EP0594758A1 - Nouveau procede de bromination aromatique - Google Patents

Nouveau procede de bromination aromatique

Info

Publication number
EP0594758A1
EP0594758A1 EP92915926A EP92915926A EP0594758A1 EP 0594758 A1 EP0594758 A1 EP 0594758A1 EP 92915926 A EP92915926 A EP 92915926A EP 92915926 A EP92915926 A EP 92915926A EP 0594758 A1 EP0594758 A1 EP 0594758A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
acid
solution
bromosuccinimide
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.)
Withdrawn
Application number
EP92915926A
Other languages
German (de)
English (en)
Inventor
Joseph Auerbach
Steven A. Weissman
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.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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 Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0594758A1 publication Critical patent/EP0594758A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B39/00—Halogenation

Definitions

  • NBS N-Bromosuccinimide
  • DBDMH Dibromodimethylhydantoin
  • 2-pyrrolidinyl)methyl]-2,6-dimethoxybenzamide shown below, is a known antipsychotic agent (U.S. Pat. No. 4,232,037).
  • Preparation of remoxipride typically involves a convergent synthesis wherein a suitably activated 3-bromo-2,6-dimethoxybenzoic acid II is coupled with the enantiomerically pure aminomethyl pyrrolidine III.
  • the instant invention provides an improved bromination process for the preparation of brominated aromatic compounds which results in quantitatively fewer of the impurities that are associated with previous disclosed bromination processes.
  • the instant invention also provides a novel reaction condition for bromination of aromatic compounds with N-bromosuccinimide or
  • dibromodimethylhydantoin wherein the solvent is an aqueous alkali solution.
  • the instant invention to provides an improved process for the preparation of
  • the present invention provides a novel process for the preparation of a bromoaromatic compound, having the formula IV:
  • R 1 , R 2 , R 4 , and R 5 are independently selected from:
  • (g) -N(C 1 -C 6 -alkyl) 2 , or R 1 , R 2 , R 3 , R 4 , or R 5 on adjacent ring carbons may be combined to form a -O-(CH 2 ) n -O- residue; provided that at least one of R 1 , R 2 , R 4 , or R 5 is -CO 2 H;
  • R 3 is C 1 -C 6 -alkoxy or -N(C 1 -C 6 -alkyl) 2 , or R 2 and R 3 or R 3 and R 4 are combined to form a -O-(CH 2 ) n -O- residue; and n is 1 to 3 ; which comprises:
  • aqueous alkali solution includes solution of an alkali base in an aqueous solvent and the like.
  • alkali base includes strong alkali bases, which include sodium hydroxide, lithium hydroxide, potassium hydroxide and the like.
  • a preferred alkali base is sodium hydroxide.
  • aqueous solvent includes water and solutions of water and a water miscible
  • water miscible co-solvent includes low-molecular-weight alcohols, dimethoxyethane, tetrahydrofuran and the like.
  • a preferred aqueous solvent is water.
  • low-molecular-weight alcohol includes hydroxyalkane compounds having from 1 to 4 carbon atoms and includes branched and straight chain alcohols.
  • the term includes methanol, ethanol, iso-propanol and the like.
  • the term "temperature . . . . sufficient to optimally convert the compound of the formula V to a salt of the compound of the formula IV” represents a temperature sufficiently high to maintain conversion of the starting material V but also sufficiently low to avoid decomposition of the starting material and the product.
  • the term includes temperatures between 0° and 30°C. A preferred temperature is between 23° and 29°C.
  • the term "length of time sufficient to optimally convert the compounds of the formula V to a salt of the compound of the formula IV” represents a period of time sufficiently long to convert the maximum amount of the starting material to the salt of the compound of the formula IV.
  • the term includes times of 1 to 40 hours.
  • a preferred length of time is a time length between 4 and 25 hours.
  • a salt of the compound of formula IV includes the salt of a carboxylic acid moiety of the product IV (if such a moiety is present) which corresponds to the alkali base employed in the aqueous alkali solution.
  • the term includes the sodium salt, lithium salt, potassium salt and the like.
  • the term "acid” includes anhydrous acids and aqueous acidic solutions.
  • anhydrous acid includes gaseous mineral acids such as hydrogen bromide, hydrogen chloride and the like.
  • aqueous acidic solution includes solutions of a mineral acid or sulfuric acid in an aqueous solvent.
  • mineral acid includes hydrogen chloride, hydrogen bromide and the like.
  • a preferred aqueous acidic solution is aqueeus
  • One embodiment of the process of the instant invention is that process wherein the brominating agent employed is N-bromosuccinimide in an amount selected from a value in the range between 1.0 to 1.5 molar equivalents with respect to starting aromatic compound V.
