, m-xylene, p- xylene or mixture thereof.
  • the preferred solvent used for alkylation is toluene.
  • the base used for alkylation is inorganic base selected from alkali metal carbonates, alkali metal hydroxides or mixture thereof.
  • the preferred base for alkylation of 2',6'- pipecoloxylidide or its enantiomer is potassium carbonate.
  • phase transfer catalyst selected from tetraalkylammonium halides, tetraalkylammonium hydroxides, tetraalkylammonium sulphates, tetraalkylammonium nitrates or mixture thereof.
  • phase transfer catalyst is tetrabutylammonium bromide.
  • the alkylating reagent is selected from alkyl halides, dialkyl sulphates, alkyl sulphonates or mixture thereof.
  • the alkylating agent is dimethyl sulphate, propyl bromide or butyl bromide.
  • the pure Mepivacaine, bupivacaine, ropivacaine or levobupivacaine thus achieved may be formulated into a dosage form by combining with one or more pharmaceutically acceptable excipients using known techniques.
  • the course of the reactions can be re resented by the following equations:
  • R is butyl
  • R is methyl— Mepivacaine
  • (S)-2',6'-pipecoloxylidide was prepared according to the example 1 using N-((S)-1- phenylethyl)phthalamic acid (0.75 eq.) in isopropanol (25 volumes).
  • N-((R)-l-phenylethyl)phthalamic acid was prepared according to the example 8 using phthalic anhydride (28.9 gm) and R-(+)-alpha-methylbenzyl amine (25 gm) in ethyl acetate (100 ml).
  • N-((S)-l-phenylethyl)succinamic acid was prepared according to the example 8 using succinic anhydride (20.62 gm) and S ⁇ (-)-alpha-methylbenzyl amine (25 gm) in ethyl acetate (100 ml).
  • N-((R)-l-phenylethyl)succinamic acid was prepared according to the example 8 using succinic anhydride (20.62 gm) and R-(-)-alpha-methylbenzyl amine (25 gm) in ethyl acetate (100 ml).
  • the mother liquor obtained in the example 1 was concentrated under reduced pressure to obtain oily residue which was hydrolysed with 7% sodium carbonate (7 lit) for two hours at room temperature to obtain a solid.
  • the solid was collected by filtration and dried to obtain (R)-2',6'-pipecoloxylidide.
  • the filtrate was further processed to recover N-((S)-l -phenylethyl)phthalamic acid.
  • Bupivacaine hydrochloride hydrate was prepared according to the example 13 using 2',6'-pipecoloxylidide and cone, hydrochloric acid instead of (S)-2',6'-pipecoloxylidide and 20% hydrochloric acid in isopropanol.
  • Ropivacaine hydrochloride hydrate was prepared according to the example 13 using propyl bromide and cone, hydrochloric acid instead of butyl bromide and 20%> hydrochloric acid in isopropanol.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé d'enrichissement énantiomérique de 2', 6'-pipécoloxylidide à l'aide d'un acide benzoïque carbamoyle chiral pour obtenir le (S)-énantiomère avec un rendement élevé et une grande pureté énantiomérique. L'invention concerne également de nouveaux intermédiaires formés dans le procédé d'enrichissement énantiomérique de 2', 6 '-pipécoloxylidide, la préparation d'acides amidiques N-substitués et l'alkylation du 2', 6'-pipécoloxylidide.
PCT/IN2012/000575 2012-07-11 2012-08-30 Procédé d'enrichissement énantiomerique de 2', 6'-pipécoloxylidide WO2014009964A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104003930A (zh) * 2014-06-13 2014-08-27 山东阿如拉药物研究开发有限公司 一种盐酸罗哌卡因的制备方法
CN105315196A (zh) * 2015-11-28 2016-02-10 山东齐都药业有限公司 一种高纯度盐酸左布比卡因精制方法
CN105585520A (zh) * 2015-12-24 2016-05-18 山东齐都药业有限公司 盐酸左布比卡因a晶型及其制备方法

Citations (4)

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Publication number Priority date Publication date Assignee Title
GB1180712A (en) * 1967-05-18 1970-02-11 Sterling Drug Inc Novel levo-1-n-butyl-2',6'-pipecoloxylidide and the Preparation Thereof
US3576854A (en) * 1968-03-15 1971-04-27 Bracco Ind Chimica Spa Method of optically resolving racemic bases and optically active n-(1-phenylethyl)-carbamyl carboxylic acids for use in said method
WO1996036606A1 (fr) * 1995-05-16 1996-11-21 Astra Aktiebolag (Publ) Nouveau procede de preparation de monohydrate d'hydrochlorure de ropivacaine
WO2009044404A1 (fr) * 2007-10-01 2009-04-09 Ramniwas Goel Procédé de préparation de (s)-ropivacaïne hydrochlorure monohydrate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1180712A (en) * 1967-05-18 1970-02-11 Sterling Drug Inc Novel levo-1-n-butyl-2',6'-pipecoloxylidide and the Preparation Thereof
US3576854A (en) * 1968-03-15 1971-04-27 Bracco Ind Chimica Spa Method of optically resolving racemic bases and optically active n-(1-phenylethyl)-carbamyl carboxylic acids for use in said method
WO1996036606A1 (fr) * 1995-05-16 1996-11-21 Astra Aktiebolag (Publ) Nouveau procede de preparation de monohydrate d'hydrochlorure de ropivacaine
WO2009044404A1 (fr) * 2007-10-01 2009-04-09 Ramniwas Goel Procédé de préparation de (s)-ropivacaïne hydrochlorure monohydrate

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Title
ACS M ET AL: "Study of the Diastereoisomers Formed between (N-alkyl)-pipecolic acid-anilides and 2R,3R-tartaric acid or O,O@?-dibenzoyl-2R,3R-tartaric acid. Do the Tartaric Acids Form Molecular-Complexes, instead of Salts During Optical Resolutions?", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 52, no. 5, 29 January 1996 (1996-01-29), pages 1637 - 1642, XP004104468, ISSN: 0040-4020, DOI: 10.1016/0040-4020(95)00992-2 *
BENJAMIN F. TULLAR: "Optical isomers of mepivacaine and bupivacaine", JOURNAL OF MEDICINAL CHEMISTRY, vol. 14, no. 9, 1 January 1971 (1971-01-01), pages 891 - 892, XP055054711, DOI: 10.1021/jm00291a033 *
FEDERSEL HANS JUERGEN ET AL: "AN EFFICIENT SYNTHESIS OF A NEW, CHIRAL 2',6'-PIPECOLOXYLIDIDE LOCAL ANESTHETIC AGENT", ACTA CHEMICA SCANDINAVICA.SERIES B - ORGANIC CHEMISTRY AND BIOCHEMISTRY, MUNKSGAARD. COPENHAGEN, DK, vol. B41, no. 10, 1 January 1987 (1987-01-01), pages 757 - 761, XP009072868 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104003930A (zh) * 2014-06-13 2014-08-27 山东阿如拉药物研究开发有限公司 一种盐酸罗哌卡因的制备方法
CN104003930B (zh) * 2014-06-13 2016-06-08 山东金诃药物研究开发有限公司 一种盐酸罗哌卡因的制备方法
CN105315196A (zh) * 2015-11-28 2016-02-10 山东齐都药业有限公司 一种高纯度盐酸左布比卡因精制方法
CN105585520A (zh) * 2015-12-24 2016-05-18 山东齐都药业有限公司 盐酸左布比卡因a晶型及其制备方法

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