Method for producing 14-bromoanthracene rings

Abstract

The present invention provides a method for producing 14-bromoanthracene rings that is safe and efficient in operation. The method for producing 14-bromoanthracene rings comprises ketalization of the 13-carbonyl group, bromination of the 14-position based on the N-bromo compound, and deketalization steps according to the following reaction route, and the steps are implemented by a one-pot method.

Description

Technical Field

[0001] The present invention relates to a method for producing 14-bromoanthracyclines from 13-methylanthracyclines, and more particularly to a method for producing 14-bromoanthracyclines by brominating the methyl group of 13-ketal-13-methylanthracycline. Background Art

[0002] 14-Bromoanthracyclines are represented by formula (1):

[0003]

Chemistry 1

[0004]

[0005] Generally, the compound represented by 1 ~R 21 Described below. Hereinafter, also referred to as "compound (1)" (equivalent to the compound of formula I in the present invention.)), is a synthetic intermediate of 14-hydroxyanthracyclines such as doxorubicin, pirarubicin and epirubicin, which are anthracycline anticancer agents. For example, as typical compounds thereof, 14-bromodaunorubicin represented by formula (2) (hereinafter, also referred to as "compound (2)"), 14-bromopirarubicin represented by formula (3), and 14-bromoepirarubicin can be cited.

[0006]

[0007] Furthermore, 14-bromoanthracyclines are also used as important intermediates for synthesizing conjugates composed of anthracyclines and biopolymers such as peptides and proteins (see Patent Document 1).

[0008] Umezawa et al. reported a method for producing a specific compound of compound (1) (Non-patent document 1, Patent document 2). For example, compound (2) is produced in two stages from the hydrochloride of daunorubicin (hereinafter also referred to as "compound (5)") via 14-bromodaunorubicin-13-dimethyl acetal (hereinafter also referred to as "compound (6)") as shown in the following reaction scheme 1.

[0009] Reaction Scheme 1: Synthesis of 14-bromoanthracyclines

[0010]

Chemistry 3

[0011]

[0012] First, the hydrochloride of compound (5) is dissolved in anhydrous methanol, and trimethyl orthoformate and dioxane are added. Then, a dichloromethane solution of bromine is added and the reaction is carried out at 25°C. The reaction solution is poured into anhydrous ether, the generated precipitate is compressed by a centrifugal separator, and the supernatant is discarded. The precipitate is washed twice with anhydrous ether, and acetone is further added and stirred at 25°C for 1 hour. The reaction solution is centrifuged again, the precipitate is washed twice with ether, and then dried to obtain the hydrochloride of compound (2).

[0013] Prior art literature

[0014] Patent Literature

[0015] Patent Document 1: Japanese Patent Application No. 2006-504657

[0016] Patent Document 2: Japanese Patent Application Laid-Open No. 56-156300

[0017] Non-patent literature

[0018] Non-patent document 1: Bulletin of the Chemical Society of Japan, 59 (1986), p423-431 Summary of the invention

[0019] Problems to be solved by the invention

[0020] The above-mentioned method for producing 14-bromoanthracyclines is not necessarily a satisfactory method mainly in the following aspects (A) and (B). (A) Bromine is used, which requires attention in operation. (B) Since anthracycline compounds that are mutagenic or have the possibility of mutagenicity are purified by filtration, it is necessary to operate the compound in powder form. Therefore, the object of the present invention is to produce 14-bromoanthracyclines without using bromine, which requires attention in operation, and without a powder operation step.

[0021] Means used to solve problems

[0022] In order to solve the above problems, the inventors of the present invention have studied the manufacturing method of 14-bromo anthracene rings in the past in many aspects. As a result, it is found that by using N-bromosuccinimide (NBS) to replace the bromine in the above-mentioned previous manufacturing method, and applying certain changes to the reaction treatment conditions, it is possible to obtain the compound represented by formula I as the final target compound from the compound represented by formula II as the starting raw material with a higher yield, and the target product of each process can be operated in a solution state. In addition, it is also found that NBS can be replaced by N-bromo compounds known to have the same bromination effect.

[0023] Therefore, this specification discloses the invention of the following main technical features or aspects.

