WO2009024685A1 - Procede de preparation du fenofibrate - Google Patents
Procede de preparation du fenofibrate Download PDFInfo
- Publication number
- WO2009024685A1 WO2009024685A1 PCT/FR2008/000972 FR2008000972W WO2009024685A1 WO 2009024685 A1 WO2009024685 A1 WO 2009024685A1 FR 2008000972 W FR2008000972 W FR 2008000972W WO 2009024685 A1 WO2009024685 A1 WO 2009024685A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- chloride
- fenofibrate
- acid
- base
- formula
- Prior art date
Links
- 229960002297 fenofibrate Drugs 0.000 title claims abstract description 16
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229960000701 fenofibric acid Drugs 0.000 claims abstract description 14
- MQOBSOSZFYZQOK-UHFFFAOYSA-N fenofibric acid Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1C(=O)C1=CC=C(Cl)C=C1 MQOBSOSZFYZQOK-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 9
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000011065 in-situ storage Methods 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 3
- 238000002955 isolation Methods 0.000 claims abstract description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 22
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 239000000203 mixture Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- -1 for example Chemical compound 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical class [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 230000000871 hypocholesterolemic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/708—Ethers
- C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
Definitions
- the present invention relates to a process for the preparation of fenofibrate.
- Fenofibrate whose structure corresponds to the formula:
- the fenofibric acid of formula it is also possible to prepare the fenofibric acid of formula: then to transform it into an ester, in particular by going through the preparation of the acid chloride by the action of cold phosphorus pentachloride (0 to 5 ° C.), then reacting the desired alcohol. According to the described tests, the acid chloride is isolated and recrystallized prior to any other transformation. Fenofibrate is prepared by esterification in a sulfuric acid medium. It is stated that the preferred method is transesterification.
- the fenofibric acid chloride is prepared in situ by the action of a chlorinating agent chosen from all the agents known to allow the realization of such a reaction, which do not affect the rest of the molecule, in particular it is selected from thionyl chloride, sulfuryl chloride, oxalyl chloride, carbonyl chloride, phosphorus trichloride or phosphoryl chloride. It is understood that the chlorinating agent makes it possible simultaneously to carry out the chlorination and dehydration of fenofibric acid of general formula (II).
- the fenofibric acid chloride is prepared in situ by the action of thionyl chloride, sulphuryl chloride, oxalyl chloride, or phosphoryl chloride and among these agents, more particularly thionyl chloride.
- the method according to the invention is implemented without the addition of a solvent.
- isopropanol is used both as a solvent and as a reagent.
- the method according to the invention is implemented in the presence of a base.
- the base may be an alkali metal carbonate or hydroxide, particularly an alkali metal carbonate such as potassium or sodium carbonate, or sodium or potassium hydroxide; the base may also be an amine, preferably a tertiary amine, and among tertiary amines, especially triethylamine or pyridine or their derivatives.
- the process according to the invention is carried out at a temperature of 60 to 90 ° C.
- the process according to the invention is carried out with an excess of chlorinating agent (thionyl chloride, sulphuryl chloride, oxalyl chloride, carbonyl chloride, triphosphorous chloride). or phosphoryl chloride).
- chlorinating agent thionyl chloride, sulphuryl chloride, oxalyl chloride, carbonyl chloride, triphosphorous chloride. or phosphoryl chloride.
- it is carried out with an excess of thionyl chloride, sulfuryl chloride, oxalyl chloride, or phosphoryl chloride.
- the process according to the invention is carried out with an excess of thionyl chloride.
- the preparation of the acid chloride is advantageously carried out in isopropanol, preferably in the presence of a slight excess of chlorinating agent, for example in the presence of an excess of thionyl chloride such as the ratio of thionyl chloride fenofibric acid is between 1, 1 and 1.5.
- the temperature is in general between 60 and 90 ° C., preferably between 80 and 90 ° C. It is not necessary to add a solvent, the isopropanol serving both solvent and reagent. From its formation, the acid chloride reacts with isopropanol to form the expected fenofibrate, especially at a temperature between 60 and 90 ° C.
- the reaction can be carried out in the presence of a base such as a carbonate, such as, for example, potassium or sodium carbonate, or in the presence of an alkaline hydroxide such as, for example, sodium or potassium hydroxide; the base is used to neutralize hydrochloric acid at the end of the fenofibrate formation reaction.
- a base such as a carbonate, such as, for example, potassium or sodium carbonate
- an alkaline hydroxide such as, for example, sodium or potassium hydroxide
- an organic base of the amine type in particular tertiary amine, for example triethylamine or pyridine or their derivatives.
- the process according to the invention is particularly advantageous because it provides a very improved yield and because it can be operated at a moderate temperature. The reaction is fast and clean, it does not require the recrystallization of the product after treatment.
- Fenofibric acid of formula (II) may be prepared as described in British Patent Application GB 1,539,897.
- Reactor A In a 250 ml double-jacketed reactor (Reactor A), 60 g of fenofibric acid (1 eq; 0.188 mol) are introduced and 120 ml of isopropanol (2 volumes). The reaction mixture is refluxed. The reaction mixture is heterogeneous. 29.11 g of thionyl chloride (1.3 eq, 0.245 mol) are added to this suspension in 3 hours. The reaction mixture is homogenized during the addition of thionyl chloride to give a yellow solution. At the end of the addition, the reaction mixture is kept under reflux for about 4 hours (the kinetics of reaction is followed by HPLC).
