JPH06509115A - Novel aromatic bromination method - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Novel aromatic bromination method Related applications This application is part of co-pending application No. 730.364 (filed July 15, 1991). This is a continuation application.

Background of the invention N-bromosuccinimide (NBS) reacts with various organic components under diverse reaction conditions. A well-known synthetic organic reagent useful for the bromination and/or oxidation of The academic review is in 5ynthetic Reagents, vol, 2 (J, S. Pizey, John fiely, New York, 1974 ) is disclosed on pages 1-63. NBS bromination of aromatic components is polar and non-polar. It has been carried out in acidic organic solvents and acidic aqueous solutions; There have been no reports on NBS bromination using aqueous solutions. like this When using a basic medium, the hydrogen bromide generated during the reaction is collected by the solvent, which It is possible to reduce side reactions that can occur when hydrogen bromide is present in the solution. There is an advantage.

Multiple bromination has also not been observed.

NBS contains dibromodimethylhydantoin (DBDM), which is not widely used. H) is a versatile organic reagent [Reed, R, A,.

See Chet Prod, 23.299 (1960)]. This reagent is NB It offers the advantages of being more stable and cheaper on a bromine equivalent basis than S. Ru. Previously reported bromination of substituted aromatics using DBDMII was performed using refluxing CC 14 or CtlCl. DBDMH is a pool disinfectant. It can also be used.

Remoxipride I ((S)-3- Bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-cymethoxy Cibenzamide) is a known psychosis treatment (U.S. Pat. No. 4.232.03). No. 7). The method for producing remoxyviride usually involves the use of suitably activated 3-bromo-2 ,6-dimethoxybenzoic acid■ to enantiomerically pure aminomethylpyrrolidi Including convergent synthesis (convergent 5 synthesis) that combines with nothing.

Z: Activating group Intermediate IVa, which is a precursor of compound H, is typically prepared using bromine and dioxic acid as follows. bromination of commercially available 2,6-dimethoxybenzoic acid using San.

Intermediate IVa is obtained from this reaction in high yield, but the products generated during the reaction and Several impurities are generated from the additional reaction of bromine and/or hydrogen bromide: .

Summary of the invention The present invention provides brominated aromatic compounds with a lower amount of impurities than conventionally disclosed bromination methods. Provided is an improved bromination method for product manufacturers.

The present invention uses N-bromosuccinimide or dibutyl succinimide whose solvent is an alkaline aqueous solution. We also present new reaction conditions for the bromination of aromatic compounds using romodimethylhydantoin. provide

Furthermore, the present invention provides 3-butyl alcohol with higher yield and less impurities than conventionally known methods. An improved process for producing lomo-2,6-dimethoxybenzoic acid is provided.

The present invention is based on the formula ■: [In the formula, R1, R2, R4 or R6 (if one of them is -Co or H) Under such conditions, R1, R2, R4 and R5 independently represent (a) hydrogen; (b) C, -cs alkyl, (C) CI-Cs alkoxy, (f)-cow(cI-C6 alkyl), (g)-N(C+-C6 alkyl )2 R1, R2, R3, R4 or on adjacent ring carbons selected from R8 is bonded to form -o-(c■,), -o-residue; R3 is C5-C6-alkoxy or -N(C,-C6-alkyl); or R2 and R3 or R3 and R4 are combined to form 10-(CI, ), -0-residue; and n is 1 to 3] A manufacturing method according to the formula V: ■ In formula 1, if substituents R1, R1, R3, R4 and rJR''+i are ylA defined above. ] in an alkaline aqueous solution, (a) N-bromosuccinimide, and (b) an odor selected from 1,3-dibromo-5,5-dimethylhydantoin. Optimal conversion of a compound of formula V to a compound of formula ■ or a salt thereof using a oxidizing agent treatment for a time and temperature sufficient to Optionally treating the reaction mixture with an acid to form a compound of formula I will provide a.

