[go: up one dir, main page]

CN111978264A - Industrial production method of deferasirox - Google Patents

Industrial production method of deferasirox Download PDF

Info

Publication number
CN111978264A
CN111978264A CN202010907957.XA CN202010907957A CN111978264A CN 111978264 A CN111978264 A CN 111978264A CN 202010907957 A CN202010907957 A CN 202010907957A CN 111978264 A CN111978264 A CN 111978264A
Authority
CN
China
Prior art keywords
compound
deferasirox
reaction
reacting
industrial production
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202010907957.XA
Other languages
Chinese (zh)
Other versions
CN111978264B (en
Inventor
张孝清
夏正洲
徐良松
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Comer Biomedical Co ltd
Original Assignee
Nanjing Comer Biomedical Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing Comer Biomedical Co ltd filed Critical Nanjing Comer Biomedical Co ltd
Priority to CN202010907957.XA priority Critical patent/CN111978264B/en
Publication of CN111978264A publication Critical patent/CN111978264A/en
Application granted granted Critical
Publication of CN111978264B publication Critical patent/CN111978264B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Landscapes

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

Abstract

The invention discloses an industrial production method of deferasirox, which comprises the following steps: (1) reacting salicylonitrile with acyl chloride or acid anhydride, and after the reaction is finished, adding an alcoholic solution of hydrogen chloride into the reaction solution to prepare a compound IV; (2) reacting the compound IV with salicyloyl chloride to obtain a compound VI; (3) and (3) reacting the compound VI with hydrazinobenzoic acid or hydrochloride thereof to obtain the deferasirox. The synthesis method provided by the invention overcomes the problems of complex operation, high pollution, potential safety hazard and the like in the existing method, and through adjusting the initial raw materials for synthesis, the synthesis method provided by the invention enables the reaction conditions of the whole process route to be mild, does not need to introduce hydrogen chloride gas in the reaction process, does not need to use ether to wash intermediate products, and does not need to use palladium-carbon catalytic hydrogenation to remove corresponding substituent groups, so that the process is greatly simplified, the production cost and the potential safety hazard are reduced, and further large-scale industrial production can be carried out.

