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WO2004089924A1 - Procede pour la preparation de 5-bromophtalide - Google Patents

Procede pour la preparation de 5-bromophtalide Download PDF

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Publication number
WO2004089924A1
WO2004089924A1 PCT/IB2003/001450 IB0301450W WO2004089924A1 WO 2004089924 A1 WO2004089924 A1 WO 2004089924A1 IB 0301450 W IB0301450 W IB 0301450W WO 2004089924 A1 WO2004089924 A1 WO 2004089924A1
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Prior art keywords
bromophthalide
process according
organic phase
solvent
citalopram
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Ceased
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PCT/IB2003/001450
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English (en)
Inventor
Jacob Oren
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Bromine Compounds Ltd
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Bromine Compounds Ltd
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Priority to AU2003214582A priority Critical patent/AU2003214582A1/en
Priority to PCT/IB2003/001450 priority patent/WO2004089924A1/fr
Publication of WO2004089924A1 publication Critical patent/WO2004089924A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans

Definitions

  • the present invention relates to a process for the preparation of 5-bromophthalide. More specifically, the present invention discloses a novel, efficient process for the preparation of 5-bromophthalide by the reduction of 4- bromophthalic anhydride.
  • 5-Bromophthalide is a useful starting material for the preparation of certain pharmacologically active substances, including the antidepressant drug citalopram.
  • the preparation of this compound from 5-bromophthalide is described in US 4,136,193 (Kefalas A/S) . This publication, however, is silent in relation to the preparation of 5- bromophthalide itself.
  • 5-bromophthalide is obtained by the liquid-phase catalytic oxidation of 4- bromo-o-xylene .
  • the reaction mixture may be treated in a simple and efficient manner to selectively isolate the desired 5-bromophthalide therefrom.
  • the entire process from the initial reduction reaction to the final purification step may be performed using the same solvent, if desired.
  • the present invention is primarily directed to a process for the preparation of 5-bromophthalide, comprising reducing 4-bromophthalic anhydride in an organic solvent, to obtain a mixture of 5-bromophthalide and 6- bromophthalide, acidifying the reaction mixture, separating the same into aqueous and organic phases and selectively crystallizing 5-bromophthalide from the organic phase.
  • the term "selectively crystallizing 5-bromophthalide from the organic phase” indicates that the crude solid that is caused to precipitate from the organic phase is specifically enriched with respect to the 5-isomer.
  • the percentage of the 5-isomer in the crude product is above 55%, more preferably above 70%, and most preferably above 80%, as determined by HPLC and gas chromatography .
  • the solvent used in the reduction reaction comprises an ether, wherein said ether is preferably selected from the group consisting of cyclic ethers, such as tetrahydrofuran (THF) and 1,4-dioxan, or ethers containing linear or branched alkyl groups, such as ethylene glycol dimethyl ether (EGDME) and methyl tert-butyl ether.
  • cyclic ethers such as tetrahydrofuran (THF) and 1,4-dioxan
  • ethers containing linear or branched alkyl groups such as ethylene glycol dimethyl ether (EGDME) and methyl tert-butyl ether.
  • GGDME ethylene glycol dimethyl ether
  • Particularly preferred ethers are tetrahydrofuran and ethylene glycol dimethyl ether.
  • the ether solvent is suitable both for the reduction reaction and for the subsequent crystallization, allowing the preferential crystallization of the 5-bromophthalide isomer from the reaction mixture, with significantly lower amounts of crystalline 6- bromophthalide being crystallized.
  • the reduction reaction and the subsequent selective crystallization may be accomplished using the same ether solvent.
