KR102686559B1 - A method for removing polymer impurities in thioctic acid and crystalizing thereof - Google Patents
A method for removing polymer impurities in thioctic acid and crystalizing thereof Download PDFInfo
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- AGBQKNBQESQNJD-UHFFFAOYSA-N alpha-Lipoic acid Natural products OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 title claims abstract description 93
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 title claims abstract description 90
- 229960002663 thioctic acid Drugs 0.000 title claims abstract description 90
- 235000019136 lipoic acid Nutrition 0.000 title claims abstract description 89
- 229920000642 polymer Polymers 0.000 title claims abstract description 63
- 239000012535 impurity Substances 0.000 title claims abstract description 59
- 238000000034 method Methods 0.000 title claims abstract description 41
- 239000003463 adsorbent Substances 0.000 claims abstract description 57
- 239000003960 organic solvent Substances 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000003929 acidic solution Substances 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 16
- 239000000741 silica gel Substances 0.000 claims description 16
- 229910002027 silica gel Inorganic materials 0.000 claims description 16
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 15
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000000746 purification Methods 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 10
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 239000000243 solution Substances 0.000 description 9
- 238000001179 sorption measurement Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 4
- 229940068511 thioctate Drugs 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 229960002446 octanoic acid Drugs 0.000 description 2
- 229910018072 Al 2 O 3 Inorganic materials 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002898 organic sulfur compounds Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
- C07D339/02—Five-membered rings
- C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B63/00—Purification; Separation; Stabilisation; Use of additives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
본 발명에서 제공하는 다량의 폴리머 분순물이 포함된 티옥트산 또는 이의 염의 정제방법은 티옥트산을 유기용매에 용해시키는 단계 및 1 내지 3 가지의 폴리머 흡착제를 첨가하고 산성용액을 적가하여 pH를 5 내지 6으로 조절하는 단계를 포함하여 이루어지는데, 상기와 같은 방법으로 티옥트산을 정제함으로써 종래기술의 문제점이었던 다량의 폴리머 불순물을 완벽하게 제거하기 어렵고 상기 폴리머 불순물의 끈적임으로 티옥트산의 결정화가 어렵다는 것을 용이하게 해결할 수 있다.The method for purifying thioctic acid or its salt containing a large amount of polymer impurities provided by the present invention includes the steps of dissolving thioctic acid in an organic solvent, adding 1 to 3 polymer adsorbents, and adding an acidic solution dropwise to adjust the pH to 5 to 5. It includes the step of adjusting to 6. By purifying thioctic acid using the above method, it is difficult to completely remove a large amount of polymer impurities, which was a problem in the prior art, and it is difficult to crystallize thioctic acid due to the stickiness of the polymer impurities. It can be solved.
Description
본 발명은 폴리머 불순물이 과량 혼합된 티옥트산을 정제하거나 티옥트산염으로부터 티옥트산을 제조하는 단계에 포함된 산(acid)첨가 공정에서 발생하는 폴리머 불순물을 효과적으로 제거하고 상기 티옥트산을 결정화하는 방법에 관한 것이다.The present invention provides a method for effectively removing polymer impurities generated in the acid addition process included in the step of purifying thioctic acid mixed with excessive polymer impurities or producing thioctic acid from thioctate salts and crystallizing the thioctic acid. It's about.
α-리포산(ALA) 또는 리포산(LA)으로 알려진 티옥트산은 카프릴산/옥탄산(caprylic acid/octanoic acid)로부터 유도된 유기 황화합물이다. 티옥트산은 동물에서 정상적으로 만들어지고 호기성 대사과정에서 필수적 요소이며, 일부 국가에서는 항산화제 또는 식이보충제로서 제조되고 또한 의약품으로 판매되고 있다.Thioctic acid, also known as α-lipoic acid (ALA) or lipoic acid (LA), is an organic sulfur compound derived from caprylic acid/octanoic acid. Thioctic acid is produced normally in animals and is an essential component of aerobic metabolism, and in some countries it is manufactured as an antioxidant or dietary supplement and sold as a pharmaceutical.
티옥트산은 융점이 낮고 물성이 까다로워서 제조하기가 용이하지 않다. 특히 제조 또는 정제과정에서 pH 또는 온도조절에 실패한다면 공정과정에서 티옥트산 폴리머 불순물이 반응기벽에 붙어 제조 수율이 저하될 뿐만 아니라 결정화도 어려워서 폴리머 불순물을 제거하고 티옥트산을 결정화하는데 많은 어려움이 있었다.Thioctic acid is not easy to manufacture because it has a low melting point and difficult physical properties. In particular, if pH or temperature control fails during the manufacturing or purification process, thioctic acid polymer impurities stick to the reactor wall during the process, not only lowering the manufacturing yield, but also making crystallization difficult, resulting in many difficulties in removing polymer impurities and crystallizing thioctic acid.