The term “alkaline aqueous solution” refers to a solution of an alkaline base in an aqueous solvent, etc. including.

The term “alkaline base” refers to sodium hydroxide, lithium hydroxide, hydroxide Contains strong alkaline bases such as potassium. A preferred alkaline base is sodium hydroxide. It is thorium.

The term "aqueous solvent" includes water and solutions of water and water-miscible cosolvents. “Water mix The term "compatible cosolvent" refers to low molecular weight alcohols, dimethoxy-ethane, tetra Contains hydrofuran, etc. The preferred aqueous solvent is water.

The term "low molecular weight alcohol" refers to hydroxyalcohols having 1 to 4 carbon atoms. Contains lucan compounds, including straight and branched chain alcohols. This term refers to methanol Contains alcohol, ethanol, isopropanol, etc.

The term "temperature sufficient to optimally convert a compound of formula V to a salt of a compound of formula ■" The term is high enough to retain conversion of starting material V, but decomposition of starting material and product represents a temperature low enough to avoid This term refers to temperatures between 0<0>C and 30<0>C.

A preferred temperature is 23°C to 29°C.

“A time sufficient to optimally convert a compound of formula V to a salt of a compound of formula ■” means: Represents the time sufficient to convert the maximum amount of starting material to the salt of the compound of formula (1). this The term includes 1 to 40 hours. A preferred time is 4 to 25 hours.

The term “salt of a compound of formula ■” refers to the term “salt of a compound of formula ■” Carboxylic acid moiety of product ■ corresponding to alkaline base used in aqueous solution Contains salt.

The term includes sodium salts, lithium salts, potassium salts, and the like.

The term "acid" includes acid anhydrides and aqueous acids.

The term “anhydrous acid” refers to gaseous mineral acids (e.g. (e.g., hydrogen bromide, hydrogen chloride, etc.).

The term "acidic aqueous solution" includes solutions of mineral acids or sulfuric acids in aqueous solvents. “mine The term "acid" includes hydrogen chloride, hydrogen bromide, etc. Preferred acidic aqueous solutions include hydrogen bromide. It is a hydrogen acid aqueous solution.

In one embodiment of the process of the invention, the brominating agent used is the starting aromatic compound V of N-bromosuccini in an amount selected from a value of 1.0-1.5 molar equivalents for This is the middle method.

One class of this embodiment includes the amount of alkaline base in the alkaline aqueous solution used. Selected from a value of 1.0 to 3.5 molar equivalents relative to the starting aromatic compound V There is a way.

Subclasses of this class of the invention include the models of N-bromosuccinimide used. After the acid moieties present in the starting aromatic compound V are neutralized relative to the equivalent weight of Selecting the molar equivalent ratio of the remaining alkaline base from a value of 1.0-1.25 There is a law.

Another class of this embodiment involves cooling and filtering the acid-treated reaction mixture to obtain a formula There are methods of the invention that provide compounds.

Another class of this embodiment includes extracting the acid-treated reaction mixture with a suitable organic solvent; After washing, drying and evaporation, there is a process according to the invention which provides a compound of formula (1).

Another embodiment of the invention provides that the brominating agent used is 0% relative to the starting aromatic compound V. ．． dibromodimethyl hydant in an amount selected from a value of 505 to 0.55 molar equivalents That's how it is.

One class of this embodiment involves determining the amount of alkaline base in the alkaline aqueous solution used. selected from a value of 1.01 to 1.1 molar equivalent relative to the aromatic compound V of the emitting substance There is a way.

Subclasses of this class of the invention include dibromodimethylhydantoin used; The acid moiety present in the starting aromatic compound V relative to the molar equivalent of The molar equivalent ratio of the alkaline base remaining afterwards is selected from a value of 0.1 to 1.25. There is a way to do it.

One of the embodiments of the present invention is the formula (a): Engineering Va A method for producing pro-7benzoic acid having the formula ■a: a benzoic acid of formula Va with N-bromosuccinimide in alkaline aqueous solution. for optimal conversion of the compound of formula IVa or the salt of the compound of formula a. treatment for sufficient time and temperature; then Optionally treating the reaction mixture with acid The method includes:

One class of this aspect of the method of the invention includes the amount of N-bromosuccinimide used. is a value of 1.0 to 1.5 molar equivalent relative to the starting material 2,6-dimethoxybenzoic acid. There are methods to choose from.

Subclasses of this embodiment include the amount of alkaline base in the alkaline aqueous solution used; is a value of 2.0 to 2.5 molar equivalents relative to the starting material 2,6-dimethoxybenzoic acid. There are methods to choose from.

As a subclass of this class of the invention, the N-prosuccinimide used remaining after neutralization of the acid moiety of 2,6-dimethoxybenzoic acid relative to the molar equivalent of A method in which the molar equivalent ratio of the alkaline base is selected from a value of 1.0 to 1.25. There is.

In another subclass of this embodiment, the acid-treated reaction mixture is cooled and filtered to provide formula I There is a method of the present invention that provides a compound of Va.

Another subclass of this embodiment includes extracting the acid-treated reaction mixture with a suitable organic solvent. and, after washing, drying and evaporation, provides a compound of formula rVa. .

Synthetic Scheme 1 below shows the reaction sequence using the method of the invention. This space The scheme is illustrative of the invention, not limiting.

xv Regarding the above formula, first, the aromatic compound of formula V is Potassic aqueous solution (e.g. NaOH aqueous solution, KOH aqueous solution, methanolic NaOH (e.g., an aqueous solution). The solution is then treated with a suitable brominating agent (e.g. N-bromine). Mosuccinimide or 1,3-dibromo-5,5-dimethyl-hydantoin) and stir the reaction mixture at room temperature for a predetermined period of time (e.g., 2 to 24 hours). Ru. The reaction mixture was then subjected to the starch potassium iodide paper test (SPT) [aqueous acetic acid; If the test is positive, Add oxidizing agent-neutralizing salt (eg, sodium sulfite, etc.). Then reaction mixture The material is treated with an acid or an acidic aqueous solution and cooled in a water bath. The formed product is manipulated (w ork-up) solution, filtering the mixture allows the next reaction to A crude product is obtained which can be used as is or further purified. For filtration If isolation by organic solvents is not suitable, standard organic solvent extraction procedures may be used.

The following synthetic scheme 2 shows the reaction order using the method of one embodiment of the present invention. It is. This scheme is illustrative of the invention and is not limiting.

Double series (1 XVa Regarding the above formula, first add 2,6-dimethoxybenzoic acid Va in an excess amount of the base. dissolved in an alkaline aqueous solution (e.g., NaOH aqueous solution, KOH aqueous solution, etc.) containing Dissolve to obtain an alkaline solution of salt ①. The solution was then diluted with N-bromosuccinimide. (NBS) and the reaction mixture at room temperature for a predetermined period of time (e.g., 2 h to 24 h). ) Stir. The reaction mixture was then subjected to the starch potassium iodide paper test (SPT) [vinegar acid aqueous solution; 1/1; iodized starch test paper wetted with v/v], the test is positive If so, add an oxidizing agent-neutralizing salt (eg, sodium sulfite, etc.). Next The reaction mixture is treated with acid or acidic aqueous solution and cooled in a water bath.

Once the mixture is filtered, it can be used as is in the next reaction or further purified. The crude product IVa is obtained.

Synthesis Scheme 3 below illustrates the use of the method of the invention in the synthesis of remoxyviride. Explain obedience. This scheme is illustrative of the invention and is not limiting. There isn't.