  • the reducing agent used in the reduction reaction of 4-bromophthalic anhydride is sodium borohydride. It has also been found that it is particularly preferable to carry out the reduction reaction in tetrahydrofuran or EGDME, using sodium borohydride, at relatively low temperatures, preferably in the range of 3-15 ° C, since at this temperature range the selectivity of the reduction reaction is shifted towards the formation of the 5- bromophthalide .
  • a second solvent which is preferably an alcohol, or a mixture of alcohol and water, is then added to said organic phase residue, and, subsequently, said 5-bromophthalide is caused to crystallize selectively from the organic phase containing said second solvent.
  • the crude 5- bromophthalide obtained following the selective crystallization is further purified by re-crystallization or reslurry, preferably from the same solvent used for the first crystallization or from an aqueous mixture thereof.
  • Another aspect of the present invention relates to the preparation of the therapeutically active compound citalopram
  • the present invention relates to a process for the production of 5-bromophthalide that is based on the reduction of 4-bromophthalic anhydride in an organic solvent according to the following reaction scheme:
  • reaction mixture is treated to selectively isolate the 5-bromophthalide therefrom.
  • the starting material, 4-bromophthalic anhydride is commercially available (Dead Sea Bromine Group, Be' er Sheva, Israel) .
  • the preparation of 4-bromophthalic anhydride is described in IL 115814. Briefly, the 4- bromophthalic anhydride starting material may be prepared by the bromination of disodium phthalate with bromine in water. At the end of the reaction, the excess bromine is removed from the crude reaction mixture, the mixture is acidified, the organic compounds are extracted using an inert organic solvent, the solvent is distilled, thereby transforming the phthalic acid moieties into anhydrides, and the crude product is distilled, to yield substantially pure 4-bromophthalic anhydride.
  • the reduction is carried out in an ether solvent, which is most preferably selected from the group consisting of tetrahydrofuran (THF) , 1,4-dioxan, ethylene glycol dimethyl ether (EGDME) and methyl tert-butyl ether.
  • ether solvents include diethyl ether, diisopropyl ether, dibutyl ether and tetrahydropyran.
  • the reduction may be carried out in a mixture of solvents comprising ether and one or more additional solvents that are inert with respect to the reduction reaction, wherein said one or more additional solvents are preferably selected from the group of hydrocarbons or halogenated hydrocarbons, such as toluene and 1,2-ethylene dichloride (EDC) .
  • one or more additional solvents are preferably selected from the group of hydrocarbons or halogenated hydrocarbons, such as toluene and 1,2-ethylene dichloride (EDC) .
  • the reduction of the 4-bromophthalic anhydride starting material is accomplished by means of a reducing agent, which is most preferably sodium borohydride.
  • the reducing agent is provided as a slurry in the solvent intended for use.
  • the optimal molar ratio of sodium borohydride to 4-bromophthalic anhydride is in the range of 0.5:1 to 0.65:1. More preferably, this ratio should have a value in the range of 0.55:1 to 0.60:1. Most preferably, this molar ratio has the value 0.57:1.
  • the weight ratio of the solvent and the 4-bromophthalic anhydride is preferably in the range of 2:1 to 5:1. More preferably, this ratio should have a value in the range of 2:1 to 3:1. Most preferably the amounts of the solvent and 4-bromophthalic anhydride should be adjusted such that the aforementioned ratio has a value of about 2.2:1.
  • the reduction is performed by adding the solution of 4-bromophthalic anhydride in the ether solvent to the slurry of sodium borohydride in the same solvent, in a gradual manner.
  • the reduction reaction is immediate and is practically complete by the end of the addition of the 4-bromophthalic anhydride.
  • the total time taken for the addition of the 4- bromophthalic anhydride solution to the reducing agent is in the range of 1 - 4 hours.
  • the reaction temperature over this time period is preferably maintained within the range of 0 - 50° C, and more preferably between 10 to 30° C. It has been found that at relatively low temperatures, preferably in the range of 3-15 ° C, the selectivity of the reduction reaction is shifted towards the formation of the 5-bromophthalide .