티옥트산의 결정화 방법 또는 티옥트산의 정제 공정에 대해 공지된 방법에서는 시클로헥산, 에틸에테르, 에틸 아세테이트, n-펜탄 등을 용매로 하여 재결정하는 단계로 구성된다. 상기 과정에서 정제된 티옥트산은 여과 및 원심분리에 의해서 회수되고 건조된다(J. Chem. Soc. Perkin Trans. 1 1988, 9, Segre et AL., J. Am. Chem. Soc, 1957, 3503; Walton et Al., J. Am. Chem. Soc, 1955, 77, 5154, Acker et Al., J. Am. Chem. Soc. 1954, 76, 6483).A known method for crystallizing thioctic acid or purifying thioctic acid consists of the step of recrystallization using cyclohexane, ethyl ether, ethyl acetate, n-pentane, etc. as a solvent. Thioctic acid purified in the above process is recovered by filtration and centrifugation and dried (J. Chem. Soc. Perkin Trans. 1 1988, 9, Segre et AL., J. Am. Chem. Soc, 1957, 3503; Walton et al., J. Am. Soc, 1955, 77, 5154, Acker et al., J. Am. Soc.
그러나 상기한 문헌 등에서 제공되는 정제방법은 티옥트산에 존재하는 잔류용매를 제거할 수 없다는 단점이 있다고 알려져 있다However, it is known that the purification method provided in the above-mentioned literature has the disadvantage of not being able to remove the residual solvent present in thioctic acid.
이러한 문제점을 해결하고자 대한민국특허등록공보 제10-1267020호에 개시된 벙법에서는 물로부터 티옥트산을 정제하는 방법을 기술하고 있다.To solve this problem, the method disclosed in Korean Patent Registration No. 10-1267020 describes a method of purifying thioctic acid from water.
또한, 티옥트산에 염기를 가하여 티옥트산염을 제조하고 이에 선택된 산을 첨가하여 적절한 pH범위에서 산성화시켜 티옥트산을 정제하는 방법도 공지되어 있다. 그러나 티옥트산염을 산성화시키는 공정에서 pH 5.5-5.7을 조절하여 극소량의 티옥트산에 첨가된 폴리머 불순물을 제거할 수는 있지만 pH조절 범위가 좁아서 pH조절에 실패할 경우에 과량의 폴리머 불순물이 발생하는 경우에는 이를 제거하기가 어렵고 폴리머 불순물의 끈적임으로 인하여 티옥트산으 결정화하는 것이 매우 어렵다는 단점이 있다. In addition, a method of purifying thioctic acid by adding a base to thioctic acid to prepare thioctic acid salt and adding a selected acid to acidify it in an appropriate pH range is also known. However, in the process of acidifying thioctate, it is possible to remove polymer impurities added to a very small amount of thioctic acid by adjusting pH 5.5-5.7, but the pH control range is narrow, so if pH control fails, excessive polymer impurities are generated. In this case, there is a disadvantage that it is difficult to remove and it is very difficult to crystallize thioctic acid due to the stickiness of the polymer impurities.
결과적으로 상기한 종래의 정제방법은 티옥트산에 존재하는 폴리머 이외의 불순물의 제거에는 효과적이지만 과량의 폴리머 불순물이 혼합된 티옥트산 정제방법으로는 적합하지 못하다.As a result, the conventional purification method described above is effective in removing impurities other than polymers present in thioctic acid, but is not suitable for purifying thioctic acid mixed with an excessive amount of polymer impurities.
본 발명은 상기와 같은 종래의 티옥트산 또는 이의 염의 정제방법의 문제점이었던 티옥트산을 포함하는 혼합물의 pH 조절의 문제점 및 다량의 폴리머 불순물이 존재할 경우에 정제 후에 폴리머 불순물이 완전히 정제되지 않아서 티오트산의 결정화가 어렵고 따라서 티옥트산을 이용한 약물을 이용하여 약제를 제조하는 것이 어렵다는 문제점을 해결하기 위한 것이다.The present invention addresses the problem of controlling the pH of a mixture containing thioctic acid, which was a problem in the conventional purification method of thioctic acid or its salt as described above, and when a large amount of polymer impurities are present, the polymer impurities are not completely purified after purification, resulting in thiocic acid This is to solve the problem that crystallization is difficult and therefore it is difficult to manufacture drugs using drugs using thioctic acid.