Description

Industrial production method of deferasirox
Technical Field
The invention relates to a synthesis method of deferasirox, in particular to an industrial production method of deferasirox.
Background
Deferasirox (deferasirox), chemically known as 4- [3, 5-bis (2-hydroxyphenyl) -1, 2, 4-triazol-1-yl ] benzoic acid, is an iron chelator product developed by nova pharmaceutical company, switzerland, and is the first routinely used oral iron expellant approved by the FDA in the united states, which has granted its orphan status for the treatment of iron overload in transfusion-independent thalassemia, and is currently on the market in over 80 countries. Oral suspensions and dispersible tablets marketed in the united states are approved for the treatment of chronic iron overload in adult and pediatric patients aged 2 and older due to blood transfusion and chronic iron overload in patients with non-transfusion dependent thalassemia (NTDT) syndrome aged 10 and older. In 2012, deferasirox was approved in the european union for the treatment of thalassemia patients aged 6 years and older with chronic iron overload due to frequent transfusions (hematocrit > 7 ml/kg/month), and also for the treatment of chronic iron overload due to transfusions when deferoxamine treatment is contraindicated or insufficient. In japan, the product is approved for the treatment of iron overload due to blood transfusion.
In 2010, dispersible tablets of deferasirox were approved for marketing in china and approved for the treatment of chronic iron overload in patients with beta thalassemia between 2 years of age and older due to frequent blood transfusions and chronic iron overload in patients with non-transfusion dependent thalassemia (NTDT) syndrome between 10 years of age and older. The chemical structural formula is as follows:
Figure BDA0002660242210000011
excessive iron deposition in human tissues and organs can cause cell damage and organ dysfunction, and the pathogenesis of the iron deposition can be divided into primary and secondary. Primary iron overload is caused by abnormalities in genetic factors and is seen in primary hemochromatosis. Clinically, secondary iron overload is common, and is mainly caused by ineffective erythropoiesis caused by various reasons such as long-term repeated blood transfusion and iron metabolic disturbance caused by liver diseases. Deferasirox is a tridentate iron chelator which can form a complex with ferric ions in a ratio of 2: 1, and is excreted from feces, thereby reducing the iron content in the human body. The deferasirox has the advantages of removing free iron and intracellular iron, preventing myocardial cells from taking up the iron, and directly removing redundant iron from the myocardial cells, so that non-transferrin in blood plasma is continuously reduced, and the deferasirox is first-line medication of patients with chronic iron overload caused by blood transfusion. The deferasirox dispersible tablet can be orally taken once a day, has good patient compliance and ensures long-term iron-removing treatment. The deferasirox has good iron-removing effectiveness, safety and patient compliance, greatly reduces the death rate of patients with thalassemia, MDS and other diseases needing long-term blood transfusion treatment, and improves the life quality of the patients.
Currently, the main preparation method of deferasirox uses salicylic acid as a raw material, and the deferasirox is obtained by chlorination with thionyl chloride, dehydration cyclization of salicylamide and ring-opening rearrangement of 4-carboxyl phenylhydrazine[1-2]. The synthetic route is as follows:
Figure BDA0002660242210000021
in the preparation method, thionyl chloride is easily volatilized and decomposed, the corrosivity is strong, reduced pressure distillation is needed after the reaction is finished, and the operation is complicated. In the reaction for preparing the compound VIII, dehydration cyclization is needed at the temperature of more than 150 ℃, the yield is about 50%, the equipment requirement is high, the operation is dangerous, the energy consumption is overlarge, and the yield is low, so that the cost of the industrial production of deferasirox is limited.
Patent WO2012025935 proposes a new synthetic route, which is to form mixed anhydride from salicylic acid and p-toluenesulfonyl chloride, and then react with salicylamide in an alcohol solvent to obtain a key intermediate of benzoxazinone, and the synthetic route is as follows:
Figure BDA0002660242210000022
in the preparation method, dehydration cyclization is still required at the temperature of more than 150 ℃ in the reaction for preparing the compound VIII, and the yield is only 40%, the equipment requirement is high, the operation is dangerous, the energy consumption is overlarge, and the yield is low. Moreover, experiments show that a large amount of byproducts are generated in the reaction of salicylic acid and p-toluenesulfonyl chloride and are generated by the reaction of the phenolic hydroxyl of salicylic acid and sulfonyl chloride, and further the yield of the intermediate VIII is reduced.
