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WO2022186617A1 - Procédé de production d'orotate de carnitine à l'aide d'un nouvel intermédiaire orotate - Google Patents

Procédé de production d'orotate de carnitine à l'aide d'un nouvel intermédiaire orotate Download PDF

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Publication number
WO2022186617A1
WO2022186617A1 PCT/KR2022/002988 KR2022002988W WO2022186617A1 WO 2022186617 A1 WO2022186617 A1 WO 2022186617A1 KR 2022002988 W KR2022002988 W KR 2022002988W WO 2022186617 A1 WO2022186617 A1 WO 2022186617A1
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WIPO (PCT)
Prior art keywords
carnitine
ortate
acid
ortic
salt
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Application number
PCT/KR2022/002988
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English (en)
Korean (ko)
Inventor
유형철
김재선
오영선
양현준
Original Assignee
제이투에이치바이오텍 (주)
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Priority to JP2023553239A priority Critical patent/JP2024511286A/ja
Priority to CN202280018800.9A priority patent/CN116964035A/zh
Publication of WO2022186617A1 publication Critical patent/WO2022186617A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a method for producing carnitine ortate salt using a novel ortate intermediate, and more particularly, a novel ortic acid tertiary amine by adding tertiary amines to ortic acid having low solubility in an organic solvent or purified water.
  • Carnitine is one of the B-complex vitamins containing the basic amino acids lysine, methionine, and NH 4 + .
  • Carnitine is a very important enzyme in transporting fatty acids to the mitochondria and breaking them down into energy.
  • L-carnitine is an endogenous substance produced in the body and plays an essential role in decomposing fat. When fat is absorbed into the mitochondria and used as energy, it is a necessary component when fatty acids pass through the mitochondrial membrane.
  • Carnitine is also used as a health functional food and medicine. In particular, it is used as a treatment for primary and secondary carnitine deficiency, myocardial metabolic disorder due to ischemic heart disease, and carnitine deficiency in patients with end-stage renal disease on hemodialysis.
  • carnitine is in the form of an intramolecular salt as shown in Formula (A), and since it has a strong habitual property, it is usually salted with other substances to inhibit absorption.
  • Korean Patent Registration No. 1291186 discloses carnitine 1,5-naphthalenedisulfonate having improved absorption and stability of carnitine as an acid addition salt of a carnitine compound.
  • it is also necessary to solve problems such as flowability of substances, while 1,5-naphthalenedisulfonate has a low density, so it is difficult to produce a finished pharmaceutical product.
  • Korean Patent No. 0294329 discloses that carnitine and ortate are provided as a pharmaceutical composition for the treatment and prevention of liver disease.
  • Carnitine ortate salt is a state in which hydrophilic carnitine and hydrophobic ortic acid are combined, and it is known that the bioavailability is higher than that of general carnitine, so that it shows the same bioavailability as carnitine at 1/3 dose.
  • Ortic acid also called vitamin B13
  • Ortic acid is known to act as an intermediate when synthesizing an enzyme that converts carbohydrates into energy in the body, helps prevent liver disorders and prevents aging, and is also known to be involved in growth promotion.
  • ortic acid is widely used as a pharmaceutically acceptable salt in pharmaceuticals.
  • Ortic acid has been reported to have several beneficial physiological activities, and it has been reported that it has an effect of preventing hepatitis and preventing liver cancer in a disease model (Orotic Acid: Synthesis, Biochemical Aspects and Physiological Role, Ciha A., Reutter, W , 1980, Springer).
  • transaminase SGPT
  • Godex and Gadenine which contain carnitine ortate for the treatment of elevated liver disease.
  • Korean Patent Application Laid-Open No. 2019-0017310 discloses a method for producing L-carnitine ortate, but not known for removing impurities from ortic acid.
  • carnitine which is hydrophilic
  • ortic acid is difficult to purify because it is not soluble in purified water or organic solvents due to its hydrophobic properties.
  • it In order to use carnitine and ortic acid pharmaceutically, it must be purified and used in the form of free acid or chloride.