상기에 설명한 티옥트산 또는 이의 염을 정제하는 데에 발생하는 문제점을 해결하기 위해서 본 발명에서 제공하는 다량의 폴리머 분순물이 포함된 티옥트산의 정제방법은 티옥트산을 유기용매에 용해시키는 단계 및 1 내지 3 가지의 폴리머 흡착제를 첨가하고 산성용액을 적가하여 pH를 조절하는 단계를 포함하여 이루어지는데, 상기와 같은 방법으로 티옥트산을 정제함으로써 종래기술의 문제점을 해결할 수 있었다.In order to solve the problems arising in purifying thioctic acid or its salt described above, the method for purifying thioctic acid containing a large amount of polymer impurities provided by the present invention includes the steps of dissolving thioctic acid in an organic solvent and 1. It includes the steps of adding to three polymer adsorbents and adding an acidic solution dropwise to adjust the pH. By purifying thioctic acid using the above method, the problems of the prior art could be solved.
본 발명에서 제공하는 티옥트산 또는 이의 염의 정제방법을 이용하여 정제함으로서 폴리머 불순물이 거의 포함되지 않은 티옥트산을 수득할 수 있고, 따라서 티옥트산의 결정화가 용이하여 티옥트산을 이용한 다양한 약물 제형의 제조가 용이하다는 장점이 있다.By purifying thioctic acid or its salt using the purification method provided by the present invention, thioctic acid containing almost no polymer impurities can be obtained. Therefore, crystallization of thioctic acid is easy, making it possible to prepare various drug formulations using thioctic acid. It has the advantage of being easy.
이하 실시예 등을 이용하여 본 발명을 자세히 설명하나, 본 발명의 범위가 하기 실시예에 의해 제한되는 것이 아니고, 상기 실시예는 당 분야에서 통상의 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.The present invention will be described in detail below using examples, etc., but the scope of the present invention is not limited by the following examples, and the examples more fully explain the present invention to those skilled in the art. It is provided for this purpose.
본 발명에서 사용되는 티옥트산이라는 용어는 티옥트산염을 포함하는 용어이다.The term thioctic acid used in the present invention includes thioctate salt.
본 발명은 폴리머 불순물이 과량 혼합된 티옥트산 또는 이의 염을 선택된 유기용매에 용해시키고 1 내지 3가지의 폴리머 흡착제를 단독 또는 상기 흡착제의 혼합물을 제조하여 이를 티옥트산에 추가함으로서 상기 폴리머 불순물을 상기 흡착제에 흡착시켜 제거함으로써 티옥트산의 순도를 높일 수 있고, 따라서 티옥트산의 결정화를 용이하게 할 수 있는 티옥트산의 정제방법에 관한 것이다.The present invention dissolves thioctic acid or a salt thereof mixed with an excessive amount of polymer impurities in a selected organic solvent, prepares 1 to 3 polymer adsorbents alone or a mixture of the adsorbents, and adds them to thioctic acid, so that the polymer impurities are transferred to the adsorbent. It relates to a method for purifying thioctic acid, which can increase the purity of thioctic acid by adsorbing and removing it and thus facilitate the crystallization of thioctic acid.
보다 구체적으로 본 발명에서 제공하는 티옥트산에 포함된 폴리머 불순물을 정제하는 방법은 (1) 물이 포함된 유기용매에 티옥트산염 및 흡착제 단독 또는 흡착제 혼합물을 투입하여 산성용액을 적가하여 pH를 5.0 내지 6.0으로 유지하고 상기 폴리머 불순물을 상기 흡착제에 흡착시키는 단계; (2) 상기 흡착제 혼합물을 여과하고 남은 여액을 층분리하여 수층을 제거하는 단계; (3)상기 층분리된 여액에 유기용매를 추가로 투입하여 티옥트산을 결정화하는 단계;로 이루어지는 것을 특징으로 한다.More specifically, the method for purifying polymer impurities contained in thioctic acid provided by the present invention is (1) adding thioctate and an adsorbent alone or a mixture of adsorbents to an organic solvent containing water and adding the acidic solution dropwise to adjust the pH to 5.0. to 6.0 and adsorbing the polymer impurities to the adsorbent; (2) filtering the adsorbent mixture and separating the remaining filtrate into layers to remove the aqueous layer; (3) crystallizing thioctic acid by additionally adding an organic solvent to the layer-separated filtrate.
상기 정제방법에서 폴리머 불순물을 흡착제에 흡착시키는 단계는 35 내지 40℃에서 수행되는 것이 바람직하다.In the purification method, the step of adsorbing polymer impurities to an adsorbent is preferably performed at 35 to 40°C.
상기 정제방법에서 사용되는 유기용매는 에틸아세테이트, 시클로헥산, n-헵탄 등의 단독 또는 혼합용매가 사용될 수 있다.The organic solvent used in the above purification method may be used alone or as a mixed solvent such as ethyl acetate, cyclohexane, and n-heptane.
상기 정제방법에서 사용되는 상기 폴리머 불순물을 제거하기 위한 흡착제는 활성탄(Activated carbon), 실리카겔(silica gel), 산화알루미늄(Al2O3) 단독 또는 이들의 혼합체를 제조하여 사용할 수 있다.The adsorbent for removing the polymer impurities used in the purification method may be activated carbon, silica gel, aluminum oxide (Al 2 O 3 ) alone or a mixture thereof.
상기 폴리머 불순물을 제거하기 위하여 상기 흡착제 혼합물을 제조하여 사용할 경우에 포함되는 상기 흡착제 각각의 함량비는 활성탄 20 내지 50%, 실리카겔 20 내지 50%, 산화알루미늄 1 내지 50%가 적합하다.When preparing and using the adsorbent mixture to remove the polymer impurities, the appropriate content ratio of each adsorbent included is 20 to 50% activated carbon, 20 to 50% silica gel, and 1 to 50% aluminum oxide.
폴리머 불순물의 함량이 티옥트산 또는 이의 염의 중량 대비 5중량%이내일 경우에는 상기 흡착제를 단독으로 사용할 수 있고, 이때에 상기 흡착제의 함량은 티옥트산 또는 티옥트산염의 중량대비 5 내지 10중량%가 사용될 수 있으며, 상기 폴리머 불순물의 함량이 티옥트산 또는 이의 염의 중량 대비 5%중량 이상일 경우에는 상기 흡착제 혼합물을 티옥트산 또는 티옥트산염의 중량대비 30중량%까지 사용할 수 있다.If the content of polymer impurities is less than 5% by weight based on the weight of thioctic acid or its salt, the adsorbent can be used alone, and in this case, the content of the adsorbent is 5 to 10% by weight based on the weight of thioctic acid or its salt. It can be used, and when the content of the polymer impurities is more than 5% by weight compared to the weight of thioctic acid or its salt, the adsorbent mixture can be used up to 30% by weight based on the weight of thioctic acid or thioctic acid salt.
상기 정제과정에서 흡착제 또는 흡착제 혼합물을 첨가하여 상기 폴리머 불순물을 제거할 경우에 적용되는 흡착 온도는 35 내지 40℃에서 수행할 때에 상기 폴리머 불순물의 함량이 가장 적은 결과를 수득하였다.When removing the polymer impurities by adding an adsorbent or adsorbent mixture in the purification process, the lowest content of the polymer impurities was obtained when the adsorption temperature applied was 35 to 40°C.
상기 흡착제 혼합물의 사용량은 폴리머 불순물의 함량이 티옥트산의 중량 대비 5중량%이내일 경우에는 티옥트산 중량대비 5 내지 10중량%가 가장 적합하였고, 상기 폴리머 불순물의 함량이 티옥트산의 중량 대비 5중량% 이상일 경우에는 상기 흡착제 혼합물을 티옥트산 또는 티옥트산염의 중량대비 30중량%까지 사용할 수 있다.The most appropriate amount of the adsorbent mixture used was 5 to 10% by weight based on the weight of thioctic acid when the content of polymer impurities was within 5% by weight compared to the weight of thioctic acid, and the content of the polymer impurities was 5% by weight compared to the weight of thioctic acid. % or more, the adsorbent mixture can be used up to 30% by weight based on the weight of thioctic acid or thioctate salt.
아래의 표 1은 상기 흡착제의 혼합비율에 따른 폴리머 불순물의 함량을 HPLC로 분석한 값을 나타낸다.Table 1 below shows the content of polymer impurities according to the mixing ratio of the adsorbent analyzed by HPLC.
티옥트산에 포함된 폴리머 불순물의 함량: 5중량%Content of polymer impurities in thioctic acid: 5% by weight
유기용매로서는 시클로헥산과 에틸아세테이트를 90:10의 함량비율로 사용함As an organic solvent, cyclohexane and ethyl acetate are used in a content ratio of 90:10.
상기 흡착체와 사용할 수 있는 유기용매로는 에틸아세테이트, 시클로헥산, n-헵탄이며, 상기 유기용매 단독 또는 혼합용매로 사용할 수 있다.Organic solvents that can be used with the adsorbent include ethyl acetate, cyclohexane, and n-heptane, and the organic solvents can be used alone or as a mixed solvent.
상기 유기용매 종류에 따라 최종적으로 정제되고 수득한 티옥트산에 포함된 폴리머 불순물의 함량에는 큰 차이가 없었으나, 상기 티옥트산의 수율 및 결정의 성상에 있어서는 현저한 차이를 나타냈다.There was no significant difference in the content of polymer impurities contained in the finally purified and obtained thioctic acid depending on the type of organic solvent, but there was a significant difference in the yield and crystal properties of the thioctic acid.