A new synthetic route is proposed in patent CN103396373B, and the synthetic route is as follows:
Figure BDA0002660242210000023
in the preparation method, firstly, when the compound IX is prepared, hydrogen chloride gas is required to be introduced into an alcohol solution, and the hydrogen chloride gas is easy to absorb moisture, strong in corrosivity and difficult to operate in industrial production; meanwhile, the intermediate IX is prepared by washing with diethyl ether, and the diethyl ether is flammable and explosive and is avoided in industrial production; and finally, when the deferasirox is prepared, palladium-carbon catalytic hydrogenation is needed, and a pressure reaction is carried out in a hydrogenation kettle, so that the potential safety hazard exists in the reaction, the reaction needs to be carried out in a special hydrogenation workshop, and a common production workshop cannot be developed, thereby limiting the scale of industrial production.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a synthesis method of deferasirox, which has mild reaction conditions, low cost and less pollution and is suitable for industrial production.
The technical scheme is as follows: the invention relates to an industrial production method of deferasirox, which comprises the following steps:
(1) reacting salicylonitrile with acyl chloride or acid anhydride, and after the reaction is finished, adding an alcoholic solution of hydrogen chloride into the reaction solution to prepare a compound IV;
(2) reacting the prepared compound IV with salicyloyl chloride to obtain a compound VI;
(3) finally, reacting the prepared compound VI with hydrazinobenzoic acid or hydrazinobenzoic acid hydrochloride to prepare deferasirox;
wherein the structural formula of the compound IV is as follows:
Figure BDA0002660242210000031
compound VI structural formula is as follows:
Figure BDA0002660242210000032
wherein, R1 is one of acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, tert-butyryl, chloroacetyl, chloroisopropionyl, chlorobutyryl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenylsulfonyl, 4-methylphenylsulfonyl or nitro-substituted phenylsulfonyl, preferably R1 is acetyl; r2 is one of methyl, ethyl, n-propyl or isopropyl; preferably R2 is methyl or ethyl.
In the step (1), the compound IV is prepared by the following method: reacting salicylonitrile with acyl chloride or acid anhydride in a lower ether solvent at room temperature, cooling to 0-5 ℃ after the reaction is finished, adding a methanol or ethanol solution of hydrogen chloride into the reaction solution, reacting at room temperature, filtering and drying after the reaction to obtain a target compound IV.
Wherein the lower ether solvent is methyl tertiary ether or isopropyl ether.
In the step (2), the compound VI is prepared by the following method: dissolving the compound IV and salicyloyl chloride in dichloromethane or chloroform or carbon tetrachloride or dichloroethane, and heating and refluxing for reaction under the action of alkali to obtain a compound VI.
Wherein the reaction temperature is 30-60 ℃.
Wherein in the step (3), the deferasirox is prepared by adopting the following method: dissolving the compound VI and p-hydrazinobenzoic acid or hydrazinobenzoic acid hydrochloride in methanol or ethanol or isopropanol, reacting at 60-80 ℃, adjusting the pH value of the solution to acidity after the reaction is finished, concentrating, filtering and drying to obtain the deferasirox.
The synthetic route of the method is as follows:
Figure BDA0002660242210000041
has the advantages that: compared with the prior art, the invention has the remarkable advantages that: the synthetic method solves the problems of complex operation, high pollution, potential safety hazard and the like in the existing method, and through adjusting the synthetic starting raw materials, the synthetic method ensures that the reaction conditions of the whole process route are mild, does not need to introduce hydrogen chloride gas in the reaction process, does not need to adopt ether to wash intermediate products, and does not need to adopt palladium-carbon catalytic hydrogenation to remove corresponding substituent groups (benzyl-Bn), thereby greatly simplifying the process, reducing the production cost and the potential safety hazard, and further being capable of carrying out large-scale industrial production; in addition, the final product obtained by the synthesis method of the invention does not need additional purification, the generated three wastes are less, the intermediate VI reacts with the p-hydrazinobenzoic acid or the hydrochloride thereof, the obtained product is directly concentrated, filtered and dried, and the purity of the obtained deferasirox is more than 99.5%.
Detailed Description
The technical solution of the present invention is further described with reference to the following specific examples.
The starting materials used in the examples are either commercially available or synthesized by standard methods known to those skilled in the art of chemical synthesis.
Example 1: preparation of 2-acetoxy-benzylidene amino acid methyl ester hydrochloride
Dissolving salicylaldehyde (11.9g, 0.1mol) in 60mL of methyl tert-ether, and uniformly stirring to obtain a mixed solution A; dissolving acetyl chloride (9.6g, 0.12mol) in 30mL of methyl tert-ether to obtain a mixed solution B, dripping the mixed solution B into the mixed solution A, reacting at room temperature, cooling the reaction solution to 0-5 ℃ after the reaction is finished, adding 30mL of hydrogen chloride methanol solution into the reaction solution, stirring for reacting for 6-8h, filtering and drying after the reaction to obtain 21.1g of solid, namely hydrochloride of a compound IV, wherein the molar yield is as follows: 92 percent.
ESI (+), mass to charge ratio (m/z): [ M + H ]]+＝194
1H-NMR(DMSO-d6，500MHz)12.6(br，2H)，7.72(m，1H)，7.46(m，1H)，7.20-7.31(m，2H)，4.35(s，3H)，3.52(s，3H)。
Example 2: preparation of 2-acetoxy-benzylidene amino acid methyl ester hydrochloride
Dissolving salicylaldehyde (11.9g, 0.1mol) in 60mL isopropyl ether, and uniformly stirring to obtain a mixed solution A; dissolving acetic anhydride (12.5g, 0.12mol) in 30mL of isopropyl ether to obtain a mixed solution B, dripping the mixed solution B into the mixed solution A, reacting at room temperature, cooling the reaction solution to 0-5 ℃ after the reaction is finished, adding 30mL of hydrogen chloride methanol solution into the reaction solution, stirring and reacting for 6-8h, filtering and drying after the reaction to obtain 19.8g of solid, wherein the yield is as follows: 86 percent.
ESI (+), mass to charge ratio (m/z): [ M + H ]]+＝194
1H-NMR(DMSO-d6，500MHz)12.3(br，2H)，7.71(m，1H)，7.43(m，1H)，7.16-7.28(m，2H)，4.31(s，3H)，3.50(s，3H)。
Example 3: preparation of 2-acetoxy-phenyl imino acid ethyl ester hydrochloride
Dissolving salicylaldehyde (6.0kg) in 30L of methyl tert-ether, and uniformly stirring to obtain a mixed solution A; dissolving acetyl chloride (5kg) in 15L of methyl tert-ether to obtain a mixed solution B, dripping the mixed solution B into the mixed solution A, reacting at room temperature, cooling the reaction solution to 0-5 ℃ after the reaction is finished, adding 30mL of hydrogen chloride ethanol solution into the reaction solution, stirring and reacting for 10-12h, filtering and drying after the reaction to obtain 11.1kg of solid, wherein the yield is as follows: 90 percent.
ESI (+), mass to charge ratio (m/z): [ M + H ]]+＝207
1H-NMR(DMSO-d6，500MHz)12.6(br，2H)，7.72(m，1H)，7.46(m，1H)，7.20-7.31(m，2H)，4.35(q，2H，J＝6.90Hz)，3.52(s，3H)，1.56(t，3H，J＝6.90Hz)。
Example 4: preparation of 2- (2-acetoxyl) -4H-1, 3-benzoxazine-4-one
Salicyloyl chloride (15.7g, 0.1mol) is dissolved in 150mL of dichloromethane, 2-acetoxy-benzene imino acid methyl ester hydrochloride (23g, 0.1mol) is added into the dichloromethane, triethylamine (35mL, 0.25mol) is dropped into the dichloromethane, after the reaction solution is heated and refluxed for reaction for 10 to 12 hours (the reaction temperature is 30 to 60 ℃), water is used for washing liquid, and an organic layer is concentrated to be dry, so that 24.5g of solid, namely a compound VI is obtained, wherein the yield is as follows: 87 percent.
ESI (+), mass to charge ratio (m/z): [ M + H ]]+＝282
1H-NMR(DMSO-d6，500MHz)67.80(m，1H)，7.72(m，1H)，7.60-7.55(m，3H)，7.35-7.30(m，2H)，7.21(m，1H)，3.61(s，3H)。
Example 5: preparation of 2- (2-acetoxyl) -4H-1, 3-benzoxazine-4-one
Salicyloyl chloride (7.85kg) was dissolved in 7L of dichloromethane, to which was added 2-acetoxy-benzeneimino acid ethyl ester hydrochloride (12.2kg), triethylamine (17.5L) was added dropwise, and after the reaction solution was heated under reflux for 10 to 12 hours (reaction temperature 30 to 60 ℃), the solution was washed with water, and the organic layer was concentrated to dryness to obtain 12.6kg of a solid with the yield: 90 percent.
Example 6: preparation of deferasirox
Adding the intermediate 2- (2-acetoxyl) -4H-1, 3-benzoxazine-4-one (28.1g, 0.1mol) into methanol (140mL), adding p-hydrazinobenzoic acid hydrochloride (18.9g, 0.1mol), heating and refluxing for about 2-4H (the reaction temperature is 60-80 ℃), cooling to room temperature, adjusting the pH of the reaction solution to 1-2 with diluted hydrochloric acid, concentrating to remove part of the solvent, cooling to room temperature, filtering, washing the solid with a small amount of cold methanol, and drying to obtain 31.7g of deferasirox, HPLC: 99.76%, yield: 85 percent.
ESI (+), mass to charge ratio (m/z): [ M + H ]]+＝374
1H-NMR(DMSO-d6，500MHz)12.16(br，s，1H)，10.60(s，1H)，10.04(s，1H)，8.12(d，2H，J＝8.5Hz)，7.86(d，2H，J＝8.5Hz)，7.62-7.59(m，2H)，7.40-7.38(m，2H)，6.95-6.90(m，3H)，6.85-6.83(m，1H)。

Claims (6)

1. An industrial production method of deferasirox is characterized by comprising the following steps:
(1) reacting salicylonitrile with acyl chloride or acid anhydride, and after the reaction is finished, adding an alcoholic solution of hydrogen chloride into the reaction solution to prepare a compound IV;
(2) reacting the prepared compound IV with salicyloyl chloride to obtain a compound VI;
(3) finally, reacting the prepared compound VI with hydrazinobenzoic acid or hydrazinobenzoic acid hydrochloride to prepare deferasirox;
wherein the structural formula of the compound IV is as follows:
Figure FDA0002660242200000011
compound VI structural formula is as follows:
Figure FDA0002660242200000012
wherein, R1 is one of acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, tert-butyryl, chloroacetyl, chloroisopropionyl, chlorobutyryl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenylsulfonyl, 4-methylphenylsulfonyl or nitro-substituted phenylsulfonyl; r2 is one of methyl, ethyl, n-propyl or isopropyl.
2. The industrial production method of deferasirox according to claim 1, wherein: in the step (1), the compound IV is prepared by adopting the following method: reacting salicylonitrile with acyl chloride or acid anhydride in a lower ether solvent at room temperature, cooling to 0-5 ℃ after the reaction is finished, adding a methanol or ethanol solution of hydrogen chloride into the reaction solution, reacting at room temperature, filtering and drying after the reaction to obtain a target compound IV.
3. The industrial production method of deferasirox according to claim 2, wherein: the lower ether solvent is methyl tertiary ether or isopropyl ether.
4. The industrial production method of deferasirox according to claim 1, wherein: in the step (2), the compound VI is prepared by the following method: dissolving the compound IV and salicyloyl chloride in dichloromethane or chloroform or carbon tetrachloride or dichloroethane, and heating and refluxing for reaction under the action of alkali to obtain a compound VI.
5. The industrial production method of deferasirox according to claim 4, wherein: the reaction temperature is 30-60 ℃.
6. The industrial production method of deferasirox according to claim 1, wherein: in the step (3), the deferasirox is prepared by adopting the following method: dissolving the compound VI and p-hydrazinobenzoic acid or hydrazinobenzoic acid hydrochloride in methanol or ethanol or isopropanol, reacting at 60-80 ℃, adjusting the pH value of the solution to acidity after the reaction is finished, concentrating, filtering and drying to obtain the deferasirox.
CN202010907957.XA 2020-09-01 2020-09-01 Industrial production method of deferasirox Active CN111978264B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010907957.XA CN111978264B (en) 2020-09-01 2020-09-01 Industrial production method of deferasirox

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010907957.XA CN111978264B (en) 2020-09-01 2020-09-01 Industrial production method of deferasirox

Publications (2)

Publication Number Publication Date
CN111978264A true CN111978264A (en) 2020-11-24
CN111978264B CN111978264B (en) 2023-01-24

Family

ID=73448698

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010907957.XA Active CN111978264B (en) 2020-09-01 2020-09-01 Industrial production method of deferasirox

Country Status (1)

Country Link
CN (1) CN111978264B (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013028132A1 (en) * 2011-08-19 2013-02-28 Nanyang Technological University Chiral phosphines for palladium-catalyzed asymmetric alpha-arylation of ester enolates to produce tertiary stereocenters in high enantioselectivity
CN103396373A (en) * 2013-07-22 2013-11-20 江苏奥赛康药业股份有限公司 Preparation method of deferasirox and intermediate compound of deferasirox
CN104884442A (en) * 2012-12-27 2015-09-02 住友化学株式会社 Tetrazolinone compound and applications thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013028132A1 (en) * 2011-08-19 2013-02-28 Nanyang Technological University Chiral phosphines for palladium-catalyzed asymmetric alpha-arylation of ester enolates to produce tertiary stereocenters in high enantioselectivity
CN104884442A (en) * 2012-12-27 2015-09-02 住友化学株式会社 Tetrazolinone compound and applications thereof
CN103396373A (en) * 2013-07-22 2013-11-20 江苏奥赛康药业股份有限公司 Preparation method of deferasirox and intermediate compound of deferasirox

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
武钦佩等: "《保护基化学》", 31 January 2007 *

Also Published As

Publication number Publication date
CN111978264B (en) 2023-01-24

Similar Documents

Publication Publication Date Title
CN101824002A (en) Water soluble triazole compound and synthesis method thereof
JPS62212334A (en) Aryl and heteroaryl ethers as antihyperanaphylatic
JPH0780871B2 (en) Novel 4-benzyl-1- (2H) -phthalazinone-derivative and process for producing the same
CA2554610A1 (en) Aryl and heteroaryl-piperidinecarboxylate derivatives, the preparation and the use thereof in the form of faah enzyme inhibitors
JPS6215546B2 (en)
JP2007503423A (en) Crystalline polymorphs of fexofenadine and method for producing them
CH644348A5 (en) OXIDIZED AMINO-ETHERS, THEIR PREPARATION PROCESS AND THE MEDICAMENT CONTAINING THEM.
CN102746231A (en) Celecoxib preparation process
CN101817798B (en) Novel environment-friendly process for preparing leflunomide
CZ20033365A3 (en) Deuterated N-substituted and alpha-substituted diphenylalkoxyacetic acid aminoalkyl esters and medicaments containing such esters
JPS5817454B2 (en) Alkylated hydroxylamine and its production method
US9018389B2 (en) Process for the preparation of Deferasirox
AU655365B2 (en) Tetrazolyl-(phenoxy and phenoxyalkyl)-piperidinylpyridazines as antiviral agents
CN111978264B (en) Industrial production method of deferasirox
CN102491953A (en) Method for synthesizing florfenicol midbody RT0131
DK157549B (en) METHOD OF ANALOGUE FOR PREPARATION OF 6- (5- (OMEGA- (1-IMIDAZOLYL) -ALKYL) -THIEN-2-YL) -3-OXO-2,3,4,5-TETRAHYDROPYRIDAZINES OR ACID ADDITION SALTS.
WO2020238779A1 (en) Method for synthesizing florfenicol
CN108689957A (en) A kind of preparation method and application of 2R/2S- trifluoromethyls morpholine and its hydrochloride
KR101149821B1 (en) Novel synthetic method of diphenylacetate derivatives
JPS63225359A (en) Phenoxyacetic acid derivative
CN116444449A (en) Preparation method of 3- (chloromethyl) -1-methyl-1H- [1,2,4] -triazole
CN101759665B (en) Substituted phenylpiperazine aryl alkanol derivatives and their application in the preparation of analgesic drugs
CN106749055A (en) A kind of preparation method of Fluconazole
CN103319358B (en) Preparation method of 7-amino heptanoic acid
JP2630877B2 (en) Optically active triazole derivatives and compositions

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant