WO2022186617A1 - Method for producing carnitine orotate using novel orotate intermediate - Google Patents

Method for producing carnitine orotate using novel orotate intermediate Download PDF

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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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carnitine
ortate
acid
ortic
salt
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PCT/KR2022/002988
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French (fr)
Korean (ko)
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유형철
김재선
오영선
양현준
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제이투에이치바이오텍 (주)
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Priority to CN202280018800.9A priority Critical patent/CN116964035A/en
Priority to JP2023553239A priority patent/JP2024511286A/en
Publication of WO2022186617A1 publication Critical patent/WO2022186617A1/en

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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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Abstract

The present invention relates to a method for producing carnitine orotate using a novel orotate intermediate, and more specifically, to a method for producing high purity carnitine orotate at high yield, wherein a novel ortic acid tertiary amine salt is produced by adding tertiary amines to ortic acid having a low solubility in an organic solvent or purified water, and then an acid-base exchange reaction with carnitine hydrochloride is performed to easily remove impurities in a single reaction solvent without using a separate crystallization solvent.

Description

신규한 오르트산염 중간체를 이용한 카르니틴 오르트산염의 제조방법Method for producing carnitine ortate using novel ortate intermediate
본 발명은 신규한 오르트산염 중간체를 이용한 카르니틴 오르트산염의 제조방법에 관한 것으로, 보다 상세하게는 유기용매 또는 정제수에 용해성이 낮은 오르트산에 3차 아민류를 첨가하여 신규한 오르트산 3차 아민염으로 제조한 후, 카르니틴 염산염과의 산염기 교환반응을 수행함으로써, 별도의 결정화 용매를 사용하지 않고도 단일 반응용매 내에서 불순물의 제거가 용이하여 고수율 및 고순도의 카르니틴 오르트산염을 제조할 수 있는 방법에 관한 것이다.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. By carrying out an acid-base exchange reaction with carnitine hydrochloride after preparation as a salt, it is easy to remove impurities in a single reaction solvent without using a separate crystallization solvent, so that high yield and high purity carnitine ortate can be prepared. it's about how
카르니틴은 염기성 아미노산 라이신과 메티오닌, 그리고 NH4 +을 포함하고 있는 비타민 B 복합체 중 하나이다. 카르니틴은 지방산을 미트콘드리아로 운반하고 이를 분해하여 에너지로 변환시키는데 매우 중요한 효소이다. 특히, L-카르니틴은 체내에서도 생성되는 내인성 물질로서 지방을 분해하는데 있어 필수적인 역할을 하는데, 지방이 미트콘드리아에 흡수되어 에너지로 사용될 경우, 지방산이 미트콘드리아의 막을 통과할 때 필요한 성분이다. 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. In particular, 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.
카르니틴은 건강기능식품 및 의약품 등으로도 사용되며, 특히 의약품에서는 1차성, 2차성 카르니틴 결핍증, 허혈성심질환에 의한 심근대사장애, 혈액 투석중인 말기 신 질환자의 카르니틴 결핍증 치료제로 사용되고 있다. 일반적으로 카르니틴은 화학식 A와 같은 분자내 염 형태로 인습성이 강한 특성이 있기 때문에 흡수성을 억제하기 위해 통상 다른 물질과 염을 형성시키기도 한다. 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. In general, 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.
[화학식 A][Formula A]
Figure PCTKR2022002988-appb-img-000001
Figure PCTKR2022002988-appb-img-000001
대한민국 등록특허 제1291186호에서는 카르니틴 화합물의 산 부가염으로서, 카르니틴의 흡수성과 안정성이 개선된 카르니틴 1,5-나프탈렌디설폰산염을 개시하고 있다. 그러나 약제학적으로 생산을 하기 위해서는 물질의 흐름성 등의 문제의 해결도 필요한 반면, 1,5-나프탈렌디설폰산염은 밀도가 낮아 약제학적 완제품으로의 생산에 어려움이 있다. 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. However, for pharmaceutical production, 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.
대한민국 등록특허 제0294329호에서는 카르니틴과 오르트산 염이 간질환 치료 및 예방용 의약 조성물로 제공하는 것을 개시하고 있다. 카르니틴 오르트산 염은 친수성인 카르니틴과 소수성인 오르트산이 결합한 상태로서, 일반적인 카르니틴보다 생체이용률이 높아서 1/3 정도의 용량으로 카르니틴과 동등한 생체 이용률을 보여준다고 알려져 있다. 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.
오르트산은 비타민 B13이라고도 하며, 당질을 에너지로 바꾸는 효소를 체내에서 합성하는 경우에 중간물질로서 작용하고, 간장 장애를 예방하고 노화를 방지하는 데 도움을 주며, 성장 촉진에도 관여하는 것으로 알려져 있다. 또한, 오르트산은 의약품에서 약제학적으로 허용되는 염으로 널리 사용되고 있다. 오르트산은 여러 유익한 생리 활성이 보고되고 있는데, 질환 모델에서 간염을 예방하는 효과 및 간암에 대한 예방효과가 있음이 보고되고 있다 (Orotic Acid: Synthesis, Biochemical Aspects and Physiological Role, CihaA., Reutter, W, 1980, Springer). 대한민국에서는 트란스아미나제(SGPT)가 상승된 간질환의 치료를 위한 용도로서 카르니틴 오르트산염이 함유되어 있는 고덱스 및 가데닌이라는 상품명으로 시판되고 있다. Ortic acid, also called vitamin B13, 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. In addition, 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). In Korea, transaminase (SGPT) is marketed under the trade names of Godex and Gadenine, which contain carnitine ortate for the treatment of elevated liver disease.
대한민국 공개특허공보 제2019-0017310호에서는 L-카르니틴 오르트산염의 제조방법에 대해 공지하고 있으나, 오르트산의 불순물 제거에 대해서는 공지되어 있지 않다. 친수성인 카르니틴과는 다르게 오르트산은 소수성 특성으로 정제수 또는 유기용매에 잘 용해되지 않기에 정제하기가 어려운 문제점을 가지고 있다. 카르티닌과 오르트산을 약제학적으로 사용하기 위해서는 유리산 또는 염화물 형태에서 정제를 하여 사용해야 하는데, 카르니틴과 다르게 오르트산은 오르트산 유리산 또는 오르트산 염화물, 즉, 나트륨 염, 칼륨 염, 칼슘 염의 형태로도 정제수 또는 유기용매 내에서 용해도가 매우 낮아 정제를 하기 어렵다. 따라서, 정제시 과량의 정제수 또는 알코올을 사용해야 하고, 결정화를 얻기 위해서 공정상 많은 시간이 필요하며, 정제수를 사용하기 때문에 수율 또한 낮은 문제점이 있다. 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. Unlike 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. 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.
따라서, 별도의 결정화 용매를 사용하지 않고도 단일 반응용매 내에서 불순물의 제거가 용이하여 고수율 및 고순도의 카르니틴 오르트산염을 제조할 수 있는 방법에 대한 요구가 여전히 존재한다.Accordingly, there is still a need for a method capable of preparing carnitine ortate in high yield and high purity by facilitating the removal of impurities in a single reaction solvent without using a separate crystallization solvent.
본 발명은 상기한 종래 기술의 문제점들을 해결하고자 한 것으로, 유기용매 또는 정제수에 용해성이 낮은 오르트산에 3차 아민류를 첨가하여 신규한 오르트산 3차 아민염으로 제조한 후, 카르니틴 염산염과의 산염기 교환반응을 수행함으로써, 별도의 결정화 용매를 사용하지 않고도 단일 반응용매 내에서 불순물의 제거가 용이하여 고수율 및 고순도의 카르니틴 오르트산염을 제조할 수 있는 방법을 제공하는 것을 기술적 과제로 한다.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.
상기한 기술적 과제를 달성하기 위하여, 본 발명의 일 측면에 따르면, (1) 반응 용매에 오르트산 및 3차 아민류를 첨가하여 오르트산 3차 아민염을 제조하는 제1단계; 및 (2) 오르트산 3차 아민염에 카르니틴 염산염을 첨가하여 카르니틴 오르트산염을 제조하는 제2단계;를 포함하는 카르니틴 오르트산염의 제조방법이 제공된다.In order to achieve the above technical object, according to one aspect of the present invention, (1) a first step of preparing an 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 a tertiary amine salt of ortic acid.
본 발명의 다른 측면에 따르면, 상기 본 발명의 방법에 따라 제조된 카르니틴 오르트산염이 제공된다. According to another aspect of the present invention, there is provided a carnitine ortate salt prepared according to the method of the present invention.
본 발명의 또 다른 측면에 따르면, 하기 화학식 1로 표시되는 오르트산 트리에틸아민염 중간체가 제공된다:According to another aspect of the present invention, there is provided an ortate triethylamine salt intermediate represented by the following formula (1):
[화학식 1][Formula 1]
Figure PCTKR2022002988-appb-img-000002
Figure PCTKR2022002988-appb-img-000002
여기서, TEA는 트리에틸아민을 나타낸다.Here, TEA represents triethylamine.
본 발명에 따른 카르니틴 오르트산염의 제조방법은 단일 반응용매 내에서 불순물 제거 공정이 용이한 친수성의 신규 중간체인 오르트산 3차 아민염을 이용하여 카르니틴 염산염과 산염기 교환반응만으로 고수율 및 고순도의 결정형 카르니틴 오르트산염을 제공할 수 있다.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.
도 1은 본 발명의 실시예 1에서 제조된 결정형 카르니틴 오르트산염에 대한 Cu-Ka 방사선을 사용하는 X-선 분말 회절분석 (PXRD) 결과를 나타낸 것이다. 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.
도 2는 본 발명의 실시예 1에서 제조된 결정형 카르니틴 오르트산염에 대한 시차주사 열량(DSC) 분석 결과를 나타낸 것이다.2 shows the results of differential scanning calorimetry (DSC) analysis for crystalline carnitine ortate prepared in Example 1 of the present invention.
도 3은 본 발명의 실시예 2에서 제조된 L-카르니틴 오르트산염과 비교예 1에서 제조된 L-카르니틴 오르트산염의 용해도 및 혼탁도를 비교한 사진이다.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.
이하, 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 카르니틴 오르트산염의 제조방법은, (1) 반응 용매에 오르트산 및 3차 아민류를 첨가하여 오르트산 3차 아민염을 제조하는 제1단계; 및 (2) 오르트산 3차 아민염에 카르니틴 염산염을 첨가하여 카르니틴 오르트산염을 제조하는 제2단계;를 포함한다. 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.
일 구체예에서, 본 발명의 카르니틴 오르트산염의 제조방법은 하기 반응식에 도시된 바와 같이 수행될 수 있다.In one embodiment, the method for preparing carnitine ortate salt of the present invention may be carried out as shown in the following scheme.
[반응식 1][Scheme 1]
Figure PCTKR2022002988-appb-img-000003
Figure PCTKR2022002988-appb-img-000003
본 발명은 정제수 또는 유기용매에 대한 난용성의 특성으로 불순물 정제가 어려운 오르트산을 신규한 중간체인 오르트산 3차 아민염으로 제조하여 유기용매에 용해시켜 불순물을 제거하고, 상기 오르트산 3차 아민염과 카르니틴 염산염의 산염기 교환 반응을 수행하여 단일 용매 내에서 결정형의 카르니틴 오르트산염을 고수율로 제공하는데 있다. 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.
오르트산은 정제수 또는 유기용매에 용해가 어려운 난용성 물질로서, 유리산 이외에 판매되고 있는 오르트산 나트륨염, 오르트산 포타슘염 또한 난용성 물질이다. 오르트산 및 오르트산 염화물을 용해시키기 위해서는 과량의 정제수, 예를 들면 정제수 40 내지 50배에서 용해가 된다. 정제수가 많이 사용되면 수율을 높이기 위한 농축 등의 일련의 제조 공정이 필요하기 때문에 산업적으로 어려움이 있다. Ortic acid is a poorly soluble substance that is difficult to dissolve in purified water or an organic solvent. In addition to the free acid, sodium ortate and potassium ortate are also poorly soluble substances. In order to dissolve ortic acid and ortic acid chloride, 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.
본 발명은 오르트산에 3차 아민을 염화물화시켜 정제수 및 유기용매, 구체적으로 메탄올에 매우 잘 용해되도록 하여 불순물 제거에 용이하게 함으로써 산업적 생산에 매우 용이하게 하기 위함이다. 또한, 오르트산 3차 아민염의 제조 반응액인 메탄올 내에서 카르니틴 염산염과 산염기 교환 반응으로 매우 간단하게 고수율 및 고순도의 결정형 카르니틴 오르트산을 얻을 수 있다. 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. In addition, 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.