  • the solubility is very low in purified water or organic solvent, so it is difficult to purify. Therefore, it is necessary to use an excess of purified water or alcohol during purification, a lot of time is required in the process to obtain crystallization, and since purified water is used, the yield is also low.
  • the present invention is to solve the problems of the prior art, and after preparing a novel ortic acid tertiary amine salt by adding tertiary amines to ortic acid having low solubility in an organic solvent or purified water, an acid with carnitine hydrochloride It is a technical task to provide a method for preparing carnitine ortate in high yield and high purity by easily removing impurities in a single reaction solvent without using a separate crystallization solvent by performing a base exchange reaction.
  • a carnitine ortate salt prepared according to the method of the present invention.
  • an ortate triethylamine salt intermediate represented by the following formula (1):
  • TEA represents triethylamine
  • the method for producing carnitine ortate according to the present invention uses an ortate tertiary amine salt, which is a new hydrophilic intermediate that is easy to remove impurities in a single reaction solvent, and has a high yield and high purity only by an acid-base exchange reaction with carnitine hydrochloride.
  • a crystalline form of carnitine ortate may be provided.
  • Example 1 shows the results of X-ray powder diffraction analysis (PXRD) using Cu-Ka radiation for crystalline carnitine ortate prepared in Example 1 of the present invention.
  • Example 2 shows the results of differential scanning calorimetry (DSC) analysis for crystalline carnitine ortate prepared in Example 1 of the present invention.
  • FIG. 3 is a photograph comparing solubility and turbidity of L-carnitine ortate prepared in Example 2 of the present invention and L-carnitine ortate prepared in Comparative Example 1.
  • FIG. 3 is a photograph comparing solubility and turbidity of L-carnitine ortate prepared in Example 2 of the present invention and L-carnitine ortate prepared in Comparative Example 1.
  • the method for producing carnitine ortate of the present invention comprises: (1) a first step of preparing ortic acid tertiary amine salt by adding ortic acid and tertiary amines to a reaction solvent; and (2) a second step of preparing carnitine ortate by adding carnitine hydrochloride to the tertiary amine salt of ortic acid.
  • the method for preparing carnitine ortate salt of the present invention may be carried out as shown in the following scheme.
  • the present invention prepares ortic acid, which is difficult to purify impurities due to its poor solubility in purified water or organic solvents, as a novel intermediate ortic acid tertiary amine salt, dissolves it in an organic solvent to remove impurities, and the ortic acid tertiary amine
  • the purpose is to provide crystalline carnitine ortate in a high yield in a single solvent by performing an acid-base exchange reaction between a salt and carnitine hydrochloride.
  • Ortic acid is a poorly soluble substance that is difficult to dissolve in purified water or an organic solvent.
  • sodium ortate and potassium ortate are also poorly soluble substances.
  • it is dissolved in an excess of purified water, for example, 40 to 50 times purified water. If a lot of purified water is used, it is industrially difficult because a series of manufacturing processes such as concentration are required to increase the yield.
  • the present invention is to facilitate industrial production by making it very well dissolved in purified water and organic solvents, specifically methanol, by chlorinated tertiary amines in ortic acid, thereby facilitating the removal of impurities.
  • high yield and high purity crystalline carnitine ortic acid can be obtained very simply by performing an acid-base exchange reaction with carnitine hydrochloride in methanol, which is a reaction solution for preparing a tertiary amine salt of ortic acid.
  • the method for producing carnitine ortate of the present invention includes the first step of (1) preparing ortic acid tertiary amine salt by adding ortic acid and tertiary amines to a reaction solvent.
  • the reaction solvent of the first step may be methanol.
  • the provided ortic acid tertiary amine salt is poorly soluble in alcohols, ketones, single-chain alkanes, organochlorinated compounds, and organonitrile compounds other than methanol.
  • the tertiary amines added in the first step may be selected from the group consisting of triethylamine, tripropylamine, tributylamine, methylpiperidine, ethylpiperidine, and combinations thereof.