- reactor A The contents of reactor A are poured hot into reactor B in about one hour.
- the reactor A is rinsed with 15 ml of isopropanol which are transferred to the reactor B.
- the mixture is stirred for a minimum of 5 minutes. Stirring is stopped and the mixture is allowed to settle.
- the lower aqueous phase is removed.
- 134 ml of water are added to the alcohol phase, maintaining the temperature of the reaction mass at 60-65 ° C.
- the reaction mass is cooled to 50 ° C. and primed with a few mg of fenofibrate.
- the mixture is kept approximately 30 minutes at 50 ° C.
- the medium crystallizes.
- the temperature is cooled to 0-5 0 C in 2 hours and then kept at least 30 minutes at this temperature (0-5 0 C).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Obesity (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08827591A EP2173701A1 (fr) | 2007-07-05 | 2008-07-07 | Procede de preparation du fenofibrate |
CN200880023238A CN101730675A (zh) | 2007-07-05 | 2008-07-07 | 制备非诺贝特的方法 |
US12/667,691 US20100185008A1 (en) | 2007-07-05 | 2008-07-07 | Method for Producing Fenofibrate |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0704852 | 2007-07-05 | ||
FR0704852A FR2918367A1 (fr) | 2007-07-05 | 2007-07-05 | Procede de preparation du fenofibrate |
FR0704996 | 2007-07-10 | ||
FR0704996A FR2918662B1 (fr) | 2007-07-10 | 2007-07-10 | Procede de preparation du fenofibrate |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2009024685A1 true WO2009024685A1 (fr) | 2009-02-26 |
Family
ID=40263047
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2008/000972 WO2009024685A1 (fr) | 2007-07-05 | 2008-07-07 | Procede de preparation du fenofibrate |
Country Status (5)
Country | Link |
---|---|
US (1) | US20100185008A1 (fr) |
EP (1) | EP2173701A1 (fr) |
KR (1) | KR20100062976A (fr) |
CN (1) | CN101730675A (fr) |
WO (1) | WO2009024685A1 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107827745A (zh) * | 2017-11-17 | 2018-03-23 | 徐州工业职业技术学院 | 一种低温均相绿色合成普鲁脂芬的方法 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103214360A (zh) * | 2013-05-17 | 2013-07-24 | 毛志英 | 一种(4-氯苯基)-[4-(1-甲基乙氧基)苯基]甲酮的合成方法 |
CN104311422B (zh) * | 2014-10-23 | 2016-05-11 | 浙江永太科技股份有限公司 | 一种降血脂药物非诺贝特的制备方法 |
KR20230139980A (ko) | 2022-03-29 | 2023-10-06 | 한국바이오켐제약 주식회사 | 페노피브릭산의 정제방법 및 이에 의해 제조된 페노피브레이트 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2157853A2 (fr) * | 1971-10-14 | 1973-06-08 | Fournier Gmbh Lab |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2003430C3 (de) * | 1969-01-31 | 1978-12-07 | Laboratorien Fournier Gmbh, 6600 Saarbruecken | p-Benzoylphenoxyisobuttersäureester, ihre Herstellung und diese enthaltende Arzneimittel |
FR2598146B1 (fr) * | 1986-04-30 | 1989-01-20 | Rech Ind | Nouveau procede de preparation de fibrates. |
-
2008
- 2008-07-07 WO PCT/FR2008/000972 patent/WO2009024685A1/fr active Application Filing
- 2008-07-07 KR KR1020097027461A patent/KR20100062976A/ko not_active Application Discontinuation
- 2008-07-07 EP EP08827591A patent/EP2173701A1/fr not_active Withdrawn
- 2008-07-07 US US12/667,691 patent/US20100185008A1/en not_active Abandoned
- 2008-07-07 CN CN200880023238A patent/CN101730675A/zh active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2157853A2 (fr) * | 1971-10-14 | 1973-06-08 | Fournier Gmbh Lab |
Non-Patent Citations (2)
Title |
---|
R.G. CLEWLEY, A. FISCHER, G.N. HENDERSON: "ipso Nitration in p-halophenyl ethers", CANADIAN JOURNAL OF CHEMISTRY, vol. 67, 1989, pages 1472 - 1479, XP002466945 * |
See also references of EP2173701A1 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107827745A (zh) * | 2017-11-17 | 2018-03-23 | 徐州工业职业技术学院 | 一种低温均相绿色合成普鲁脂芬的方法 |
CN107827745B (zh) * | 2017-11-17 | 2020-11-03 | 徐州工业职业技术学院 | 一种低温均相绿色合成普鲁脂芬的方法 |
Also Published As
Publication number | Publication date |
---|---|
US20100185008A1 (en) | 2010-07-22 |
EP2173701A1 (fr) | 2010-04-14 |
KR20100062976A (ko) | 2010-06-10 |
CN101730675A (zh) | 2010-06-09 |
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