본 발명의 카르니틴 오르트산염의 제조방법은, (1) 반응 용매에 오르트산 및 3차 아민류를 첨가하여 오르트산 3차 아민염을 제조하는 제1단계를 포함한다.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.
제1단계의 반응 용매는 메탄올을 사용할 수 있다. 제공된 오르트산 3차 아민염은 메탄올 이외에 알콜류, 케톤류, 단일 체인 알칸류, 유기염화 화합물, 유기니트릴 화합물에는 잘 용해되지 않는다. 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.
상기 제1단계에서 첨가되는 3차 아민류는 트리에틸아민, 트리프로필아민, 트리부틸아민, 메틸피페리딘, 에틸피페리딘 및 이들의 조합으로 이루어진 군으로부터 선택되는 것일 수 있다. The tertiary amines added in the first step may be selected from the group consisting of triethylamine, tripropylamine, tributylamine, methylpiperidine, ethylpiperidine, and combinations thereof.
상기 제1단계에서 오르트산 1 당량에 대하여 3차 아민류 1 내지 3 당량, 예를 들면 1 내지 2.5 당량, 1 내지 2 당량 또는 1 내지 1.5 당량을 첨가할 수 있다. 3차 아민류가 상기 수치보다 적게 첨가되는 경우에는 오르트산 3차 아민염이 충분히 제조되지 않아 카르니틴 오르트산염의 수율 및 순도가 낮아질 수 있고, 반대로 3차 아민류가 상기 수치보다 많게 첨가되는 경우에는 추가적인 효과를 얻을 수 없다.In the first step, 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. When the tertiary amine is added less than the above value, 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.
상기 제1단계는 20℃ 내지 60℃, 예를 들면 20℃ 내지 55℃ 또는 20℃ 내지 50℃에서, 0.5 내지 3시간, 예를 들면 0.5 내지 2시간 또는 0.5 내지 1.5시간 동안 수행될 수 있다. 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.
일 구체예에서, 상기 제1단계에서 반응 용매에 오르트산 및 3차 아민류를 첨가한 후, 환류 및 냉각 공정을 추가로 수행할 수 있다. In one embodiment, after ortic acid and tertiary amines are added to the reaction solvent in the first step, reflux and cooling processes may be additionally performed.
본 발명의 또 다른 측면에 따르면, 본 발명의 카르니틴 오르트산염의 제1단계에서 얻어지는 오르트산 3차 아민염의 일 구체예로서, 하기 화학식 1로 표시되는 오르트산 트리에틸아민염 중간체가 제공된다:According to another aspect of the present invention, as an example of the tertiary amine salt of ortic acid obtained in the first step of the carnitine ortate salt of the present invention, an intermediate of ortic acid triethylamine salt represented by the following formula (1) is provided:
[화학식 1][Formula 1]
Figure PCTKR2022002988-appb-img-000004
Figure PCTKR2022002988-appb-img-000004
여기서, TEA는 트리에틸아민을 나타낸다.Here, TEA represents triethylamine.
본 발명의 카르니틴 오르트산염의 제조방법은 (2) 오르트산 3차 아민염에 카르니틴 염산염을 첨가하여 카르니틴 오르트산염을 제조하는 제2단계를 포함한다. 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.
본 발명의 제조방법은 단일 반응 용매, 구체적으로는 메탄올 내에서 카르니틴 염산염을 가하는 공정만으로 카르니틴 오르트산염을 제조할 수 있으며, 부산물로 생성되는 3차 아민 염산염, 일 구체예에서의 트리에틸아민 염산염은 동일 반응용매 즉, 메탄올에 용해되기 때문에, 결정형으로 석출되는 카르니틴 오르트산염만 여과공정만으로 간단하게 목적물을 제공할 수 있다. 또한, 단일 반응 용매 내에서 제조된 카르니틴 오르트산 염은 환류 및 냉각공정만으로 고수율 및 고순도의 신규 결정형을 제공한다. In the production method of the present invention, 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. In addition, 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.