  • 1 to 3 equivalents of tertiary amines for example, 1 to 2.5 equivalents, 1 to 2 equivalents, or 1 to 1.5 equivalents, may be added based on 1 equivalent of ortic acid.
  • the ort acid tertiary amine salt is not sufficiently prepared, so the yield and purity of the carnitine ortate may be lowered. No effect can be obtained.
  • the first step may be performed at 20°C to 60°C, for example, 20°C to 55°C or 20°C to 50°C, for 0.5 to 3 hours, for example 0.5 to 2 hours or 0.5 to 1.5 hours.
  • reflux and cooling processes may be additionally performed.
  • an intermediate of ortic acid triethylamine salt represented by the following formula (1) is provided:
  • TEA represents triethylamine
  • the method for producing carnitine ortate of the present invention includes (2) a second step of preparing carnitine ortate by adding carnitine hydrochloride to a tertiary amine salt of ortic acid.
  • carnitine ortate can be prepared only by adding carnitine hydrochloride in a single reaction solvent, specifically methanol, and tertiary amine hydrochloride produced as a by-product, triethylamine hydrochloride in one embodiment Since silver is dissolved in the same reaction solvent, that is, methanol, only the carnitine ortate precipitated in a crystalline form can provide the target product simply by the filtration process.
  • the carnitine ortate salt prepared in a single reaction solvent provides a novel crystalline form with high yield and high purity only by refluxing and cooling.
  • 1 equivalent to 1.5 equivalents of carnitine hydrochloride may be added with respect to 1 equivalent of ortic acid tertiary amine salt.
  • carnitine hydrochloride is added less than the above value, the yield and purity of carnitine ortate may be lowered.
  • the second step may be performed at 0°C to 10°C, for example, 0°C to 8°C or 0°C to 6°C, for 0.5 to 2 hours, for example 0.6 to 1.8 hours or 0.8 to 1.5 hours.
  • reflux and cooling processes may be additionally performed.
  • a carnitine ortate salt prepared according to the method of the present invention.
  • the carnitine orthate salt of the present invention may be DL-carnitine ortate or L-carnitine ortate, and is 9.6 ⁇ 0.2, 14.9 ⁇ 0.2, and 14.9 ⁇ 0.2 in X-ray powder diffraction analysis (PXRD) using Cu-Ka radiation. 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 16.8 ⁇ 0.2, 18.8 ⁇ 0.2, 19.5 ⁇ 0.2, 20.7 ⁇ 0.2, 20.9 ⁇ 0.2, 21.7 ⁇ 0.2, 21.9 ⁇ 0.2, 24.2 ⁇ 0.2, 24.5 ⁇ 0.2, 25.0 ⁇ 0.2, 25.7 2 ⁇ diffraction angle peaks may be exhibited at ⁇ 0.2, 25.9 ⁇ 0.2, 26.8 ⁇ 0.2, 27.1 ⁇ 0.2, 28.7 ⁇ 0.2, 30.2 ⁇ 0.2 and 31.7 ⁇ 0.2.
  • carnitine ortate of the present invention has an endothermic onset temperature of 193 in differential scanning calorimetry (DSC) analysis. °C ⁇ 2 °C and endothermic temperature 197 °C ⁇ 2 It may represent °C.
  • the reaction solution was filtered to remove impurities, and 15.2 g of carnitine hydrochloride was added to the filtrate, dissolved, refluxed for 2 hours, and stirred at 0-5° C. for 1 hour to precipitate crystals.
  • the precipitated crystals were filtered and washed with 10 ml of methanol, and then the crystals were vacuum-dried at 45-50° C. for 12 hours to obtain carnitine ortate having a content of 100.4% and a yield of 98% (19.9 g).
  • the reaction solution was filtered to remove impurities, and 15.2 g of L-carnitine hydrochloride was added to the filtrate, dissolved, refluxed for 2 hours, and stirred at 0-5° C. for 1 hour to precipitate crystals.
  • the precipitated crystals were filtered and washed with 10 ml of methanol, and the crystals were vacuum-dried at 45-50° C. for 12 hours to obtain carnitine ortate having a content of 100.2% and a yield of 98% (19.9 g).