[0024] Embodiment 1: A method for producing a compound represented by formula I, or a pharmacologically acceptable salt thereof, or a solvate thereof,

[0025]

Chemistry 4

[0026]

[0027] The method comprises:

[0028] (a) reacting a compound represented by formula II with a compound represented by formula CR 23 (OR 22 )3 represented by the orthoester, the formula R 22 A step of mixing an alkanol represented by OH to form a ketal represented by formula III;

[0029]

Chemistry 5

[0030]

[0031]

Chemistry 6

[0032]

[0033] (b) a step of generating a bromoketal represented by formula IV by mixing a reaction mixture containing the ketal of formula III generated in step (a) with an N-bromo compound selected from N-bromosuccinimide (NBS), N-bromoacetamide (NBA), 1,3-dibromo-5,5-dimethylhydantoin (DBH) and dibromoisocyanuric acid (DBI);

[0034]

Chemistry 7

[0035]

[0036] (c) a step of converting the compound represented by formula IV into a compound represented by formula I by mixing a reaction mixture containing the compound represented by formula IV produced in step (b) with an acid and water;

[0037] (d) a step of separating an organic layer containing the compound represented by Formula I from a mixture obtained by mixing the deketalization reaction mixture of step (c) with an extraction organic solvent capable of dissolving the compound represented by Formula I; and

[0038] (e) A step of obtaining the compound represented by Formula I in the form of an organic solution from the organic layer separated in the step (d).

[0039] The variable R in the above formulas 1~R 23 The groups are defined as follows.

[0040]

Table 1

[0041]

[0042] In the above table,

[0043] R as a substituent 14 ~R 19 It may be a cycloalkyl group having 3 to 6 carbon atoms,

[0044] The CH group of the cycloalkyl group may be substituted by N,

[0045] Secondary carbon can be replaced by NH, O, S,

[0046] One of the hydrogen atoms of the cycloalkyl group may be replaced by a methoxy group.

[0047] In addition, the substituent R 16 or R 17 and a substituent selected from R 18 and R 19 Any of can be bonded via 1 or 2 carbons.

[0048] Mode 2: The production method according to Mode 1, characterized in that the N-brominated compound is NBS.

[0049] Embodiment 3: The production method according to Embodiment 1 or 2, wherein the solvent containing the alkanol in the step (a) further contains an organic sulfonic acid.

[0050] Embodiment 4: The production method according to Embodiment 3, characterized in that the organic sulfonic acid is selected from p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid and trimethylsilyl trifluoromethanesulfonate.

[0051] Embodiment 5: The production method according to Embodiment 3 or 4, further comprising a step of neutralizing the reaction mixture from step (a) with an organic base before carrying out step (b).

[0052] Embodiment 6: The production method according to Embodiment 5, characterized in that the organic base is selected from tri-C1~C3-alkylamine, amidine, guanidine, aniline and pyridine.

[0053] Aspect 7: The production method according to any one of aspects 1 to 6, wherein step (b) is performed in a solvent containing an aprotic polar organic solvent.

[0054] Embodiment 8: The production method according to Embodiment 7, wherein the aprotic organic solvent is selected from tetrahydrofuran, dioxane and dimethoxyethane.

[0055] Embodiment 9: The production method according to any one of Embodiments 1 to 7, wherein the acid in step (c) is hydrobromic acid.

[0056] Aspect 10: The production method according to aspect 9, wherein the hydrobromic acid is added as a solution contained in an aqueous solution containing an alkali metal salt of hydrobromic acid.

[0057] Mode 11: The production method according to Mode 10, characterized in that the alkali metal salt is potassium hydrobromide or sodium hydrobromide.

[0058] Embodiment 12: The production method according to any one of Embodiments 1 to 10, further comprising adding a base to the reaction mixture from step (c) before carrying out step (d).

[0059] Mode 13: The production method according to Mode 12, characterized in that the base is selected from sodium bicarbonate, potassium bicarbonate, tri-C1~C3 alkyl-amine, amidine, guanidine, aniline and pyridine.

[0060] Aspect 14: The production method according to any one of aspects 1 to 10, wherein the extraction organic solvent in step (d) is a C4-C6-alkyl ketone.

[0061] Mode 15: The production method according to Mode 14, characterized in that the C4~C6-alkyl ketone is selected from methyl ethyl ketone, methyl butyl ketone, ethyl butyl ketone, methyl isobutyl ketone and ethyl isobutyl ketone.

[0062] Embodiment 16: The production method according to any one of Embodiments 1 to 14, wherein the compound represented by Formula I is provided in the form of a solution of C4-C6-alkyl ketone. DETAILED DESCRIPTION

[0063] Technical terms used in this specification are used as terms having meanings commonly used in the relevant technical fields unless otherwise defined.