제2단계에서 오르트산 3차 아민염 1당량에 대하여 카르니틴 염산염 1당량 내지 1.5 당량을 첨가할 수 있다. 카르니틴 염산염이 상기 수치보다 적게 첨가되는 경우에는 카르니틴 오르트산염의 수율 및 순도가 낮아질 수 있고, 반대로 카르니틴 염산염이 상기 수치보다 많게 첨가되는 경우에는 추가적인 효과를 얻을 수 없다.In the second step, 1 equivalent to 1.5 equivalents of carnitine hydrochloride may be added with respect to 1 equivalent of ortic acid tertiary amine salt. When carnitine hydrochloride is added less than the above value, the yield and purity of carnitine ortate may be lowered.
상기 제2단계는 0℃ 내지 10℃, 예를 들면 0℃ 내지 8℃ 또는 0℃ 내지 6℃에서, 0.5 내지 2시간, 예를 들면 0.6 내지 1.8시간 또는 0.8 내지 1.5시간 동안 수행될 수 있다. 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.
일 구체예에서, 상기 제2단계에서 오르트산 3차 아민염에 카르니틴 염산염을 첨가한 후, 환류 및 냉각 공정을 추가로 수행할 수 있다. In one embodiment, after adding carnitine hydrochloride to the tertiary amine salt of ortic acid in the second step, reflux and cooling processes may be additionally performed.
본 발명의 다른 측면에 따르면, 상기 본 발명의 방법에 따라 제조된 카르니틴 오르트산염이 제공된다. According to another aspect of the present invention, there is provided a carnitine ortate salt prepared according to the method of the present invention.
본 발명의 카르니틴 오르트산염은 DL-카르니틴 오르트산염 또는 L-카르니틴 오르트산염일 수 있으며, Cu-Ka 방사선을 사용하는 X-선 분말 회절분석 (PXRD)에서 9.6±0.2, 14.9±0.2, 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±0.2, 25.9±0.2, 26.8±0.2, 27.1±0.2, 28.7±0.2, 30.2±0.2 및 31.7±0.2에서 2θ회절각 피크를 나타내는 것일 수 있다.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 2θ 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.
또한, 본 발명의 카르니틴 오르트산염은 시차주사 열량(DSC) 분석에서 흡열개시온도 193 ℃ ±2 ℃ 및 흡열온도 197 ℃ ±2 ℃를 나타내는 것일 수 있다. In addition, carnitine ortate of the present invention has an endothermic onset temperature of 193 in differential scanning calorimetry (DSC) analysis. ℃ ±2 ℃ and endothermic temperature 197 ℃ ±2 It may represent °C.
이하, 실시예 및 비교예를 통하여 본 발명을 보다 상세하게 설명한다. 그러나, 본 발명의 범위가 이들로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through Examples and Comparative Examples. However, the scope of the present invention is not limited thereto.
[실시예][Example]
[실시예 1] DL-카르니틴 오르트산염의 제조[Example 1] Preparation of DL-carnitine ortate
250 mL 3구 플라스크에 메탄올 50 mL 및 오르트산 10 g을 가하고 실온에서 혼탁용액에 6.5g의 트리에틸아민을 가하여, 용해된 오르트산 트리에틸아민 염화물을 제조하였다. 50 mL of methanol and 10 g of ortic acid were added to a 250 mL three-necked flask, and 6.5 g of triethylamine was added to the turbid solution at room temperature to prepare a dissolved triethylamine chloride of ortic acid.
상기 반응액을 여과하여 불순물을 제거하고 여과액에 카르니틴 염산염 15.2g을 가한 후 용해하여 2시간 환류시키고, 0~5℃ 온도에서 1시간 교반하여 결정을 석출시켰다. 석출된 결정을 여과하고 메탄올 10ml로 세척한 후, 결정을 45~50℃에서 12시간 동안 진공 건조하여 함량 100.4%, 수율 98%의 카르니틴 오르트산염을 얻었다 (19.9g).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).