하기한 표 2에는 상기 유기용매 사용에 따른 티옥트산의 수율 및 결정의 성상을 나타냈는데, 상기 유기용매로서 시클로헥산 90%에 에틸아세테이트 10% 혼합액을 사용할 때에 상기 티옥트산의 수율 및 결정의 성상이 모두 만족하는 결과를 나타냈다.Table 2 below shows the yield and crystal properties of thioctic acid according to the use of the organic solvent. When a mixture of 90% cyclohexane and 10% ethyl acetate was used as the organic solvent, the yield of thioctic acid and the crystal properties were All showed satisfactory results.
또한, 본 발명에서는 라세미 티옥트산을 선택된 광학활성체 염기와 반응시켜 R 또는 S의 광학활성을 나타내는 티옥트산염을 수득하고, 여기에 산성용액을 가하여 R 또는 S 광학활성체의 티옥트산을 제조한 후에 상기 흡착제 혼합물을 첨가하여 폴리머 불순물을 제거함으로써 상기 R 또는 S 티옥트산의 결정화를 용이하게 할 수 있었다.In addition, in the present invention, racemic thioctic acid is reacted with a selected optically active base to obtain a thioctic acid salt showing optical activity of R or S, and an acidic solution is added thereto to prepare thioctic acid of R or S optically active substance. After this, the adsorbent mixture was added to remove polymer impurities, thereby facilitating crystallization of the R or S thioctic acid.
본 발명에서 제공하는 티옥트산의 정제방법은 (1) 물이 혼합된 유기용매에 R-티옥트산염 및 선택된 흡착제 혼합물을 투입하고 산성용액을 적가하여 pH를 5.0 내지 6.0으로 유지하고 폴리머 불순물을 상기 흡착제에 흡착시키는 단계, (2) 상기 흡착제 혼합물을 여과하고 남은 여액을 층분리하여 수층을 제거하는 단계, (3) 상기 층분리한 유기용매에 적절한 용매를 추가 투입하여 R-티옥트산을 결정화하는 단계를 수행하였을 때에 R-티옥트산의 수득율 및 결정성상이 가장 우수한 결과는 나타내어, 종래기술에 제시된 정제방법을 적용하였을 때보다, 상기 R-티옥트산에 존재하는 폴리머 불순물을 제거하는 공정에 상기 흡착제 단독 또는 흡착제 혼합물을 사용하여 상기 폴리머 분순물을 제거하는 것이 훨씬 탁월하다는 것을 보여준다. The method for purifying thioctic acid provided by the present invention is (1) adding R-thioctate and a selected adsorbent mixture to an organic solvent mixed with water, adding an acidic solution dropwise to maintain pH at 5.0 to 6.0, and removing polymer impurities as described above. Adsorbing to an adsorbent, (2) filtering the adsorbent mixture and separating the remaining filtrate to remove the aqueous layer, (3) adding an appropriate solvent to the separated organic solvent to crystallize R-thioctic acid. When the step was performed, the yield and crystalline phase of R-thioctic acid were the best, showing that the adsorbent was used in the process of removing polymer impurities present in the R-thioctic acid compared to when the purification method presented in the prior art was applied. It is shown that the removal of these polymer impurities using adsorbents alone or in combination is far superior.
본 발명에서 사용되는 산성 용액은 인산, 염산, p-톨루엔설폰산, 포름산 등에서 선택되는 어느 하나를 사용할 수 있으며, 가장 바람직하게는 인산이다.The acidic solution used in the present invention may be any one selected from phosphoric acid, hydrochloric acid, p-toluenesulfonic acid, formic acid, etc., most preferably phosphoric acid.
본 발명에서 사용되는 흡착제는 활성탄, 실리카겔, 산화알루미늄 등의 단독 또는 이들 흡착제의 혼합물을 사용할 수 있으며, 그 함량은 티옥트산염 중량에 대하여 1 내지 30 중량%내에서 수행할 수 있다.The adsorbent used in the present invention can be activated carbon, silica gel, aluminum oxide, etc., alone or a mixture of these adsorbents, and the content can be within 1 to 30% by weight based on the weight of thioctate.
상기 흡착체 단독 또는 흡착제 혼합물과 사용할 수 있는 유기용매로는 에틸아세티이트, 시클로헥산, n-헵탄이 단독 또는 이의 혼합물이며, 폴리머 불순물을 제거하기 위한 흡착온도는 35 내지 40℃에서 상기 흡착제의 흡착 효율이 가장 바람직한 결과를 나타내었다.Organic solvents that can be used with the adsorbent alone or with the adsorbent mixture include ethyl acetite, cyclohexane, and n-heptane alone or a mixture thereof, and the adsorption temperature for removing polymer impurities is 35 to 40° C. Adsorption efficiency showed the most desirable results.
하기한 표 3은 온도에 따른 상기 흡착제의 효율을 나타내었다.Table 3 below shows the efficiency of the adsorbent according to temperature.
흡착용매: 에틸아세테이트Adsorption solvent: ethyl acetate
35% 인산을 물에 희석한 후 상기 희석용액으로 pH를 5.0 내지 6.0으로 조절함After diluting 35% phosphoric acid in water, adjust the pH to 5.0 to 6.0 with the diluted solution.
실시예 1Example 1
티옥트산(폴리머 불순물 함량 5.0%) 100g을 시클로헥산 900ml 및 에틸아세테이트 100ml의 혼합액에 넣고 35~40℃에서 용해시킨다.Add 100 g of thioctic acid (polymer impurity content 5.0%) to a mixture of 900 ml of cyclohexane and 100 ml of ethyl acetate and dissolve at 35-40°C.
흡착제로서 활성탄:실리카겔:산화알루미늄의 함량비를 40:50:10으로 하여 제조된 흡착제 혼합물 10g을 첨가하고 30분간 교반시킨 후 여과하여 상기 흡착제 혼합물을 제거한다.As an adsorbent, 10 g of an adsorbent mixture prepared with a content ratio of activated carbon: silica gel: aluminum oxide of 40:50:10 was added, stirred for 30 minutes, and then filtered to remove the adsorbent mixture.
남은 여액을 5~10℃로 냉각하여 여과한 후에 35~40℃에서 건조시켜 90g의 티옥트산을 수득하였다.The remaining filtrate was cooled to 5~10℃, filtered, and dried at 35~40℃ to obtain 90g of thioctic acid.
상기 티옥트산에 포함된 폴리머 불순물 함량: 0.04%Polymer impurity content contained in the thioctic acid: 0.04%
실시예 2Example 2
티옥트산(폴리머 불순물 함량 5.0%) 100g을 시클로헥산 900ml 및 에틸아세테이트 100ml의 혼합액에 넣고 35~40℃에서 용해시킨다.Add 100 g of thioctic acid (polymer impurity content 5.0%) to a mixture of 900 ml of cyclohexane and 100 ml of ethyl acetate and dissolve at 35-40°C.
흡착제로서 활성탄:실리카겔:산화알루미늄의 함량비를 50:40:10으로 하여 제조된 흡착제 혼합물 10g을 넣고 30분간 교반시킨 후 여과하여 상기 흡착제를 제거한다. 여액을 5~10℃로 냉각하여 여과한 후 35~40℃에서 건조시켜 90g의 티옥트산을 수득하였다.As an adsorbent, 10 g of an adsorbent mixture prepared with a content ratio of activated carbon: silica gel: aluminum oxide of 50:40:10 was added, stirred for 30 minutes, and then filtered to remove the adsorbent. The filtrate was cooled to 5~10℃, filtered, and dried at 35~40℃ to obtain 90g of thioctic acid.
상기 티옥트산에 포함된 폴리머 불순물의 함량: 0.06%Content of polymer impurities contained in the thioctic acid: 0.06%
실시예 3Example 3
티옥트산(폴리머 불순물 함량 5.0%) 100g을 시클로헥산 900ml 및 에틸아세테이트 100ml의 혼합액에 넣고 35~40℃에서 용해시킨다.Add 100 g of thioctic acid (polymer impurity content 5.0%) to a mixture of 900 ml of cyclohexane and 100 ml of ethyl acetate and dissolve at 35-40°C.
흡착제로서 활성탄:실리카겔의 함량비를 50:50으로 하여 흡착제 혼합물을 제조한 후에 상기 흡착제 혼합물 10g을 넣고 30분간 교반시킨 후 여과하여 흡착제를 제거한다. 여액을 5~10℃로 냉각하여 여과한 후 35~40℃에서 건조시켜 90g의 티옥트산을 수득하였다.After preparing an adsorbent mixture using the activated carbon:silica gel content ratio of 50:50 as the adsorbent, 10 g of the adsorbent mixture was added, stirred for 30 minutes, and then filtered to remove the adsorbent. The filtrate was cooled to 5~10℃, filtered, and dried at 35~40℃ to obtain 90g of thioctic acid.
상기 티옥트산에 포함된 폴리머 불순물의 함량: 0.09%Content of polymer impurities contained in the thioctic acid: 0.09%
비교예 1Comparative Example 1
티옥트산(폴리머 불순물 함량 5.0%) 100g을 10℃에서 물 2,900ml에 현탁하였다. 30% 소듐히드록시수용액 62g을 1시간에 걸쳐 적가하여 pH 9인 용액을 얻는다. 상기 용액을 진공에서 여과하고 5℃까지 냉각한다. 여기에 8% 인산 수용액을 pH 5.5를 얻을 때까지 90분에 걸쳐 적가한 후에 생성된 반응물을 여과하여 30~35℃에서 건조시켜 90g의 티옥트산을 수득하였다.100 g of thioctic acid (polymer impurity content 5.0%) was suspended in 2,900 ml of water at 10°C. Add 62 g of 30% sodium hydroxy aqueous solution dropwise over 1 hour to obtain a solution with pH 9. The solution is filtered under vacuum and cooled to 5°C. An 8% aqueous phosphoric acid solution was added dropwise over 90 minutes until pH 5.5 was obtained, and the resulting reaction product was filtered and dried at 30-35°C to obtain 90g of thioctic acid.
상기 티옥트산에 포함된 폴리머 불순물의 함량: 4.8%Content of polymer impurities contained in the thioctic acid: 4.8%
실시예 4Example 4
(R)-티옥트산-(R)-메틸벤질아민염 100g을 에틸아세테이트 300ml 및 물 100ml에 현탁시키고 폴리머 제거용 흡착제 혼합물(활성탄:실리카겔:산화알루미늄의 함량비가 50:40:10)을 투입하고, 35~40℃에서 30분간 교반시킨 후에 5~10℃로 냉각한 후에 35% 인산용액을 물에 10배 희석시킨 용액 30ml를 30분간 적가시켜 pH 5.4로 유지하였다.100 g of (R)-thioctic acid-(R)-methylbenzylamine salt was suspended in 300 ml of ethyl acetate and 100 ml of water, and an adsorbent mixture for polymer removal (activated carbon: silica gel: aluminum oxide content ratio of 50:40:10) was added. , After stirring at 35-40℃ for 30 minutes, cooling to 5-10℃, 30ml of a 35% phosphoric acid solution diluted 10 times in water was added dropwise over 30 minutes to maintain pH at 5.4.
상기 흡착제 혼합물을 여과하고 여액을 층분리 하여 물을 제거하고 시클로헥산 2,700ml를 투입한 후에 0~5℃에서 3시간 교반하였다. 상기 용액을 여과한 후에 시클로헥산 100ml로 세척한 후 35~40℃에서 진공건조시켜 56.0g(수율: 89.0%)의 (R)-티옥트산을 수득하였다The adsorbent mixture was filtered, the filtrate was separated into layers to remove water, and 2,700 ml of cyclohexane was added and stirred at 0-5°C for 3 hours. The solution was filtered, washed with 100 ml of cyclohexane, and dried under vacuum at 35-40°C to obtain 56.0 g (yield: 89.0%) of (R)-thioctic acid.
상기 티옥트산에 포함된 폴리머 불순물의 함량: 0.08%Content of polymer impurities contained in the thioctic acid: 0.08%
비교예 2Comparative Example 2
(R)-티옥트산-(R)-메틸벤질아민염 100g을 에틸 아세테이트 300ml 및 물 100ml에 현탁시키고 5~10℃로 냉각한 후 35% 인산용액을 물에 10배 희석시킨 용액 30ml를 30분간 적가하여 pH 5.4로 유지하였다.Suspend 100 g of (R)-thioctic acid-(R)-methylbenzylamine salt in 300 ml of ethyl acetate and 100 ml of water, cool to 5-10°C, and add 30 ml of 35% phosphoric acid solution diluted 10 times in water for 30 minutes. It was added dropwise and the pH was maintained at 5.4.
상기 용액을 층분리 하여 물을 제거한 후에 시클로헥산 2,700ml를 투입하고 0~5℃에서 3시간 교반하였다. 상기 용액을 여과하고 시클로헥산 100ml로 세척한 후에 35~40℃에서 진공건조시켜 56.8g(수율: 90.3%)의 (R)-티옥트산을 수득하였다.After the solution was separated into layers to remove water, 2,700 ml of cyclohexane was added and stirred at 0-5°C for 3 hours. The solution was filtered, washed with 100 ml of cyclohexane, and dried under vacuum at 35-40°C to obtain 56.8 g (yield: 90.3%) of (R)-thioctic acid.
상기 티옥트산에 포함된 폴리머 불순물 함량: 0.5%Polymer impurity content contained in the thioctic acid: 0.5%
상기에서는 본 발명에서 제공하는 티옥트산의 정제방법을 수행한 결과를 설명하기 위해서 실시예를 제시하였으나, 본 발명의 범위가 상기 실시예에 의해 한정되는 것이 아님은 통상의 기술자에게는 자명한 것이다.In the above, examples were presented to explain the results of performing the method for purifying thioctic acid provided by the present invention, but it is obvious to those skilled in the art that the scope of the present invention is not limited by the examples.
본 발명은 산업상이용가능하다.The present invention is applicable industrially.
Claims (10)
물이 포함된 유기용매에 티옥트산 또는 이의 염 및 흡착제 혼합물을 투입하여 산성용액을 적가하여 pH를 5.0 내지 6.0으로 유지하고 상기 폴리머 불순물을 상기 흡착제에 흡착시키는 단계;
상기 흡착제 혼합물을 여과하고 남은 여액을 층분리하여 수층을 제거하는 단계;
상기 층분리된 여액에 유기용매를 추가로 투입하여 티옥트산을 결정화하는 단계;로 이루어지는 것을 특징으로 하며,
상기 흡착제 혼합물은 활성탄, 실리카겔 및 산화알루미늄을 혼합하여 형성되고 상기 각 성분의 혼합비율은 활성탄 20 내지 50%, 실리카겔 20 내지 50% 및 산화알루미늄 1 내지 50%인 것을 특징으로 하는 티옥트산 또는 이의 염에 포함된 폴리머 불순물을 정제하는 방법
Regarding a method for purifying polymer impurities contained in thioctic acid or its salt, the purification method includes
Adding thioctic acid or a salt thereof and an adsorbent mixture to an organic solvent containing water, adding an acidic solution dropwise to maintain pH at 5.0 to 6.0, and adsorbing the polymer impurities to the adsorbent;
filtering the adsorbent mixture and separating the remaining filtrate into layers to remove the water layer;
Characterized by comprising the step of crystallizing thioctic acid by additionally adding an organic solvent to the layer-separated filtrate,
The adsorbent mixture is formed by mixing activated carbon, silica gel, and aluminum oxide, and the mixing ratio of each component is 20 to 50% activated carbon, 20 to 50% silica gel, and 1 to 50% aluminum oxide. Thioctic acid or a salt thereof Method for purifying polymer impurities contained in
The method of claim 1, wherein the organic solvent is at least one selected from cyclohexane, ethyl acetate, and n-heptane.
The method of claim 1, wherein the content ratio of activated carbon, silica gel, and aluminum oxide contained in the adsorbent mixture is 50:40:10 to 40:50:10. method
The method of claim 1, wherein the acidic solution is any one selected from phosphoric acid, hydrochloric acid, p-toluenesulfonic acid, and formic acid.
The method of claim 1, wherein the organic solvent further included in the layer-separated filtrate is cyclohexane.
The method according to any one of claims 1, 2, and 5 to 7, wherein the step of adsorbing the polymer impurities to the adsorbent is performed at 35 to 40 ° C. Method for purifying contained polymer impurities
The method of claim 1, wherein when the content of the polymer impurities is 1 to 5% by weight based on the weight of thioctic acid or its salt, the content of the adsorbent is 5 to 10% by weight based on the weight of thioctic acid or thioctic acid. Method for purifying polymer impurities contained in its salts
The method of claim 1, wherein when the content of the polymer impurities is 5% by weight or more based on the weight of thioctic acid or its salt, the content of the adsorbent is 10 to 30% by weight based on the weight of thioctic acid or its salt. Method for purifying polymer impurities contained in
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| US5281722A (en) | 1991-11-16 | 1994-01-25 | Degussa Ag | Preparation and use of salts of the pure enantiomers of alpha-lipoic acid |
| JP2006510621A (en) * | 2002-11-26 | 2006-03-30 | ビーエーエスエフ アクチェンゲゼルシャフト | Method for purifying lipoic acid |
| CN102603709A (en) | 2012-03-02 | 2012-07-25 | 海南灵康制药有限公司 | Thioctic acid compound and preparation method thereof |
| CN113292533A (en) | 2021-05-25 | 2021-08-24 | 四川智强医药科技开发有限公司 | Method for purifying polymer impurities in lipoic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5281722A (en) | 1991-11-16 | 1994-01-25 | Degussa Ag | Preparation and use of salts of the pure enantiomers of alpha-lipoic acid |
| JP2006510621A (en) * | 2002-11-26 | 2006-03-30 | ビーエーエスエフ アクチェンゲゼルシャフト | Method for purifying lipoic acid |
| CN102603709A (en) | 2012-03-02 | 2012-07-25 | 海南灵康制药有限公司 | Thioctic acid compound and preparation method thereof |
| CN113292533A (en) | 2021-05-25 | 2021-08-24 | 四川智强医药科技开发有限公司 | Method for purifying polymer impurities in lipoic acid |
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