  • reaction following the completion of the addition of the 4-bromophthalic anhydride solution to the reducing agent, the reaction is allowed to continue for a further period of time with stirring at about 20° C.
  • the excess reducing agent is neutralised, preferably by means of the addition of water and an acid, until a pH of less than 4 is obtained. More preferably the pH following the addition of the acid should be approximately 2.
  • the acid is selected from the group consisting of 50% sulphuric acid and concentrated hydrochloric acid, although other inorganic or organic acids may be used.
  • the weight ratio of water to concentrated hydrochloric acid is preferably in the range of 1-6:1. Most preferably this ratio has the value 3:1.
  • the reaction mixture is heated to a temperature of preferably between 50 and 65° C, most preferably between 55 and 60° C, at which temperature the reaction mixture separates into a lower aqueous phase and an upper, clear, organic phase containing the mixture of 5-bromophthalide and 6-bromophthalide in the organic solvent.
  • the organic phase is preferably washed with aqueous NaCl solution (10% w:w), to remove the residues of H 3 B0 3 formed during the work-up.
  • the desired product that is, 5-bromophthalide
  • the organic phase which consists of the ether solvent used for the reduction reaction.
  • the crystallization may be induced by decreasing the volume of the solution, or by cooling said solution, or by adding an antisolvent thereto, or, most preferably, by a combination of said operations.
  • a portion of the ether solvent is removed by distillation.
  • the amount of the ether removed by distillation is 40 - 70% of the starting amount.
  • the crude 5- bromophthalide is then selectively crystallized from the organic phase residue by gradual cooling to a final temperature of 30° C, and then holding the residue at that temperature for a period of one hour.
  • the reduction reaction and the subsequent selective crystallization may be accomplished using the same ether solvent.
  • the isolation of the desired 5- bromophthalide may be accomplished according to the following route.
  • the organic phase may be treated to remove most (e.g., between 70 and 95%) of the solvent by distillation, following which an alcohol, or an aqueous solution of said alcohol, is added to the residual organic solvent containing the mixture of isomers.
  • the desired 5-bromophthalide is then selectively crystallized from said alcohol solution.
  • the alcohol is ethanol .
  • the 5-bromophthalide it is possible to further purify the 5-bromophthalide to greater than 98% purity, by means of re-crystallization from, or reslurry in, the solvent used for the crystallization, either dry or in an aqueous mixture containing between 5-20% (wt) water.
  • the amount of THF used for the re-crystallization is such that the weight ratio of THF to the crude 5-bromophthalide is between 3.5:1 and 1.5:1, and preferably 2.0:1.
  • 5-bromophthalide obtained according to the present invention is a useful intermediate in the preparation of the therapeutic agent citalopram ⁇ chemical name: l-[3- (dimethylamino)propyl] -1- (4-fluorophenyl) -1,3- dihydroisobenzofuran-5- carbonitrile ⁇ .
  • Methods for converting 5-bromophthalide into the final therapeutic compound are well known in the art. According to one approach (US 4,136,193), citalopram may be obtained from 5- bromophthalide by reacting said 5-bromophthalide with a
  • 5-bromophthalide obtained according to the process of the present invention may be converted into 5-cyanophthalide, using the procedures described, inter alia, in WO 01/49672, according to which 5-bromophthalide is reacted with a cyano source, such as cuprous cyanide.
  • the intermediate obtained, 5- cyanophthalide may be converted into citalopram according to the methods described, inter alia, in EP 171943 and WO 02/60886.
  • 5-cyanophthalide may successively react with suitable Gringard reagents (4-fluorophenyl magnesium halogenide and N, N-dimethylaminopropyl magnesium halogenide) , to give the following
  • Neutralisation of the excess sodium borohydride was performed by the careful addition of 120 g water and 60g hydrochloric acid (as a 32% aqueous solution) .
  • the pH of the neutralized reaction mixture dropped to pH 1-2, and the temperature rose from 25° C to 30° C.