[실시예 2] L-카르니틴 오르트산염의 제조[Example 2] Preparation of L-carnitine ortate
250 mL 3구 플라스크에 메탄올 50 mL 및 오르트산 10 g을 가하고 실온에서 혼탁용액에 6.5g의 트리에틸아민을 가하여, 용해된 오르트산 트리에틸아민 염화물을 제조하였다. 50 mL of methanol and 10 g of ortic acid were added to a 250 mL three-necked flask, and 6.5 g of triethylamine was added to the turbid solution at room temperature to prepare a dissolved triethylamine chloride of ortic acid.
상기 반응액을 여과하여 불순물을 제거하고 여과액에 L-카르니틴 염산염 15.2g을 가한 후 용해하여 2시간 환류시키고, 0~5℃ 온도에서 1시간 교반하여 결정을 석출시켰다. 석출된 결정을 여과하고 메탄올 10ml로 세척한 후, 결정을 45~50℃에서 12시간 동안 진공 건조하여 함량 100.2%, 수율 98%의 카르니틴 오르트산염을 얻었다 (19.9g).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).
[비교예 1] 공개특허공보 제10-2019-0017310호에 개시된 방법에 의한 L-카르니틴 오르트산염의 제조[Comparative Example 1] Preparation of L-carnitine ortate by the method disclosed in Korean Patent Application Laid-Open No. 10-2019-0017310
250 mL 3구 플라스크에 아세톤 100 ml 및 증류수 15ml의 혼합 용매를 가하고 L-카르니틴 10g, 오르트산 유리산 9.68g을 가하여 5시간 환류하였다. 반응용액을 20~25℃로 냉각하여 결정을 석출 시키고 여과한 후, 실온에서 24시간 건조시켜 수율 92%의 흰색 결정 L-카르니틴 오르트산염을 얻었다. (18.1g)A mixed solvent of 100 ml of acetone and 15 ml of distilled water was added to a 250 mL three-necked flask, and 10 g of L-carnitine and 9.68 g of ortic acid free acid were added, followed by reflux for 5 hours. The reaction solution was cooled to 20-25°C to precipitate crystals, filtered, and dried at room temperature for 24 hours to obtain white crystals of L-carnitine ortate in a yield of 92%. (18.1 g)
본 발명의 실시예 1에서 제조된 결정형 카르니틴 오르트산염에 대한 Cu-Ka 방사선을 사용하는 X-선 분말 회절분석 (PXRD) 결과를 도 1에 나타내었다. 또한, 본 발명의 실시예 1에서 제조된 결정형 카르니틴 오르트산염에 대한 시차주사 열량(DSC) 분석 결과를 도 2에 나타내었다. 상기 도 1 및 도 2의 분석 결과로부터, 본 발명의 방법에 따라 제조된 화합물이 신규한 결정형 카르니틴 오르트산염에 해당함을 확인할 수 있었다. 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 . In addition, the results of differential scanning calorimetry (DSC) analysis of the crystalline carnitine ortate prepared in Example 1 of the present invention are shown in FIG. 2 . From the analysis results of FIGS. 1 and 2 , it was confirmed that the compound prepared according to the method of the present invention corresponds to a novel crystalline form of carnitine ortate.
또한, 본 발명의 실시예 2에서 제조된 L-카르니틴 오르트산염과 비교예 1에서 제조된 L-카르니틴 오르트산염의 용해도 및 혼탁도를 비교한 사진을 도 3에 나타내었다. 기존의 합성법으로 제조된 비교예 1의 경우 용해되지 않은 불순물로 인해 실시예에 비해 혼탁도가 떨어짐을 확인할 수 있다.In addition, 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 . In the case of 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.

Claims (11)

  1. (1) 반응 용매에 오르트산 및 3차 아민류를 첨가하여 오르트산 3차 아민염을 제조하는 제1단계; 및(1) a first step of preparing an ortic acid tertiary amine salt by adding ortic acid and tertiary amines to a reaction solvent; and
    (2) 오르트산 3차 아민염에 카르니틴 염산염을 첨가하여 카르니틴 오르트산염을 제조하는 제2단계;를 포함하는(2) a second step of preparing carnitine ortate by adding carnitine hydrochloride to ortic acid tertiary amine salt;
    카르니틴 오르트산염의 제조방법.A process for the preparation of carnitine ortate.
  2. 제1항에 있어서, 제1단계의 반응 용매는 메탄올인, 카르니틴 오르트산염의 제조방법.The method of claim 1, wherein the reaction solvent in the first step is methanol.
  3. 제1항에 있어서, 제1단계의 3차 아민류는 트리에틸아민, 트리프로필아민, 트리부틸아민, 메틸피페리딘, 에틸피페리딘 및 이들의 조합으로 이루어진 군으로부터 선택되는 것인, 카르니틴 오르트산염의 제조방법.The method of claim 1, wherein the tertiary amines in the first step are selected from the group consisting of triethylamine, tripropylamine, tributylamine, methylpiperidine, ethylpiperidine, and combinations thereof. A method for producing a torate.
  4. 제1항에 있어서, 제1단계에서 오르트산 1 당량에 대하여 3차 아민류 1 내지 3 당량을 첨가하는, 카르니틴 오르트산염의 제조방법.The method according to claim 1, wherein in the first step, 1 to 3 equivalents of tertiary amines are added with respect to 1 equivalent of ortic acid.
  5. 제1항에 있어서, 제1단계는 20℃ 내지 60℃에서 0.5 내지 3시간 동안 수행되는, 카르니틴 오르트산염의 제조방법.The method of claim 1 , wherein the first step is performed at 20° C. to 60° C. for 0.5 to 3 hours.
  6. 제1항에 있어서, 제2단계에서 오르트산 3차 아민염 1당량에 대하여 카르니틴 염산염 1당량 내지 1.5 당량을 첨가하는, 카르니틴 오르트산염의 제조방법.The method according to claim 1, wherein in the second step, 1 to 1.5 equivalents of carnitine hydrochloride is added with respect to 1 equivalent of ortic acid tertiary amine salt.
  7. 제1항에 있어서, 제2단계는 0℃ 내지 10℃에서 0.5 내지 2시간 동안 수행되는, 카르니틴 오르트산염의 제조방법.The method of claim 1 , wherein the second step is performed at 0° C. to 10° C. for 0.5 to 2 hours.
  8. 제1항 내지 제7항 중 어느 한 항의 방법에 따라 제조된 카르니틴 오르트산염.A carnitine ortate salt prepared according to the method of any one of claims 1 to 7.
  9. 제8항에 있어서, Cu-Ka 방사선을 사용하는 X-선 분말 회절분석 (PXRD)에서 9.6±0.2, 14.9±0.2, 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±0.2, 25.9±0.2, 26.8±0.2, 27.1±0.2, 28.7±0.2, 30.2±0.2 및 31.7±0.2에서 2θ회절각 피크를 나타내는, 카르니틴 오르트산염9. The method of claim 8, wherein in X-ray powder diffraction analysis (PXRD) using Cu-Ka radiation 9.6±0.2, 14.9±0.2, 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±0.2, 25.9±0.2, 26.8±0.2, 27.1±0.2, 28.7±0.2, Carnitine ortate showing 2θ diffraction angle peaks at 30.2±0.2 and 31.7±0.2
  10. 제8항에 있어서, 시차주사 열량(DSC) 분석에서 흡열개시온도 193℃±2℃ 및 흡열온도 197℃±2℃를 나타내는, 카르니틴 오르트산염The method according to claim 8, wherein the differential scanning calorimetry (DSC) analysis shows an endothermic onset temperature of 193°C±2°C and an endothermic temperature of 197°C±2°C, carnitine ortate salt
  11. 하기 화학식 1로 표시되는 오르트산 트리에틸아민염 중간체:Ortic acid triethylamine salt intermediate represented by the following formula (1):
    [화학식 1][Formula 1]
    Figure PCTKR2022002988-appb-img-000005
    Figure PCTKR2022002988-appb-img-000005
    여기서, TEA는 트리에틸아민을 나타낸다.Here, TEA represents triethylamine.
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KR20150014307A (en) * 2013-07-29 2015-02-06 한국생명공학연구원 Pharmaceutical composition for preventing or treating muscle weakness diseases comprising Orotic Acid
CN106045919A (en) * 2016-07-07 2016-10-26 黄冈华阳药业有限公司 Preparation method of L-carnitine orotate
KR20190017310A (en) * 2017-08-10 2019-02-20 주식회사 셀트리온화학연구소 Salts of L-Carnitine Compound with Improved Pharmaceutical Properties, a process for preparing the same, and a pharmaceutical composition containing the same

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