  • a class of this embodiment is the process wherein the amount of the alkali base in the aqueous alkali solution employed is selected from a value in the range between 1.0 and 3.5 molar equivalents with respect to starting aromatic compound V.
  • aromatic compound V has been neutralized to the molar equivalent of N-bromosuccinimide utilized is selected from a value in the range between 1.0 and 1.25.
  • dibromodimethylhydantoin in an amount selected from a value in the range between 0.505 to 0.55 molar equivalents with respect to starting aromatic compound V.
  • a class of this embodiment is the process wherein the amount of the alkali base in the aqueous alkali solution employed is selected from a value in the range between 1.01 and 1.1 molar equivalents with respect to starting aromatic compound V.
  • aromatic compound V has been neutralized to the molar equivalent of dibromodimethylhydantoin utilized is selected from a value in the range between 0.1 and 1.25.
  • One embodiment of the instant invention is the process for the preparation of a bromobenzoic acid, having the formula IVa:
  • One class of this embodiment of the process of the instant invention is that process wherein the amount of N-bromosuccinimide employed is selected from a value in the range between 1.0 to 1.5 molar equivalents with respect to starting
  • the amount of the alkali base in the aqueous alkali solution employed is selected from a value in the range between 2.0 and 2.5 molar
  • 2,6-dimethoxybenzoic acid has been neutralized to the molar equivalent of N-bromosuccinimide utilized is selected from a value in the range between 1.0 and 1.25.
  • the aromatic compound of the formula V is dissolved in an aqueous alkali solution containing a excess amount of equivalents of base, such as aqueous NaOH solution, aqueous KOH solution, methanolic aqueous NaOH and the like.
  • a suitable brominating agent such as N-bromosuccinimide or 1,3-dibromo-5,5-dimethyl- hydantoin, and the reaction mixture is stirred at room temperature for a period of time, such as 2 hours to 24 hours.
  • the reaction mixture is then tested by a potassium iodide starch paper test (SPT) [starch iodide test paper that has been wetted with aqueous acetic acid; 1/1; v/v)] and if the test is positive, an oxidant-neutralizing salt, such as sodium sulfite and the like, is added.
  • SPT potassium iodide starch paper test
  • the reaction mixture is then treated with an acid or an acidic aqueous solution and cooled in an ice bath. If the product formed is insoluble in the work-up solution, filtration of the mixture provides the crude product IV which may be used as is in a subsequent reaction or further purified. If isolation by filtration is not appropriate a standard organic solvent extractive work-up may be employed.
  • 2,6-dimethoxybenzoic acid Va is dissolved in an aqueous alkali solution containing an excess amount of equivalents of base, such as aqueous NaOH
  • the aminomethylpyrrolidine component VII of remoxipride is prepared from enantiomerically pure L-proline VIII.
  • L-proline is esterified and the ester treated with ammonia in a suitable solvent, such as methanol, ethanol and the like, to provide the amide IX.
  • the amide is ring N-ethylated by treating it with an aklylating agent such as ethyl bromide and the like, in the presence of a base, such as potassium carbonate, sodium carbonate, and the like, in a suitable solvent such as ethanol.
  • the amide X is subsequently reduced with a suitable reducing agent, such as lithium aluminum hydride and the like, to provide compound VII.
  • activating reagent such as thionyl chloride, carbonyl diimidazole and the like, to provide an activated acid which is reacted, without isolation, with compound VII, to provide crude remoxipride I.
  • Example 1 is provided as representative of previously known preparations of the intermediate
  • N-bromosuccinimide (Aldrich 99%), was added with brisk stirring to the cold solution. The reaction temperature rose to 8°C over two minutes then cooled back to 4°C over an additional 4 minutes. The cooling bath was removed and the reaction was allowed to warm to room temperature reaching 21°C after 0.5 hr. and 26°C after about one hour. The temperature rose to 27 to 28°C for the remaining reaction time. The total time since NBS addition was 2 hr. 10 min. The reaction at this point gave a positive potassium iodide starch paper test (SPT). The reaction was then treated with 0.5 gm Na 2 SO 3 which resulted in a negative SPT.
  • SPT sodium iodide starch paper test
  • the reaction was diluted with 50 mL of water and was treated, in portions, with 12 mL concentrated aqueous HBr (2.43 equiv.) causing precipitation of the product.