[0064] The variable R in the above formulas 1 ~R 23 In the definition of a group, OH, NH2, NH, H, O, and N, which are substituents themselves or constitute a part of them, represent hydroxyl groups, amino groups, imino groups, hydrogen atoms, oxygen atoms, and nitrogen atoms. n H 2n+1And following these groups, for example, n=1-5 represents an alkyl group having 1 to 5 carbon atoms. In addition, such an alkyl group may be chain or branched, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-heptyl, 4-methylbutyl, 3-methylbutyl, 2-ethylpropyl, and the like. n=1-3 refers to a group having 1 to 3 carbon atoms in the above-mentioned specific groups. Although not limited, among these groups, a group having 1 or 2 carbon atoms and being a chain alkyl group is preferably used in the production method disclosed in this specification. Furthermore, the C1-C3-alkyl group and the C4-C6-alkyl ketone group constituting a part of the compound used in the present production method are C1-C3-alkyl, C4-C6-alkyl ketone, and C1-C3-alkyl. n (n represents a positive number.) Each of the above-mentioned alkyl groups having n carbon atoms can be used. The alkyl groups in the tri-C1-C3-alkyl group and C4-C6-alkyl ketone partially having these groups can be the same or different. In addition, OCH2C6H5 represents a benzyloxy group.

[0065] The method disclosed in this specification is not limited, and can be generally represented as in the following reaction scheme 2. In the following description or description, the variable R in each formula is 1 ~R 23 Unless otherwise defined, the radicals are as defined above.

[0066] Reaction Scheme 2

[0067]

Chemistry 8

[0068]

[0069] [About each process]

[0070] Treatments (i) and (ii) in the above reaction scheme 2 correspond to step (a) in embodiment 1, treatment (iii) corresponds to step (b) in embodiment 1, and treatment (iv) corresponds to step (c) in embodiment 1.

[0071] In the conventional methods for producing 14-bromoanthracene rings described in Patent Documents 1 and 2, bromination with bromine and ketalization of the 13-keto functional group in the anthracene ring occur simultaneously. On the other hand, NBS is well known in the technical field of general organic synthesis as a safer bromination reagent that generally replaces bromine (e.g., Tetrahedron 70 (240) 3949-3961).

[0072] However, in the above conventional method, when only NBS is used instead of bromine, although the formation of compound (6) in the above reaction scheme 1 can be confirmed, the conversion rate from compound (5) is significantly lower than that when bromine is used. Therefore, the results of examining and studying each reaction in the reaction scheme 1 are that if a compound of formula II corresponding to compound (5) is firstly reacted in the presence of an alkanol R 22 OH, especially in the presence of an organic sulfonic acid in methanol, especially p-toluenesulfonic acid (or toluenesulfonic acid) with the orthoester CR 23 (OR 22 )3, especially trimethyl orthoformate, to generate as a reaction intermediate a 13-dimethyl ketal (refer to Formula III), especially daunorubicin-13-dimethyl ketal, corresponding to the compound of Formula (7) in Reaction Scheme 2 (or also represented by Formula II). After that, a bromination reaction is performed by adding an N-brominated compound, and it can be confirmed that the yield of the compound represented by Formula (IV), especially Compound (6) is increased. Furthermore, if the acid is neutralized with an organic base, especially triethylamine, before the bromination, and the bromination reaction is performed in a mixed solvent containing a non-protonic polar solvent such as tetrahydrofuran, dioxane and dimethoxyethane, it can be confirmed that the yield is further improved, and Compound (6) can be obtained at a yield comparable to that in the case of bromine.

[0073] Thus, in the method disclosed in the present specification, step (a) and step (b) are independent, and step (b) is performed after step (a).

[0074] In the disclosed method of this specification, it is not limited to the compounds listed as "especially" in the above, and the compounds within the scope of the above-mentioned method can be used to mix each reactant and / or solvent, and the desired reaction is carried out. In the case of such mixing and mixing in other steps, these treatments can be implemented without adding order restrictions as long as they are not specifically stated. In this method, even if the reaction mixture contains solids, it is not necessary to separate the target ketal (represented by formula III.) as solids, and the next bromination can be carried out while maintaining the state of the solution. Further, as the above-mentioned organic sulfonic acid, it is not limited, and organic sulfonic acids such as p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid and trimethylsilyl trifluoromethanesulfonate can be listed. Bromination is not limited and can be carried out by using N-bromo compounds selected from N-bromosuccinimide (NBS), N-bromoacetamide (NBA), 1,3-dibromo-5,5-dimethylhydantoin (DBH) and dibromoisocyanuric acid (DBI) alone or in combination.