  • FIG. 1 The results of X-ray powder diffraction analysis (PXRD) using Cu-Ka radiation for the crystalline carnitine ortate prepared in Example 1 of the present invention are shown in FIG. 1 .
  • DSC differential scanning calorimetry
  • FIG. 3 a photograph comparing the solubility and turbidity of L-carnitine ortate prepared in Example 2 of the present invention and L-carnitine ortate prepared in Comparative Example 1 is shown in FIG. 3 .
  • Comparative Example 1 prepared by the conventional synthesis method, it can be seen that the turbidity is lower than that of Example due to undissolved impurities.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un procédé de production d'orotate de carnitine à l'aide d'un nouvel intermédiaire orotate, et plus spécifiquement, un procédé de production d'orotate de carnitine de grande pureté à un rendement élevé, un nouveau sel d'amine tertiaire d'acide ortique étant produit par ajout d'amines tertiaires à de l'acide ortique ayant une faible solubilité dans un solvant organique ou de l'eau purifiée, puis une réaction d'échange acide-base avec du chlorhydrate de carnitine est effectuée pour éliminer facilement les impuretés dans un solvant de réaction unique sans utiliser de solvant de cristallisation séparé.
PCT/KR2022/002988 2021-03-04 2022-03-03 Procédé de production d'orotate de carnitine à l'aide d'un nouvel intermédiaire orotate WO2022186617A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2023553239A JP2024511286A (ja) 2021-03-04 2022-03-03 新規なオロチン酸塩中間体を用いたカルニチンオロチン酸塩の製造方法
CN202280018800.9A CN116964035A (zh) 2021-03-04 2022-03-03 利用新型乳清酸盐中间体的肉碱乳清酸盐的制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2021-0028782 2021-03-04
KR1020210028782A KR102552918B1 (ko) 2021-03-04 2021-03-04 신규한 오르트산염 중간체를 이용한 카르니틴 오르트산염의 제조방법

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WO2022186617A1 true WO2022186617A1 (fr) 2022-09-09

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS375199B1 (fr) * 1959-12-28 1962-06-19
RU2084441C1 (ru) * 1993-06-18 1997-07-20 Всероссийский научный центр по безопасности биологически активных веществ Способ получения кислотно-аддитивных солей труднорастворимых карбоновых кислот и аминов или аминокислот
KR20150014307A (ko) * 2013-07-29 2015-02-06 한국생명공학연구원 오로트산을 포함하는 근력약화 관련 질환의 예방 또는 치료용 약학적 조성물
CN106045919A (zh) * 2016-07-07 2016-10-26 黄冈华阳药业有限公司 一种左旋肉碱乳清酸盐的制备方法
KR20190017310A (ko) * 2017-08-10 2019-02-20 주식회사 셀트리온화학연구소 약제학적 성질이 개선된 l-카르니틴 화합물의 염, 이의 제조방법, 이를 함유하는 약학 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS375199B1 (fr) * 1959-12-28 1962-06-19
RU2084441C1 (ru) * 1993-06-18 1997-07-20 Всероссийский научный центр по безопасности биологически активных веществ Способ получения кислотно-аддитивных солей труднорастворимых карбоновых кислот и аминов или аминокислот
KR20150014307A (ko) * 2013-07-29 2015-02-06 한국생명공학연구원 오로트산을 포함하는 근력약화 관련 질환의 예방 또는 치료용 약학적 조성물
CN106045919A (zh) * 2016-07-07 2016-10-26 黄冈华阳药业有限公司 一种左旋肉碱乳清酸盐的制备方法
KR20190017310A (ko) * 2017-08-10 2019-02-20 주식회사 셀트리온화학연구소 약제학적 성질이 개선된 l-카르니틴 화합물의 염, 이의 제조방법, 이를 함유하는 약학 조성물

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CN116964035A (zh) 2023-10-27
KR20220125856A (ko) 2022-09-15
KR102552918B1 (ko) 2023-07-10
JP2024511286A (ja) 2024-03-13

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