  • Phase separation was achieved by heating the mixture to 58° C, at which point two clearly distinguishable phases were observed: a heavy aqueous phase having a density of 1.15 g/ml, and a clear organic phase having a density of 1.03 g/ml.
  • the lower, aqueous, phase (159 g) was carefully removed, following which the organic phase was washed with aqueous NaCl solution (140 g, 10% w/w) to remove the residues of H 3 B0 3 formed during the work-up, then the THF (267 g) was partially distilled off from the organic phase over a temperature range of 70 to 75° C in a reboiler.
  • Crude 5-bromophthalide was then crystallized from the organic phase residue (317 g) by adding 30 g water and controlled cooling of said residue from 75° C to 30° C over a period of one hour, following which the temperature was held constant at 30° C for a further one hour.
  • the crystallized material was filtered and washed with lOOg THF.
  • the filtration residue thus formed (113 g, LOD ⁇ 25%) was found to contain approximately 90% 5-bromophthalide and 10% 6-bromophthalide.
  • a slurry of 100 g of the wet, crude 5-bromophthalide was prepared in 140 g of THF containing 6% water at 25° C. This slurry was then heated to 60° C, and held at that temperature for one hour. Re-crystallization of the 5-bromophthalide was achieved by lowering the temperature from 60° C to 25°C over a period of one hour, and then holding at the lower temperature for a further one hour. The crystallized product was then filtered and washed with 40 g of THF, following which 65 g of wet residue was dried at 80° C for a period of 2 hours.
  • the feed solution for the reaction was prepared by dissolving 227 g of 4-bromophthalic anhydride in 300 g of ethylene glycol dimethyl ether at 20° C. This solution was then added to the reducing agent, which was prepared as a slurry of 22.7 g of sodium borohdyride in 200 g ethylene glycol dimethyl ether at 20°C. As the starting material was added to the reducing agent slurry, an increase in temperature from 20°C to 30°C was noted. After approximately 3.0 hours, all of the 4-bromophthalic anhydride had been added to the sodium borohydride slurry, and the reaction was allowed to continue, with stirring, for a further one hour at 26° C.
  • Neutralisation of the excess sodium borohydride was performed by the careful addition of 200 g water and 70 g hydrochloric acid (as a 32% aqueous solution) .
  • the pH of the neutralized reaction mixture dropped to pH 1-2, and the temperature rose from 26° C to 31° C.
  • Phase separation was achieved by heating the mixture to 50° C, at which point two clearly distinguishable phases were observed: a heavy aqueous phase and a clear organic phase.
  • the lower, aqueous, phase (223 g) was carefully removed, following which the organic phase was washed with aqueous NaCl solution (200 g, 15% w/w) to remove the residues of H 3 B0 3 formed during the work-up, then the aqueous ethylene glycol dimethyl ether (262 g) was partially distilled off from the organic phase over a temperature range of 74 to 91° C in a reboiler.
  • Crude 5-bromophthalide was then crystallized from the organic phase residue by controlled cooling of said residue from 91°C to 25° C over a period of one hour, following which the temperature was held constant at 25° C for a further one hour.
  • the crystallized material was filtered and washed with aqueous 50% ethylene glycol dimethyl ether.
  • the filtration residue thus formed was found to contain approximately 80% 5-bromophthalide and 20% 6-bromophthalide.
  • a slurry of 240 g of the wet, crude 5-bromophthalide was prepared in 240 g of aqueous 90% ethylene glycol dimethyl ether at 25° C. This slurry was then heated to 85° C to obtain a solution, and re-crystallisation of the 5-bromophthalide was achieved by lowering the temperature from 85° C to 25°C over a period of one hour, and then holding at the lower temperature for a further one hour. The crystallized product was then filtered and washed with 90 g of aqueous 90% ethylene glycol dimethyl ether, following which 97 g of wet residue was dried at 80° C for a period of 2 hours. The dried product thus formed (83 g) was subjected to HPLC analysis, and was found to contain >99% 5-bromophthalide. The direct yield was approximately 38%.
  • the feed solution for the reaction was prepared by dissolving 57 g of 4-bromophthalic anhydride in 53 g of DMF at 25° C. This solution was then added to the reducing agent, which was prepared as a slurry of 9.5 g of sodium borohydride in 100 g DMF, pre-cooled to 5° C prior to addition of said solution. After approximately 3 hours, all of the 4-bromophthalic anhydride had been added to the sodium borohydride slurry, and the reaction was allowed to continue, with stirring, for a further one hour.
  • a slurry of 30.3 g of the wet, crude 5-bromphthalide was prepared in 50 ,g of ethanol at 25° C. This slurry was then heated to 75° C and held at that temperature for one hour. Re- crystallization of the 5-bromophthalide was achieved by lowering the temperature from 75 to 25° C over a period of one hour, and then holding at the lower temperature for a further one hour. The crystallized product was then filtered and washed with ethanol, prior to being dried at 80° C for a period of two hours. The dried product thus formed (8.1 g) was subjected to HPLC and NMR analysis, and was found to contain approximately 90% 5-bromophthalide. The overall yield of 5-bromophthalide was approximately
  • Example 2 Operating essentially as described in Example 1, the effect of changing the molar ratio of sodium borohydride: 4- bromophthalic anhydride (NaBH 4 : 4-BPAn) on the conversion of 4-bromophthalic anhydride to 5-bromophthalide (5-BP) and 6- bromophthalide (6-BP) was investigated. HPLC was used in order to determine the relative amounts of the starting material and products. The results are presented in Table II.
  • the feed solution for the reaction was prepared by dissolving 455 g of 4-bromophthalic anhydride in 545 g of THF at 25° C. This solution was then added to the reducing agent, which was prepared as a slurry of 48 g of sodium borohydride ⁇ in 450 g THF pre-cooled to 5° C prior to the addition of said solution. As the starting material was added to the reducing agent slurry, an increase in temperature from 5°C to 15°C was noted. After approximately 3 hours, all of the 4-bromophthalic anhydride had been added to the sodium borohydride slurry, and the reaction was allowed to continue, with stirring, for a further one hour at 25° C.
  • Neutralisation of the excess sodium borohydride was performed by the careful addition of 300 g water and 150 g hydrochloric acid (as a 32% aqueous solution) .
  • the pH of the neutralized reaction mixture dropped to pH 1-2, and the temperature rose from 25° C to 32° C.
  • Phase separation was achieved by heating the mixture to 55° C, at which point two clearly distinguishable phases were observed: a heavy aqueous phase and a clear organic phase.
  • the lower, aqueous, phase 600 g was removed, following which the organic phase was washed with aqueous NaCl solution (400 g, 10% w/w) to remove the residues of H3BO3 formed during the work-up, then the aqueous THF (750 g) was distilled off from the organic phase over a temperature range of 70 to 77° C in a reboiler.
  • Aqueous ethanol (700 g, 95%) and water (150 g) were added to the organic phase residue, which was heated to reflux.
  • Crude 5-bromophthalide was then crystallized by controlled cooling of the solution from 75° C to 30° C over a period of one hour, following which- the temperature was held constant at 30° C for a further one hour.
  • the crystallized material was filtered and washed with 250 g aqueous ethanol (95%) .
  • the filtration residue thus formed (272 g, LOD ⁇ 23%) was found to contain approximately 80% 5-bromophthalide and 20% 6- bromophthalide .
  • a slurry of 260 g of the wet, crude 5-bromophthalide was prepared in 540 g of ethanol containing 5% water at 25° C. This slurry was then heated to -70-80° C, and held at that temperature for one hour. Re-crystallization of the 5-bromophthalide was achieved by lowering the temperature from 80° C to 25°C over a period of one hour, and then holding at the lower temperature for a further one hour. The crystallized product was then filtered and washed with 150 g of aqueous 95% ethanol, following which 180 g of wet residue was dried at 80° C for a period of 2 hours. The dried product thus formed (145 g) was subjected to HPLC and NMR analysis, and was found to contain >98% 5-bromophthalide. The yield was approximately 35%. Examples 13 to 15