[0075] In step (a), a compound of formula II is reacted with a compound of formula CR 23(OR 22 )3 and the orthoester of formula R 22 The alkanol represented by OH is mixed for reaction, the molar ratio of the compound of formula II to the orthoester is 1:1 to 1:8, preferably 1:2 to 1:6, more preferably 1:3 to 1:5, the molar ratio of the compound of formula II to the organic sulfonic acid is 1:0.01 to 1:1, preferably 1:0.05 to 1:0.5, more preferably 1:0.1 to 1:0.3, the reaction temperature is 0°C to 30°C, preferably 5°C to 15°C, more preferably 8°C to 12°C, and the reaction time can be selected from 0.5 to 24 hours, preferably 1 to 12 hours, more preferably 2 to 6 hours. Regarding the ratio of the orthoester, the ratio of the organic sulfonic acid, and the reaction time, under the conditions listed as more preferred, there is an advantage of improved yield.

[0076] After step (a) and before step (b), if the organic sulfonic acid in the reaction solution of step (a) is neutralized with a base, the yield of the bromide in step (b) can be improved. Examples of such a base include organic bases such as tri-C1 to C3-alkylamines (herein, the tri-C1 to C3-alkyl groups may be the same or different, such as triethylamine, isopropylethylamine, etc.), pyridine, guanidine, amidine, and aniline, which may be used alone or in combination of two or more.

[0077] In step (b), the N-bromo compound added to the reaction solution prepared as described above is not limited, and NBS is added, for example. As a result, it is easy to operate the respective target products (compounds of formula II and formula III) in the step (a) and the step (b) in a solution state, so that these steps can be easily carried out in a one-pot method. The molar ratio of the N-bromo compound to formula II or formula III is 1:1 to 1:6, preferably 1:1 to 1:4, and more preferably 1:1 to 1:2. In addition, the solvent for carrying out step (b) can be a mixed solvent composed of solvents such as alkanol in step (a), tetrahydrofuran, dioxane or dimethoxyethane. The volume ratio of this solvent to the alkanol in step (a) can be 1:0.2 to 1:4, preferably 1:0.5 to 1:3, and more preferably 1:1 to 1:2. In addition, the N-bromo compound can be added after adding these aprotic organic solvents, or the N-bromo compound can be dissolved in these aprotic organic solvents and added as a solution. The reaction temperature is 0°C to 50°C, preferably 10°C to 40°C, more preferably 20°C to 30°C, and the reaction time can be selected from 0.5 to 24 hours, preferably 1 to 12 hours, more preferably 2 to 6 hours. Regarding the molar ratio of the N-bromo compound, the reaction temperature and the reaction time, when carried out under more preferred conditions, there is an advantage of improved yield.

[0078] Step (c) is a deketalization reaction of the compound of formula IV obtained in step (b), and generally, the reaction can be carried out by reacting water with ketal in the presence of an acid catalyst according to a conventional method. However, when acetone and an aqueous solution of hydrobromic acid are added to the reaction solution after the reaction of step (b) as in Patent Document 2 to attempt deketalization, the byproduct of conversion of 14-bromine of compound (2) to 14-chloro is obtained in the addition of compound (6) to compound (2) in reaction route 1, and the target compound (2) may not be obtained in high yield. Therefore, the inventors of the present invention have repeatedly studied and found that such disadvantages can be eliminated by adding hydrobromic acid and a metal hydrobromide salt to the bromination reaction solution obtained in step (b) and reacting, thereby obtaining a compound of formula (I) in high yield. It is further found that if a metal hydrobromide salt is present, the reaction solution can be separated into two layers, an organic layer and an aqueous layer containing the 14-bromoform, by simply adding an organic solvent after the reaction, and the 14-bromoform can be extracted with an organic solvent (step (d)), thereby avoiding the powder operation step. As such a metal salt, there are alkali metal salts, such as potassium hydrobromide, sodium hydrobromide, etc. Therefore, in the method disclosed in this specification, it is preferred to use an aqueous sodium bromide solution containing hydrobromic acid as an acid to carry out the deketalization reaction. The step (c) can also be implemented together with the steps (a) and (b) by a one-pot method.