  • the mixture was cooled to ice bath temperature and filtered off (fritted glass funnel, M porosity).
  • the solid was slurried and washed in portions with 125 mL of ice cold pure water (the pH at the end of the filtration rose to 3°C.
  • the precipitate was suction dried under a nitrogen stream and then dried overnight under high vacuum at 75°C.
  • the product weighed 9.95 gm.
  • Method B Preparation Using N-Bromosuccinimide and Aqueous Sodium Hydroxide at 4 hour 20 min.
  • reaction mixture was cooled to 2°C then the cooling bath was removed allowing the reaction temperature to rise to room temperature. After 4 hr . and 20 min . the reaction gave a positive SPT.
  • the reaction mixture was treated with 8 grams of sodium sulfite which resulted in a negative SPT. The insolubles were filtered from the reaction mixture and the filtrate returned to the reaction vessel. An additional 650 mL of water was added to the
  • the solid was suction dried under nitrogen then under high vacuum at 60°C overnight to provide 140.8 grams of the desired product (92.7% yield; 97.1% wt.% pure containing 0.29 wt.% of unreacted starting material and no detectable water by KF titration).
  • N-bromosuccinimide (121.93 grams, Aldrich 99%, 1.2 equiv) in portions: about 90 grams was added over three minutes and the reaction temperature rose to 8°C. The reaction temperature then decreased to 6°C and the remaining NBS was added. The temperature rose again to 8°C and then the reaction mixture cooled down to 3°C and the ice/water cooling bath was removed. The temperature of the reaction mixture was allowed to rise to room temperature. After 21 hr. 34 min. the reaction mixture gave a weakly positive
  • the reaction mixture is treated with 2.0 grams of sodium sulfite which resulted in a negative SPT.
  • the reaction mixture was filtered to remove a small amount of insoluble matter.
  • the filtered reaction mixture was returned to a clean 5 liter reaction vessel and diluted with 650 mL of water.
  • To the stirred reaction mixture was added 167.57 mL of concentrated 48% aqueous HBr over three minutes. A copious precipitate formed.
  • the mixture was stirred and cooled to 3°C and the solids were filtered off through a 3 L (M) porosity funnel with a fritted disk. The solid was washed with 1352 mL of ice cold water in portions then dried with suction under nitrogen and then overnight at 60°C under high vacuum.
  • the isolated product weight was 142.9 grams 94.82% yield/97.91 wt.% pure which when corrected for sample used in HPLC reaction monitoring calculates to 143.7 grams/95.4% yield.
  • the product contained residual starting material of 0.14 HPLC area % and no detectable water by KF titration. The following impurities were detected by HPLC in the crude
  • succinimide 0.573 area %
  • 3,5-dibromo- 2,6-dimethoxybenzoic acid 0.146 area %
  • reaction mixture rose to 10°C and then the cooling bath was removed. The reaction was warmed to room temperature and was stirred for a total of 27 hours. The reaction at this point gave a weakly positive SPT.
  • the reaction mixture was treated with 1 gm of sodium sulfite which resulted in the reaction mixture giving a negative SPT.
  • the reaction mixture was cooled to 0° - 1°C and was acidified with 15.95 mL of concentrated
  • the copious precipitated reaction mixture was filtered cold through a fritted glass suction
  • 2,6-Dimethoxybenzoic acid (99.0 g, 538 mmols) is stirred with 500 mL of water at room temperature, followed by the addition of 5N aqueous NaOH (110 mL, 550 mmol).
  • the resulting orange solution is cooled to 20°C by a cold water bath and DBDMH (80.2 g, 272.1 mmols) is added in portions over 5 min. while maintaining the internal temperature at ⁇ 25°C.
  • the mixture was allowed to stir at 20-25°C for 4.5 hours and worked up as described in Method A hereinabove.
  • the crude product was recrystallized from aqueous ethanol to provide 122.6 g of the desired product. Analytical evaluation of the product and the mother liquors from the
  • the reaction mixture was aged at 15°C for 3 hours and the solid which formed was collected by filtration and washed with 60 mL of water.
  • the solid was dried under high vacuum at 70°C for 12 hours to provide 87.9 g of the crude desired product (93.0% pure, 79% yield).
  • the following impurities were detected by HPLC in the crude
  • reaction product 3,5-dibromo-2,6-dimethoxybenzoic acid: 0.385 area %; 3,5-dibromo-2-hydroxy- 6-methoxybenzoic acid: 4.05 area %; and
  • NaOH o-Anisic acid (4.56g, 30 mmols) was charged in a 250 mL flask and a solution of 2.64g (66 mmol) of NaOH in 47 mL of water was added. The anisic acid was dissolved with stirring and the solution then cooled to 0° to 5°C with an ice/methanol bath. NBS (6.41g, 36 mmol) was added in portions to the
  • the filtrate from the solid contains another 2% yield of brominated product.
  • the isolated product contains 0.3 wt% of

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouveau procédé de bromination de fractions aromatiques faisant appel à du N-bromosuccinimide ou à de la dibromodiméthylhydantoïne dans un milieu alcalin aqueux. Ledit procédé de bromination est utilisé pour préparer un intermédiaire qui entre dans la composition du remoxipride, un composé antipsychotique.
EP92915926A 1991-07-15 1992-07-15 Nouveau procede de bromination aromatique Withdrawn EP0594758A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US73036491A 1991-07-15 1991-07-15
PCT/US1992/005901 WO1993002036A1 (fr) 1991-07-15 1992-07-15 Nouveau procede de bromination aromatique
US730364 2000-12-05

Publications (1)

Publication Number Publication Date
EP0594758A1 true EP0594758A1 (fr) 1994-05-04

Family

ID=24935035

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92915926A Withdrawn EP0594758A1 (fr) 1991-07-15 1992-07-15 Nouveau procede de bromination aromatique

Country Status (4)

Country Link
EP (1) EP0594758A1 (fr)
JP (1) JPH06509115A (fr)
CA (1) CA2112127A1 (fr)
WO (1) WO1993002036A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4415704B4 (de) * 1994-05-04 2005-01-27 Ina-Schaeffler Kg Linearwälzlager
US6001883A (en) * 1998-06-24 1999-12-14 American Cyanamid Company Fungicidal 2-methoxybenzophenones
US6127570A (en) * 1999-06-10 2000-10-03 American Cyanamid Company Fungicidal substituted 2-hydroxybenzophenones
EP3284734B1 (fr) * 2015-04-13 2021-12-01 Sumitomo Seika Chemicals Co., Ltd. Procédé de production d'acides benzoïques 2-halogénés
CN105859732B (zh) * 2016-04-11 2018-04-06 浙江海正药业股份有限公司 制备ad‑35的工艺

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE411118B (sv) * 1978-03-23 1979-12-03 Astra Laekemedel Ab Ett forfarande for framstellning av 2,6-dialkoxibensamider med terapentiska egenskaper
US4639518A (en) * 1984-09-24 1987-01-27 Ortho Pharmaceutical Corporation Substituted quinazolinediones

Non-Patent Citations (1)

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Title
See references of WO9302036A1 *

Also Published As

Publication number Publication date
WO1993002036A1 (fr) 1993-02-04
CA2112127A1 (fr) 1993-02-04
JPH06509115A (ja) 1994-10-13

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