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Furan Compounds (AREA)

Abstract

L’invention concerne un procédé consistant à réduire de l’anhydride 4-bromophtalique en un solvant organique en vue d’obtenir un mélange de 5-bromophtalide et de 6-bromophtalide, à acidifier le mélange réactionnel, à séparer celui-ci en des phases aqueuse et organique et à effectuer une cristallisation sélective du 5-bromophtalide contenu dans la phase organique.
PCT/IB2003/001450 2003-04-11 2003-04-11 Procede pour la preparation de 5-bromophtalide Ceased WO2004089924A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003214582A AU2003214582A1 (en) 2003-04-11 2003-04-11 Process for the preparation of 5-bromophthalide
PCT/IB2003/001450 WO2004089924A1 (fr) 2003-04-11 2003-04-11 Procede pour la preparation de 5-bromophtalide

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PCT/IB2003/001450 WO2004089924A1 (fr) 2003-04-11 2003-04-11 Procede pour la preparation de 5-bromophtalide

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010134630A1 (fr) * 2009-05-21 2010-11-25 住友化学株式会社 Procédé de fabrication d'un phthalide substitué par halogène
CN107082769A (zh) * 2017-06-02 2017-08-22 上海合全药物研发有限公司 一种5‑溴苯酞的工业化制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998001437A1 (fr) * 1996-07-03 1998-01-15 Basf Aktiengesellschaft Procede de preparation de phthalides

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Publication number Priority date Publication date Assignee Title
WO1998001437A1 (fr) * 1996-07-03 1998-01-15 Basf Aktiengesellschaft Procede de preparation de phthalides

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DONATI, C. ET AL.: "Potential GABAb Receptor Antagonists. III Folded Baclofen Analogues Based on Phthalide", AUSTRALIAN JOURNAL OF CHEMISTRY, vol. 42, 1989, pages 787 - 795, XP009013284 *
HOUBEN-WEYL: "METHODEN DER ORGANISCHEN CHEMIE, 6/2. PASSAGE TEXT", SAUERSTOFF-VERBINDUNGEN 1, METHODEN DER ORGANISCHEN CHEMIE, STUTTGART, G. THIEME VERLAG, DE, vol. TEIL 2 BAND 6, 1963, pages 731 - 733, XP002051920 *
JOHN W PATTERSON: "The Alder-Rickert Reaction in a Synthesis of m-Chlorophenols and 4-Chloromycophenolic Acid", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 60, no. 3, 1995, pages 560 - 563, XP002115532, ISSN: 0022-3263 *
SANTANIELLO, E. ET AL: "Further Studies on Sodium Borohydride-Polyethylene Glycol 400 as a Novel Reducing System", JOURNAL OF ORGANIC CHEMISTRY, vol. 52, 1987, pages 671 - 674, XP002246370 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010134630A1 (fr) * 2009-05-21 2010-11-25 住友化学株式会社 Procédé de fabrication d'un phthalide substitué par halogène
JP2011026295A (ja) * 2009-05-21 2011-02-10 Sumitomo Chemical Co Ltd ハロゲン置換フタリドの製造法
KR20120023801A (ko) * 2009-05-21 2012-03-13 스미또모 가가꾸 가부시키가이샤 할로겐 치환된 프탈라이드의 제조법
CN102428076A (zh) * 2009-05-21 2012-04-25 住友化学株式会社 卤代苯酞的制造方法
US20120142946A1 (en) * 2009-05-21 2012-06-07 Sumitomo Chemical Company, Limited Production method of halogen-substituted phthalide
EP2433933A4 (fr) * 2009-05-21 2012-10-10 Sumitomo Chemical Co Procédé de fabrication d'un phthalide substitué par halogène
US8604221B2 (en) 2009-05-21 2013-12-10 Sumitomo Chemical Company, Limited Production method of halogen-substituted phthalide
TWI498323B (zh) * 2009-05-21 2015-09-01 Sumitomo Chemical Co Method for the production of halogen substituted phthalocyanines
KR101703771B1 (ko) 2009-05-21 2017-02-07 스미또모 가가꾸 가부시키가이샤 할로겐 치환된 프탈라이드의 제조법
CN107082769A (zh) * 2017-06-02 2017-08-22 上海合全药物研发有限公司 一种5‑溴苯酞的工业化制备方法

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