[0079] The molar ratio of the compound of formula II to hydrobromic acid is 1:0.01 to 1:100, preferably 1:0.1 to 1:50, more preferably 1:1 to 1:10, and the molar ratio of the compound of formula II to the metal hydrobromide is 1:20 to 1:150, preferably 1:50 to 1:130, more preferably 1:70 to 1:120. Based on 1 g of the metal hydrobromide, the amount of water used to dissolve the metal hydrobromide is 0.1 mL to 10 mL, preferably 0.5 mL to 5 mL, more preferably 1 mL to 3 mL, the reaction temperature is -10°C to 50°C, preferably 0°C to 40°C, more preferably 10°C to 30°C, and the reaction time is 0.2 to 48 hours, preferably 0.5 to 24 hours, more preferably 1 to 12 hours. With respect to the molar ratio of hydrobromic acid, the molar ratio of the metal hydrobromide, the reaction temperature, and the reaction time, the reaction yield is improved under more preferred conditions.

[0080] In step (d), the compound of formula I can be dissolved in the reaction mixture finally obtained in step (c). If necessary, the mixture obtained by mixing the non-water-miscible extraction organic solvent is cooled to about 10°C or the organic layer containing the compound of formula I is separated from the aqueous layer containing solids according to the situation at room temperature. Originally, the salt of 14-brominated anthracycline is difficult to dissolve in the above-mentioned non-water-miscible organic solvent, but it is found that it is dissolved in a mixed solvent with the solvent used in step (a) and step (b), and liquid separation extraction can be performed, which can avoid powder operation. In this step, more specifically, an aqueous solution of alkali, especially sodium bicarbonate, is added to the reaction mixture and stirred, and then the above-mentioned organic solvent is added for further stirring, and the organic layer and the aqueous layer are separated after standing to separate the organic layer. The same liquid separation and separation operation can be performed on the aqueous layer several times. By adding an appropriate amount of alkali, it has the advantage of increasing the yield of 14-brominated anthracycline. The ratio of hydrobromic acid to alkali is 1:0.01 to 1:10, preferably 1:0.05 to 1:5, and more preferably 1:0.1 to 1:2 in terms of molar ratio. The organic solvent is not limited as long as it can perform the liquid separation, and may be a C4 to C6-alkyl ketone, such as methyl ethyl ketone, methyl butyl ketone, ethyl butyl ketone, methyl isobutyl ketone, and ethyl isobutyl ketone. The amount used may be determined in the optimal amount by taking into account the solubility of the compound of formula I, the amount of water in the reaction mixture, and the like. This step may be carried out together with step (a), step (b), and step (c) by a one-pot method, but the reaction mixture may also be transferred to a treatment layer dedicated to liquid separation as required.

[0081] In step (e), the organic layer separated in step (d) containing the compound of formula I is separated or obtained. The obtaining operation can be performed using a decanter or an appropriate solution suction pump commonly used in the technical field.

[0082] The organic layer thus obtained can be used directly if appropriate, or it can be concentrated and / or other organic solvents can be added as needed, and the compound of formula I contained in the solution can be used for the next reaction. After the above steps, the compound of formula I is obtained in the form of hydrobromide.

[0083] [Example]

[0084] Example 1, Synthesis of 14-bromodaunorubicin

[0085] 7.9 g (14.0 mmol) of daunorubicin hydrochloride was dissolved in 63 mL of methanol at room temperature, 6.2 mL (56.7 mmol) of trimethyl orthoformate was added to the solution at 10°C, and then 599 mg of p-toluenesulfonic acid monohydrate was added, and the solution was stirred for 3 hours. A mixed solution of 0.44 mL of triethylamine and 4 mL of dioxane was added to the reaction solution, and then heated to 22°C.

[0086] Next, an NBS-dioxane solution obtained by dissolving 3 g (16.9 mmol) of NBS in 108 mL of dioxane was added and stirred for 90 minutes, and then the temperature of the solution was cooled to 10°C.

[0087] 7.2 mL of hydrobromic acid was added to an aqueous solution obtained by dissolving 72.3 g of sodium bromide in 112 mL of water, and stirred. The mixture was mixed with the reaction solution and stirred for about 16 hours.

[0088] After the reaction, an aqueous solution obtained by dissolving 5.8 g of sodium bicarbonate in 90 mL of water was mixed with the reaction solution and heated to 25° C., and then the organic layer and the aqueous layer were separated by adding 800 mL of methyl ethyl ketone to obtain a 14-bromodaunorubicin hydrobromide methyl ethyl ketone solution (10.1 mmol, yield 72%).

[0089] Comparative Example:

[0090] Example of using NBS to replace bromine under known conditions

[0091] 6.3 mL of methanol and 11 mL of dioxane were added to 0.79 g (1.40 mmol) of daunorubicin hydrochloride and stirred. After confirming dissolution, the solution was cooled to 9° C. After adding 0.4 mL of trimethyl orthoformate, 299 mg of NBS was added, and the solution was stirred at 9° C. After 105 minutes, the conversion rate of 14-bromodaunorubicin-13-dimethyl ketal was 4.6%.

Claims

1. A method for producing a compound represented by formula I, or a pharmacologically acceptable salt thereof, The method comprises: (a) reacting a compound represented by formula II with a compound represented by formula CR 23 (OR 22 )3 represented by the orthoester, the formula R 22 A step of mixing an alkanol represented by OH and an organic sulfonic acid to produce a ketal represented by formula III; (b) a step of obtaining a bromoketal represented by formula IV by mixing the reaction mixture containing the ketal represented by formula III produced in step (a) with an N-bromo compound selected from N-bromosuccinimide NBS, N-bromoacetamide NBA, 1,3-dibromo-5,5-dimethylhydantoin DBH and dibromoisocyanuric acid DBI in a solvent containing an aprotic polar organic solvent; (c) a step of converting the compound represented by formula IV into a compound represented by formula I by mixing the reaction mixture containing the bromoketal represented by formula IV produced in step (b) with hydrobromic acid and water; (d) a step of separating an organic layer containing the compound represented by Formula I from a mixture obtained by mixing the reaction mixture obtained in step (c) with an extraction organic solvent capable of dissolving the compound represented by Formula I; as well as (e) a step of obtaining a compound represented by formula I in the form of an organic solution from the organic layer separated in step (d), The variable R in the above formulas 1 ~R 23 The definition of the group is as follows: 【Table 1】 In the above table, R as a substituent 14 ~R 19 is optionally replaced by a cycloalkyl group having 3 to 6 carbon atoms, wherein the CH group of the cycloalkyl group is optionally replaced by N, The secondary carbon is optionally substituted by NH, O, S, One of the hydrogen atoms of the cycloalkyl group is optionally replaced by a methoxy group, In addition, the substituent R 16 or R 17 and a substituent selected from R 18 and R 19 Any of are optionally bonded via 1 or 2 carbons.

2. The manufacturing method according to claim 1, characterized in that: The N-bromo compound is NBS.

3. The manufacturing method according to claim 1, characterized in that: The organic sulfonic acid is selected from p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid and trimethylsilyl trifluoromethanesulfonate.

4. The manufacturing method according to claim 1, characterized in that: The method further includes the step of neutralizing the reaction mixture from step (a) with an organic base before carrying out step (b).

5. The manufacturing method according to claim 4, characterized in that: The organic base is selected from tri-C1-C3-alkylamines, amidines, guanidines, aniline and pyridine.

6. The manufacturing method according to claim 1, characterized in that: The aprotic polar organic solvent is selected from tetrahydrofuran, dioxane and dimethoxyethane.

7. The manufacturing method according to claim 1, characterized in that: The hydrobromic acid is added as a solution contained in an aqueous solution containing an alkali metal salt of hydrobromic acid.

8. The manufacturing method according to claim 7, characterized in that: The alkali metal salt is potassium hydrobromide or sodium hydrobromide.

9. The production method according to any one of claims 1 to 7, characterized in that: The method further comprises adding a base to the reaction mixture from step (c) before carrying out step (d).

10. The manufacturing method according to claim 9, characterized in that: The base is selected from sodium bicarbonate, potassium bicarbonate, tri-C1-C3 alkyl-amine, amidine, guanidine, aniline and pyridine.

11. The production method according to any one of claims 1 to 7, characterized in that: The extraction organic solvent in step (d) is a C4-C6-alkyl ketone.

12. The manufacturing method according to claim 11, characterized in that: The C4-C6-alkyl ketone is selected from methyl ethyl ketone, methyl butyl ketone, ethyl butyl ketone, methyl isobutyl ketone and ethyl isobutyl ketone. 13 . The production method according to claim 1 , wherein the compound represented by formula I is provided in the form of a solution of a C4-C6-alkyl ketone.

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