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CN111247127B - Process for the production of intermediate compounds for the synthesis of medicaments - Google Patents

Process for the production of intermediate compounds for the synthesis of medicaments Download PDF

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Publication number
CN111247127B
CN111247127B CN201880067548.4A CN201880067548A CN111247127B CN 111247127 B CN111247127 B CN 111247127B CN 201880067548 A CN201880067548 A CN 201880067548A CN 111247127 B CN111247127 B CN 111247127B
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formula
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CN111247127A (en
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朴钟元
李锡柱
柳仁爱
金奉赞
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LG Chem Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/02—Monohydroxylic acyclic alcohols
    • C07C31/04—Methanol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D211/74—Oxygen 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C61/12—Saturated polycyclic compounds
    • C07C61/125—Saturated polycyclic compounds having a carboxyl group bound to a condensed ring system
    • C07C61/13—Saturated polycyclic compounds having a carboxyl group bound to a condensed ring system having two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to a method of treating a compound of formula 2 by reacting a carboxylic acid protecting group (P 2 ) A method for preparing a compound of formula 1 by selective deprotection, wherein the compound of formula 1 is an essential intermediate for synthesizing an antidiabetic agent for inhibiting DPP-IV.

Description

Process for the production of intermediate compounds for the synthesis of medicaments
Technical Field
Cross Reference to Related Applications
The present application claims priority based on korean patent application No. 10-2017-0153334 filed on 11/16/2018 and korean patent application No. 10-2018-01266663 filed on 10/23/2018, and the entire contents of the disclosures in said korean patent applications are incorporated herein by reference.
The present invention relates to a method for preparing a compound of formula 1, which is an essential intermediate for inhibiting the synthesis of antidiabetic agents of dipeptidyl peptidase IV (hereinafter also referred to as "DPP-IV").
Background
It is known that the compound disclosed in international application publication WO 12/030106, which is useful as an antidiabetic agent for inhibiting dipeptidyl peptidase IV (DPP-IV) (see the compound of chemical formula 1 of international application publication WO 12/030106), exhibits excellent inhibitory activity against DPP-IV enzyme, and thus is useful for treating and preventing diseases caused by the enzyme, including diabetes, obesity, etc. In the preparation of such DPP-IV inhibitor compounds, international application publication WO 12/030106 discloses a method for preparing the same from a compound of the following chemical formula 1 as an essential intermediate.
[ chemical formula 1]
On the other hand, heretofore, in order to prepare the compound of chemical formula 1, a carboxylic acid protecting group (P 2 ) Deprotection to give the compound of formula 1. Specifically, the protecting group in the compound of chemical formula 2 is a butoxycarbonyl group (P 1 Boc) and the leaving group is a tert-butyl group (P 2 ) In the case of (a), the compound of chemical formula 1 is prepared as follows: (1) By using acidic conditions (in particular strong acids such as sulfuric acid), methylene chloride, aqueous sodium hydroxide and di-tert-butyl carbonate (Boc) 2 O) hydrolysis of the protecting group P 2 To deprotect it, or (2) hydrolyze protecting group P by using alkaline conditions (especially aqueous sodium hydroxide solution) and ethanol, water reflux conditions 2 And deprotect it. In particular, when P 2 When a benzyl group, a methyl group, an ethyl group and an isopropyl group are used, hydrolysis conditions using a base specified in (2) of the two conditions are employed.
[ chemical formula 2]
However, such a method of preparing the compound of chemical formula 1 has disadvantages in that the reaction is performed under substantially non-stringent conditions and a large amount of reaction solvent should be used, and an additional concentration process is required.
Disclosure of Invention
Technical problem
Accordingly, the present inventors have conducted intensive studies to solve the above-mentioned drawbacks of the prior art, and as a result, have confirmed that when sodium hydroxide in solid form is particularly used among bases, the yield can be significantly improved under mild conditions, and that economic feasibility and productivity are high because a small amount of reaction solvent is used but economical and no additional concentration process is required.
Accordingly, an object of the present invention is to provide a method for preparing a compound of formula 1, which is an intermediate for synthesizing an antidiabetic agent that inhibits DPP-IV, by using sodium hydroxide under alkaline conditions, which can significantly improve yield even under mild conditions, and which has high economic feasibility and productivity because a small amount of reaction solvent is used and no additional concentration process is required, unlike conventional methods.
Technical solution
As one aspect for solving the problem, the present invention relates to a method for preparing a compound of formula 1, characterized in that the method comprises the steps of: for two protecting groups of the compound of formula 2 (i.e., P 1 And P 2 ) Carboxylic acid protecting groups (P) among the protecting groups 2 ) Selective deprotection is performed and the deprotection is performed by using a base in solid form and a lower alcohol.
Advantageous effects
The preparation method of the present invention is very useful because it has the following advantages: 1) a compound of formula 1, which is an intermediate of an oral insulin-independent antidiabetic agent by inhibiting DPP-IV, can be produced in high yield even under mild conditions, 2) production costs are reduced by reducing the amount of a reaction solvent, and thus economical, and 3) improvement effects such as improvement in productivity can be achieved by eliminating a concentration process.
Detailed Description
Hereinafter, the present invention will be described in detail based on the reaction formula. However, the following equations are intended to aid in understanding the present invention and are not intended to limit the present invention in any sense.
For the purpose of illustrating the preparation method of the present invention, it is shown in the following reaction scheme 1.
[ reaction type 1]
Wherein R1, R2, R3 and R4 are each independently hydrogen, halogen, or substituted or unsubstituted C 1 -C 4 An alkyl group. P (P) 1 Is an amine protecting group and is a carbonyl group, an acyl group, a sulfonyl group, an acetyl group or a benzyl group, and preferably P 1 Boc (butoxycarbonyl), cbz (benzyloxycarbonyl) or Fmoc (9-fluorenylmethoxycarbonyl), more preferably Boc. P (P) 2 Is a carboxylic acid protecting group and is preferably a benzyl group, an ethyl group, an isopropyl group or a tert-butyl group, more preferably a tert-butyl group.
In the present invention, one feature of the present invention is that when the compound represented by the formula 2 is prepared by reacting a carboxylic acid protecting group (P 2 ) In deprotection to give the compound of chemical formula 1, a base in solid form is used as a reaction base, unlike the previous use of an aqueous solution or a base in liquid form (e.g., aqueous sodium hydroxide solution, etc.). The base used in the present invention in the solid form may be sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide or a combination thereof, and preferably, the compound of chemical formula 1 is obtained by using sodium hydroxide solid.
The amount of the reaction base to be used is preferably 1 to 4 equivalents, preferably 1 to 2 equivalents, based on the compound of chemical formula 2.
In addition, as the reaction solvent used in the reaction, a lower alcohol having 1 to 6 carbon atoms and a mixed solvent thereof are used. Specifically, the lower alcohol having 1 to 6 carbon atoms may be one or more selected from methanol, ethanol, isopropanol and mixed alcohols (co-solvents) thereof, and preferably, ethanol may be used. The amount of the reaction solvent used is 1-fold (mL/g) to 7-fold (mL/g), preferably 2-fold (mL/g) to 3-fold (mL/g), of the compound of formula 2. Unlike the method of preparing chemical formula 1 according to conventional alkaline conditions, the reaction solvent of the present invention is characterized in that a small amount of the reaction solvent is used.
Specifically, the reaction temperature during deprotection may vary depending on the reaction conditions, but in the case of the present invention, the reaction may be performed at a temperature lower than the reflux conditions (e.g., 30 to 80 ℃) due to technical features. The reaction time may be preferably 1 to 6 hours, more preferably 3 hours or less, but is not limited thereto.
As another aspect, the preparation method of the present invention may further include a step of crystallizing the compound of formula 1 obtained according to the above method. The solvent used for crystallization may be one or more solvents selected from water, methanol, ethanol, isopropanol and a mixed solvent (co-solvent) thereof, but is not limited thereto, and it is preferably water or a mixed solvent of ethanol and water. In the crystallization step, crystals can be produced by controlling the pH using an acid, and the pH is preferably 2.5 to 3.0.
Hereinafter, the present invention will be described in more detail with reference to preparation examples and examples, which are intended to aid in understanding the present invention, and the scope of the present invention is not limited thereto in any way.
Detailed Description
Example 1: synthesis of (3S) -3-t-Butoxycarbonylamino-4- (5, 5-difluoro-2-oxopiperidinyl) butanoic acid
After 462.3kg of t-butyl (3S) -3-t-butoxycarbonylamino-4- (5, 5-difluoro-2-oxopiperidinyl) butyrate, 729.6kg of ethanol, and 82.2kg of sodium hydroxide were added as starting materials to the reactor at room temperature, the temperature was raised to a range of 40 to 50℃and allowed to react for 3 hours. After the completion of the reaction, 3699kg of water was added, and 3N aqueous hydrochloric acid was added dropwise to control pH to 2.5 to 3.0, and crystallization was carried out. The title compound was produced as a solid which was filtered and washed with a mixed solution of water and ethanol, t-butyl methyl ether, and then dried to obtain 347.6kg of the title compound (content: 97.5%, yield: 85.5%).
1 H NMR(500MHz,DMSO-d6)δ1.32(s,9H),2.20-2.43(m,6H),3.26-3.31(m,2H),3.61(m,1H),3.81(m,1H),4.02(m,1H),6.73(d,J＝8.6Hz,1H),12.16(s,1H)。
Example 2: synthesis of (3S) -3-t-Butoxycarbonylamino-4- (5, 5-difluoro-2-oxopiperidinyl) butanoic acid
After 412.2kg of t-butyl (3S) -3-t-butoxycarbonylamino-4- (5, 5-difluoro-2-oxopiperidinyl) butyrate, 2049.0kg of ethanol and 299.7kg of 6N aqueous sodium hydroxide solution as starting materials were added to the reactor, the reflux reaction was carried out at an elevated temperature. After the reaction was completed, it was concentrated and 1649kg of water was added to dissolve it. The aqueous layer was washed with 1221.8kg of t-butyl methyl ether, and a 3N aqueous hydrochloric acid solution was added dropwise to control the pH to 3.0 to 3.5, and a crystallization process was performed. The title compound was produced as a solid which was filtered and washed with water and t-butyl methyl ether, and then dried to obtain 309.8kg of the title compound (content: 97.4%, yield: 85.4%).
Example 3: synthesis of (3S) -3-t-Butoxycarbonylamino-4- (5, 5-difluoro-2-oxopiperidinyl) butanoic acid
After 449.2kg of t-butyl (3S) -3-t-butoxycarbonylamino-4- (5, 5-difluoro-2-oxopiperidinyl) butyrate, 2033.0kg of ethanol and 361.9kg of 6N aqueous sodium hydroxide solution were added as starting materials, reflux reaction was performed at an elevated temperature. After the reaction was completed, it was concentrated and 1796.9kg of water was added to dissolve it. 354.4kg of ethanol was added and 3N aqueous hydrochloric acid was added dropwise to control pH at first 4.1 to 5.0 and then 2.5 to 3.0, and crystallization was carried out. The title compound was produced as a solid which was filtered and washed with a mixed solution of water and ethanol, and then dried to obtain 325.0kg of the title compound (content: 95.5%, yield: 80.6%).
Example 4: synthesis of (3S) -3-t-Butoxycarbonylamino-4- (5, 5-difluoro-2-oxopiperidinyl) butanoic acid
After 43.0g of t-butyl (3S) -3-t-butoxycarbonylamino-4- (5, 5-difluoro-2-oxopiperidinyl) butyrate, 213.7g of ethanol and 8.8g of a 6N aqueous sodium hydroxide solution were added as starting materials, reflux reaction was performed at an elevated temperature. After the reaction was completed, it was concentrated and 172.0g of water was added to dissolve it. 33.9g of ethanol was added and 3N aqueous hydrochloric acid was added dropwise to control pH at first 4.1 to 5.0 and then 2.5 to 3.0, and crystallization was carried out. The title compound was produced as a solid which was filtered and washed with a mixed solution of water and ethanol, and then dried to obtain 35.5g of the title compound (content: 93.0%, yield: 89.6%).
Example 5: synthesis of (3S) -3-t-Butoxycarbonylamino-4- (5, 5-difluoro-2-oxopiperidinyl) butanoic acid
After 43.0g of tert-butyl (3S) -3-t-butoxycarbonylamino-4- (5, 5-difluoro-2-oxopiperidinyl) butyrate, 67.9g of ethanol and 8.8g of sodium hydroxide were added as starting materials, the temperature was raised to 70℃for reaction. After the reaction was completed, it was cooled and 344.0g of water was added. A 3N aqueous hydrochloric acid solution was added dropwise to control the pH at first to 4.1 to 5.0, then to 2.5 to 3.0, and a crystallization process was performed. The title compound was produced as a solid which was filtered and washed with a mixed solution of water and ethanol, and then dried to obtain 37.7g of the title compound (content: 92.4%, yield: 94.4%).
Example 6: synthesis of (3S) -3-t-Butoxycarbonylamino-4- (5, 5-difluoro-2-oxopiperidinyl) butanoic acid
After 43.0g of tert-butyl (3S) -3-t-butoxycarbonylamino-4- (5, 5-difluoro-2-oxopiperidinyl) butyrate, 67.9g of ethanol and 8.8g of sodium hydroxide were added as starting materials, the temperature was raised to 30℃for reaction. After the reaction was completed, it was cooled and 344.0g of water was added. A 3N aqueous hydrochloric acid solution was added dropwise to control the pH at first to 4.1 to 5.0, then to 2.5 to 3.0, and a crystallization process was performed. The title compound was produced as a solid which was filtered and washed with a mixed solution of water and ethanol, and then dried to obtain 37.7g of the title compound (content: 94.1%, yield: 94.2%).
Experimental example: comparison of (3S) -3-t-Butoxycarbonylamino-4- (5, 5-difluoro-2-oxopiperidine according to preparation conditions Yield of base) butyric acid
In order to compare the yields of the compounds of chemical formula 1 according to the base, reaction temperature and reaction solvent used, the compounds of chemical formula 1 were prepared from the compounds of chemical formula 2, which were prepared according to the conditions of table 1 below, and the results are also shown in table 1.
TABLE 1 comparison of yields of the compounds of chemical formula 1 according to the base, reaction temperature and reaction solvent used
As can be seen from the results of the comparative experiments described in table 1, it was confirmed that when a solid base such as sodium hydroxide solid is used (items 4 to 6), the amount of the reaction solvent can be reduced and the reaction can be performed at a temperature lower than the reflux condition, as compared with an alkaline aqueous solution such as sodium hydroxide aqueous solution, thereby obtaining the compound of chemical formula 1 in a higher yield. This is preferable because, when the reaction solvent is reduced, since the compound of chemical formula 1 can be obtained as a solid by performing acidification using an acid in a mixed solvent of ethanol and water and without performing a concentration process of the solvent after the completion of the reaction, the productivity can be improved.

Claims (5)

1. A process for preparing a compound of the following chemical formula 1, which comprises reacting P of a compound of the following chemical formula 2 1 And P 2 Carboxylic acid protecting groups P among the protecting groups 2 A step of selective deprotection, wherein the deprotection uses a solid base as a reaction base and a lower alcohol as a reaction solvent:
[ chemical formula 1]
[ chemical formula 2]
Wherein the method comprises the steps of
R1, R2, R3 and R4 are independently hydrogen or halogen, or C 1 -C 4 An alkyl group, a hydroxyl group,
P 1 is an acyl group, a sulfonyl group or a benzyl group as an amine protecting group,
P 2 is a benzyl group, a methyl group, an ethyl group, an isopropyl group or a tert-butyl group;
the reaction base is one or more selected from the following: sodium hydroxide, lithium hydroxide, potassium hydroxide, and calcium hydroxide;
the reaction solvent is a lower alcohol having 1 to 6 carbon atoms; and the amount of the reaction solvent is 2mL to 3mL per 1g of the compound of formula 2;
the deprotection is carried out at a reaction temperature of 30-80 ℃; and is also provided with
The reaction base is used in an amount of 1 to 4 equivalents based on the compound of chemical formula 2.
2. The method according to claim 1, wherein the lower alcohol having 1 to 6 carbon atoms is methanol, ethanol or a mixed solvent thereof.
3. The method of claim 1, further comprising the step of additionally recrystallizing the compound of formula 1 obtained by deprotection.
4. A process according to claim 3, wherein the recrystallisation uses one or more solvents selected from the group consisting of: water, methanol, ethanol, isopropanol and mixed solvents thereof.
5. The method of claim 1, wherein the acyl group is an acetyl group.
CN201880067548.4A 2017-11-16 2018-10-23 Process for the production of intermediate compounds for the synthesis of medicaments Active CN111247127B (en)

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KR20170153334 2017-11-16
KR10-2017-0153334 2017-11-16
PCT/KR2018/012575 WO2019098551A1 (en) 2017-11-16 2018-10-23 Method for preparing intermediate compound for synthesizing pharmaceutical

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JPH04316526A (en) * 1991-04-15 1992-11-06 Asahi Chem Ind Co Ltd Alkali hydrolysis of carboxylic acid ester
CN101151265A (en) * 2005-04-01 2008-03-26 株式会社Lg生命科学 Dipeptidyl peptidase-iv inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
CN101903386A (en) * 2007-12-21 2010-12-01 株式会社Lg生命科学 Dipeptidyl peptidase-IV inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as active agent
CN103080088A (en) * 2010-09-03 2013-05-01 株式会社Lg生命科学 Production method of intermediate compound for synthesizing medicament

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Publication number Priority date Publication date Assignee Title
JPH04316526A (en) * 1991-04-15 1992-11-06 Asahi Chem Ind Co Ltd Alkali hydrolysis of carboxylic acid ester
CN101151265A (en) * 2005-04-01 2008-03-26 株式会社Lg生命科学 Dipeptidyl peptidase-iv inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
CN101903386A (en) * 2007-12-21 2010-12-01 株式会社Lg生命科学 Dipeptidyl peptidase-IV inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as active agent
CN103080088A (en) * 2010-09-03 2013-05-01 株式会社Lg生命科学 Production method of intermediate compound for synthesizing medicament

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Title
张澄清编著.氢氧化锂.《润滑脂生产》.北京：中国石化出版社,2007,第50页. *
杨光富主编.羧基的保护.《有机合成》.上海：华东理工大学出版社,2010,第118-121页. *

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RU2741389C1 (en) 2021-01-25
BR112020009568A2 (en) 2021-03-09
KR20190056296A (en) 2019-05-24
CO2020006788A2 (en) 2020-06-09
CN111247127A (en) 2020-06-05
PH12020550635A1 (en) 2021-02-22

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