All degrees are in degrees Celsius. All crude product purity percentages are weight percentages. , HPLC [YMCAQ-301 column (S-5120^0DS) reverse phase; mobile phase : 58% 0.071 pH 1,8 phosphate buffer, 48% C1, CN; 225 The yield of the desired product is determined by converting the pure monobrominated product to It was nice. All percentages of impurities disclosed were determined by HPLC and were added to the desired product. It is the area percentage of

500L round bottom 4 neck 24/ with mechanical stirrer and digital thermometer 40 Into the ST reaction vessel, add powdered 2,6-dimethoxybenzoic acid (D11B^) (^1 drich-99%, 8.0 g, 43.473 gmol), deionized water (5 0*L) and 5N NaOH aqueous solution (18,25*L, 2.1 equivalents). Ta.

The mixture was stirred to dissolve the acid and the temperature was increased to 30°C.

The solution was cooled to 2°C in a water bath and maintained at that temperature. Then, while stirring vigorously Powdered N-bromosuccinimide (^1drich-99%, 8.2 0g) was added. The reaction temperature was increased to 8°C for 2 minutes, then 4°C for an additional 4 minutes. It was cooled to The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and after 0.5 h to 21 °C. The temperature was then raised to 26°C after about 1 hour. For the remaining reaction time, increase the temperature to 27. The temperature was increased to 28°C. Total time from NBS addition was 2 hours 10 minutes.

At this point, the potassium iodide starch paper test (SPT) result from the reaction mixture is positive. Met. The reaction mixture was then treated with Na1SO1 (0,5 g) resulting in SP T became negative. The reaction mixture was diluted with water (50*L) and concentrated with 11Br aqueous solution ( 12*L, 2.43 eq.), the product precipitated. blend was cooled to water bath temperature and filtered off (fritted glass funnel, pore size M). slurry solids - and washed little by little with water-cooled pure water (125i+L) (pH at the end of filtration). (was raised to 3°C). The precipitate was suction dried under a stream of nitrogen and then incubated at 75°C under high vacuum. Dry overnight. The product weighed 9.95 g. This tlPLc analysis from 1.1% by weight of unreacted starting material/1.4% yield and the desired monobrominated product. Contains 97.9% by weight/85.8% yield and Karl Fischer ( KF) titration revealed that it contained no detectable water.

5 liter round bottom 4 neck 24 with mechanical stirrer and digital thermometer /40 Into the ST reaction vessel, add powdered 2,6-dimethoxybenzoic acid (Aidrich). 99%, 104g, 565mmol), 5N NaOH aqueous solution (255kaku1 ．． 1275 mmol, 2.256 eq) and water (650 sL) were added.

The mixture was stirred to dissolve the DMB^ and then cooled to 0 °C in an ice/MeOH bath. Ta. Powdered N-bromosuccinimide (Aldrich 99%, 121.9g, 1.2 equivalents) was added little by little, and NBS (90g) was added over 2 minutes. was added, the reaction temperature was raised to 5° C., and an additional 31.9 g was added. reaction mixture After cooling to 2°C, the cooling bath was removed and the reaction temperature was allowed to rise to room temperature. 4 hours After 20 minutes, the reaction showed a positive SPT. The reaction mixture was dissolved in sodium sulfite (8 g ), SPT became negative. Insoluble matter is filtered from the reaction mixture, and the filtrate is was returned to the reaction vessel. More water (650+*L) was added to the filtrate. Concentrated 48% bromide Hydrogen acid aqueous solution (167, 57*L, 2.6 eq.) was added to the reaction mixture in 1 minute. The product precipitated. The thick reaction mixture was diluted with water (500 sL) and heated to 0-5 °C. Cool to , then filter through a 3 liter funnel with a fritted filter plate of pore size (M). Ta. The solid was further washed in portions with water (1150*L). From the final filtrate, bromine A weakly positive test result was obtained. The solid was sucked dry under nitrogen and then heated under high vacuum at 60°C. After drying under air overnight, the desired product (140.8 g, 92.7% yield; 97.1% by weight of pure product containing 0.29% by weight of starting material, by KF titration (free of detectable water) was obtained.

5 liter round bottom 4 neck 24 with mechanical stirrer and digital thermometer /40 Into the ST reaction vessel, add powdered 2,6-dimethoxybenzoic acid (Aidrich). 99%, 104 g, 565.1 mmol), 5N NaOH aqueous solution (255 sL, 1275 mmol 1.2.256 equivalents) and water (650*L) were added .

The mixture was stirred to dissolve the DMB and then cooled to 1°C.

Powder N-dibromoxinimide (121.93 g, Aidri ch 99%, 1.2 equivalents) was added little by little, about 90 g was added over 3 minutes, and the reaction The temperature was increased to 8°C. The reaction temperature was then lowered to 6 °C and the remaining NBS was added. did. The temperature was raised again to 8 °C, then the reaction mixture was cooled to 3 °C and ice/water cooled. The cooling bath was removed. The temperature of the reaction mixture was increased to room temperature. After 21 hours and 34 minutes, The reaction mixture showed a weakly positive SPT. The reaction mixture was dissolved in sodium sulfite (2.0 g ), SPT became negative. Filter the reaction mixture to remove small amounts of insoluble material. quality was removed.

Transfer the filtered reaction mixture to a clean 5 liter reaction vessel and dilute with water (650+eL). Diluted. A concentrated 48% aqueous HBr solution (167,5 7 L) was added in 3 minutes. A large amount of precipitate formed. Stir the mixture and cool to 3°C. The solids were filtered off through a 3 L (M) pore size funnel equipped with a fritted filter plate. solid The body was washed in portions with ice-cold water (1352 mL), then suction dried under nitrogen and dried on high heat. Dry under vacuum at 60° C. overnight. The weight of the isolated product was 142.9 g. The yield was 94.82%/purity was 97.91fl1%, and HPLC reaction monitoring After correcting for the sample used, this is estimated to be 143.7g/95.4% yield. It was done. The product contained 0.14+1 PLC area % residue of starting material. , contained no detectable water by IF titration. Crude product with less impurities Detected by medium HPLC; Succinimide: 0.573 area%; 3.5-dibromo -2,6-dimethoxybenzoic acid: Q, 146 area%; and 3,5-dibromo-2 -Hydroxy-6-methoxybenzoic acid: 0.012 area %.

500L round bottom 4 neck 24/ with mechanical stirrer and digital thermometer 40 Into the S7 reaction vessel, add powdered 2,6-dimethoxybenzoic acid (^1drich 9 9%, 8.0g, 43.473mmol), potassium hydroxide (86.8% pure degree, 7.02g, 2.5 equivalents, 108.68ml+ol) and water (45s L) was filled. The reaction mixture was stirred and heated to 50"C to dissolve the mixture. . The mixture was cooled to 1° C. and powdered N-bromosuccinimide (9.38 g, 99 % purity, 1,2 eq.) was added to the reaction mixture.

The temperature of the reaction mixture was increased to 10° C. and the cooling bath was removed.

The reaction mixture was allowed to warm to room temperature and stirred for a total of 27 hours. At this point the reaction mixture is It showed a weakly positive SPT. Treat the reaction mixture with sodium sulfite (1 g) and the reaction mixture showed a negative SPT. The reaction mixture was cooled to 0°C to 1°C and the strong odor was removed. Acidified with hydrohydric acid (15.95 layers added in portions over 1 minute).

The heavily precipitated reaction mixture was filtered through a fritted glass suction funnel. filtrate The precipitate was washed little by little with a water-cooled lNHBr aqueous solution (125 L). and suction dry under nitrogen. The precipitate was dried at 60°C overnight. The product is 10.5 g, and when analyzed by HPLC, 1.9% by weight of unreacted starting material/yield 2.6% and 90.1% by weight of the desired product (83.3% yield), K No water was detected by F titration.

2.6-dimethoxybenzoic acid (99.0 g, 538 mmol) was dissolved in water (538 mmol) at room temperature. 00mL), and then stirred with 5N NaOH aqueous solution (110L, 550mL). mm.

l) was added. The resulting orange solution was cooled to 20°C in an ice-water bath, and the internal temperature was maintained at <25°C. DBDMH (80.2 g, 272.1 mmol) was added little by little over 5 minutes while maintaining Added one. The mixture was stirred at 20-25 °C for 4.5 h and as described in the method above. operated on. Recrystallization of the crude product from aqueous ethanol yields the desired product 1 22.6g was obtained. Analytical measurements of the product and mother liquor from recrystallization indicate that 3-bro The analytical yield of mo-2,6-dimethoxybenzoic acid was 90.0%, and the The analytical yield of mo-2,6-dimethoxybenzoic acid was 2.1%.

Method F Preparation with Bromine in Nidioxane (Example of Conventional Method) 2 liter round bottom flask 2,6-dimethoxybenzoic acid (99%, 72 g, 391.2 mmol) ) and dioxane (237 g).

The solution was cooled to 15°C and bromine (62.1 g, 99.5%, 1 eq.) was added to the temperature. The mixture was added dropwise over 2 hours while maintaining the temperature at 17-19°C. The reaction mixture was heated at 20°C for 2 hours. Stir for a while and then water (90 sL) was added dropwise to the mixture over 30 minutes. 1 of the mixture It was cooled to 5° C. and additional water (834 μL) was added dropwise over 2 hours. reaction mixture The material was aged at 15° C. for 3 hours, the solid formed was collected by filtration, and water (60 sL) Washed with. Drying the solid under high vacuum at 70°C for 12 hours yields the crude desired product. A product (87.9 g, purity 93.0%, yield 79%) was obtained.

The following impurities were detected by 1'1 PLC in the crude reaction product; 3 ,5-dibromo-2,6-dimethoxybenzoic acid: 0.385 area%; 3,5-di Bromo-2-hydroxy-6-methoxybenzoic acid: 4.05 area%; Lomo-2-hydroxy-6-methoxybenzoic acid: 2.91 area %.

Using the method described in Example 1, Method E above, 3.4.5-trimethoxyben After brominating aromatic acid with DBDMH and reacting at 20-25°C for 25 hours, the following results (min. yield) was obtained.

2-Bromo-3,4,5-trimethoxybenfF#: 91. lX; 3, 4.5- Trimethoxybenzoic acid: 3.7%: 2.6-dipromo 3.4.5-trimeth Xybenzoic acid: 2.0%.

Using the method described in Example 1, Method E above, 2,3-dimethoxybenzoic acid was After bromination with DBDMH and reaction at 20-25°C for 22 hours, the following results (analytical yield )was gotten.

6-bromo-2,3-dimethoxybenzoic acid: 90.3%; 2,3-dimethoxybenzoic acid Nizoic acid, 7%: 5-bromo-2,3-dimethoxybenzoic acid: 2°5%.

Using the method described in Example 1, Method E above, piperonyl acid was After bromination and reaction at 20-25°C for 22 hours, the following results (analytical yield) were obtained: .

2-Promopiperonilic acid: 86.0%: Biberonylic acid nia, 7%.

Fill a 250 mL flask with 0-anisic acid (4.56 g, 30 m-ol), A solution of NaOH (2.64 g, 66 mmol) in water (47 mL) was added.

Stir to dissolve the anisic acid, then cool the solution to 0°C to 5°C in an ice/methanol bath. Rejected. Add NBS (6.41 g, 36 mmol) little by little to the reaction flask. After the addition was complete, the reaction mixture was warmed to room temperature. Stir the reaction mixture at room temperature for 48 hours. During this time, it was monitored by analytical LC. After 48 hours, additional NBS (0.2 eq. , 5 mol) was added to the reaction mixture and the reaction mixture was stirred for an additional 7 h at room temperature. Ta. Working as described in Example 1, Method A, a solid (7.34 g, HPLC As a result, 98.5% purity and 1.5% solids (unreacted starting material; yield 93%) were obtained. Ta. The filtrate from the solids contained an additional 2% yield of brominated product.

Using the method described in Example 1, Method E above, 0-anisic acid was prepared with DBDllH. After bromination and reaction at 20-25°C for 18 hours, the following results (analytical yield) were obtained: .

5-bromo-2-methoxybenzoic acid: 98%.

The isolated product contains 0.3% by weight of unreacted product.

International search report. M/lle. ? /I’IC0゜.

,,,, PCT/IJS 92105901 front page continuation (51) Int, C1,5 identification code Office serial number CO7D 317/68 9165-4CI

Claims (10)

[Claims] 1. Formula 1V: ▲There are mathematical formulas, chemical formulas, tables, etc.▼IV [In the formula, R1, R2, R4 or R5 R1, R2, R4 and under the condition that at least one is -CO2H R5 independently represents (a) hydrogen; (b) C1-C6 alkyl, (c) C1-C6 alkoxy, (d) -OH, (e) -CO2H, (f) -CO2(C1-C6 alkyl), (g)-N(C1-C6 alkyl)2 R1, R2, R3, R4 or on adjacent ring carbons selected from R5 can be combined to form a -O-(CH2)n-O- residue; R3 is C1-C6-alkoxy or -N(C1-C6-alkyl)2 or R2 and R3 or R3 and R4 combine to form -O-(CH2)n -O- residue; and n is 1 to 3] or its alkali A method for producing a metal salt, the formula V: ▲There are mathematical formulas, chemical formulas, tables, etc.▼V in an alkaline aqueous solution, (a) N-promosuccinimide, and (b) Bromination selected from 1,3-dipromo-5,5-dimethylhydantoin to optimally convert a compound of formula V to a compound of formula IV or a salt thereof using a treatment for sufficient time and temperature; then optionally treating the reaction mixture with an acid to form a compound of formula IV. Law. 2. The amount of brominating agent used is between 0.505 and 1.5 molar equivalents relative to the compound of formula V. 2. A method according to claim 1, characterized in that the selection is made from quantity values. 3. Claim 1, wherein the brominating agent is lupromosuccinimide. How to put it on. 4. The alkaline aqueous solution is replaced with an aqueous solution of sodium hydroxide or an aqueous solution of potassium hydroxide. 4. A method according to claim 3, characterized in that it is selected from solutions. 5. A method according to claim 1, characterized in that the acid is an acidic aqueous solution. 6. The brominating agent is 1,3-dipromo-5,5-dimethylhydantoin. A method according to claim 1, characterized in that: 7. 1,3-dipromo-5,5-dimethylene used in the method relative to the amount of compound V The amount of ruhydantoin is selected from 0.505 to 0.55 molar equivalents, and the amount of compound V The amount of alkaline base in the alkaline aqueous solution is 1.01 to 1.1 molar equivalent 7. A method according to claim 6, characterized in that selecting from: 8. Formula IVa: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A method for producing a compound with IVa, and the formula Va: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Benzoic acid of Va in an alkaline aqueous solution , (a) N-promosuccinimide, and (b) 1,3-dipromo-5,5-dime A compound of formula Va is converted to a compound of formula IVa using a brominating agent selected from tylhydantoin. or a salt of the compound of formula IVa for a period of time and at a temperature sufficient to achieve optimal conversion to the compound of formula and then optionally treating the reaction mixture with an acid. The method includes. 9. Claim 8, characterized in that the brominating agent is N-promosuccinimide. How to put it on. 10. The brominating agent is 1,3-dipromo-5,5-dimethylhydantoin 9. The method according to claim 8, characterized in that: