CN114105872B - Intermediate for preparing procaterol hydrochloride and preparation method thereof - Google Patents
Intermediate for preparing procaterol hydrochloride and preparation method thereof Download PDFInfo
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- CN114105872B CN114105872B CN202111607619.5A CN202111607619A CN114105872B CN 114105872 B CN114105872 B CN 114105872B CN 202111607619 A CN202111607619 A CN 202111607619A CN 114105872 B CN114105872 B CN 114105872B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D215/24—Oxygen atoms attached in position 8
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Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to an intermediate for preparing procaterol hydrochloride and a preparation method thereof. The invention provides an intermediate, which has a structural formula shown in the specification. The invention provides an intermediate for preparing procaterol hydrochloride and a preparation method thereof, 8-butyryloxy quinolone is adopted as a raw material, and the problems of unstable use, more side reactions caused by raw material 2-bromobutyryl chloride or 2-bromobutyryl bromide reagent, namely severe and difficult control of bromine bromination reaction conditions, poor process stability and reproducibility and inconvenient use are avoided. When the method is used for preparing procaterol hydrochloride, the method has the advantages of simple and easily controlled synthesis process, improved efficiency and suitability for large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to an intermediate for preparing procaterol hydrochloride and a preparation method thereof.
Background
Procaterol (Procaterol Hydrochloride) is 5- (1-hydroxy-2-isopropylamino butyl) -8-hydroxyquinolone, and its hydrochloride is used as a selective beta 2 receptor agonist bronchodilator for treating dyspnea caused by bronchial asthma, chronic obstructive pulmonary disease, asthmatic bronchitis, acute bronchitis, chronic bronchitis, etc. In 1980, tablets, oral liquids, powder mists, aerosols and other dosage forms were approved for sale. The 2019 edition of national medical insurance includes the group B medical insurance for granules, oral liquid, tablets and capsules.
There are few published patent documents concerning the synthetic process of this product, and Yoshizaki, shiro et al disclose a raw synthetic process route for procaterol hydrochloride in 1976.
There are two synthetic processes for procaterol 6. Firstly, the original grinding process using 8-hydroxyquinolone 1 as a starting material is reported, procaterol hydrochloride is obtained by reacting procaterol with hydrochloric acid, and the reaction process is as follows:
and secondly, 8-hydroxyquinolone 1 is synthesized by taking 8-hydroxyquinoline as a starting material. The main difference with the original grinding process is that 2-bromobutyryl bromide is used as an acylation reagent instead of 2-bromobutyryl chloride, and the rest processes are similar, and the reaction process is as follows:
the two synthesis processes have advantages and disadvantages, and from the comprehensive consideration of relatively simple process and raw material sources, the authors consider that the technical route disclosed by the original research is more suitable for industrial production, but research finds that the original research route has the problem that the key intermediate 3 cannot be obtained by the reaction of 1 and 2 under the catalysis of anhydrous aluminum trichloride.
Disclosure of Invention
The invention provides an intermediate for preparing procaterol hydrochloride, which adopts 8-butyryloxy quinolone as a raw material, avoids using unstable raw material 2-bromobutyryl chloride or 2-bromobutyryl bromide reagent which causes more side reactions, and also avoids the process of separating and purifying the intermediate.
The technical scheme of the invention is as follows:
the first technical problem to be solved by the invention is to provide an intermediate, wherein the structural formula of the intermediate is as follows:
the second technical problem to be solved by the invention is to provide a preparation method of the intermediate, which comprises the following steps in sequence:
step 1: performing Fries rearrangement reaction on 8-butyryloxy quinolone, butyryl chloride and a catalyst in an organic solvent to obtain a mixture of 5-butyryl-8-hydroxyquinolone (2A) and 7-butyryl-8-hydroxyquinolone (2B);
step 2: reacting the mixture of 5-butyryl-8-hydroxyquinolone (2A) and 7-butyryl-8-hydroxyquinolone (2B) obtained in step 1 directly with a benzyl compound and a base without isolation to obtain a mixture of 5-butyryl-8-benzyloxyquinolone (3A) and 7-butyryl-8-benzyloxyquinolone (3B);
step 3: reacting the mixture of 5-butyryl-8-benzyloxyquinolone (3A) and 7-butyryl-8-benzyloxyquinolone (3B) obtained in step 2 without isolation with pyridinium tribromide in tetrahydrofuran to obtain 5- (2-bromobutyryl) -8-benzyloxyquinolone (4A); or:
reacting the 5-butyryl-8-benzyloxy quinolone (3A) obtained in step 2 with pyridinium tribromide in tetrahydrofuran to obtain 5- (2-bromobutyryl) -8-benzyloxy quinolone (4A).
Further, in the step 2, the molar ratio of the mixture of 5-butyryl-8-hydroxyquinolone (2A) and 7-butyryl-8-hydroxyquinolone (2B) to the benzyl compound is 1:1.1 to 1.4, preferably 1:1.2 to 1.3.
Further, in the step 2, the molar ratio of the mixture to the alkali is 1:1.5-3.0, preferably 1:2-2.5.
Further, in the step 2, the reaction temperature is 60 to 100 ℃, preferably 80 to 90 ℃.
Further, in step 2, the reaction time of the mixture with the benzyl compound is 2 to 5 hours, preferably 3 to 4.5 hours.
Further, in step 2, the base is potassium carbonate or sodium carbonate.
Further, in step 2, the benzyl compound is selected from the group consisting of: benzyl bromide, benzyl chloride, benzyl p-toluenesulfonate, benzyl benzenesulfonate or benzyl p-nitrobenzenesulfonate.
Further, in the step 3, the molar ratio of the mixture of 5-butyryl-8-benzyloxyquinolone (3A) and 7-butyryl-8-benzyloxyquinolone (3B) to pyridinium tribromide is 1:1-1.3, preferably 1:1.1-1.2.
Further, in the step 3, when only 3A is reacted, the molar ratio of the 5-butyryl-8-benzyloxyquinolone (3A) to the pyridinium tribromide is 1:1 to 1.3, preferably 1:1.1 to 1.2.
Further, in the step 3, the ratio of the mixture of 5-butyryl-8-benzyloxyquinolone (3A) and 7-butyryl-8-benzyloxyquinolone (3B) to tetrahydrofuran is 1g to (8-12) mL, preferably 1g to (9-11) mL.
Further, in the step 3, when only 3A is reacted, the ratio of 5-butyryl-8-benzyloxyquinolone (3A) to tetrahydrofuran is 1g to (8-12) mL, preferably 1g to (9-11) mL.
Further, in the step 3, the reaction temperature is 10 to 70 ℃, preferably 15 to 40 ℃.
Further, in the step 3, the reaction time is 2 to 6 hours, preferably 3 to 5 hours.
Further, in the step 1, the molar ratio of the 8-butyryloxy-quinolone to butyryl chloride is 1: (1 to 1.6), preferably 1: (1.2 to 1.3).
In the step 1, the molar ratio of the 8-butyryloxy quinolone to the catalyst is 1:2-5, and 1:2.5-3.0.
Further, in step 1, the catalyst is a Lewis acid, preferably anhydrous aluminum trichloride.
In step 1, the organic solvent used in the Fries rearrangement reaction is chloroform, carbon disulfide, 1, 2-dichloroethane or dioxane.
Further, in the step 1, the ratio of the 8-butyryloxy quinolone to the organic solvent is 1g to (8-14) mL, preferably 1g to (10-12) mL;
further, in the step 1, the Fries rearrangement reaction temperature is 60 to 120 ℃, preferably 80 to 100 ℃.
In step 1, the Fries rearrangement reaction time is 5-14 h, preferably 6-10.
The third technical problem to be solved by the present invention is to indicate the use of the above-mentioned intermediates for the preparation of procaterol hydrochloride.
The fourth technical problem to be solved by the present invention is to indicate a process for preparing procaterol hydrochloride from the above-mentioned intermediate, said process for preparing procaterol hydrochloride from the intermediate comprising the steps of:
step 1): ammonolysis reaction is carried out on an intermediate 5- (2-bromobutyryl) -8-benzyloxy carbostyril (4A) and isopropylamine in tetrahydrofuran to obtain 5- (2-isopropylamine butyryl) -8-benzyloxy carbostyril (5A);
step 2): reducing 5- (2-isopropylamine butyryl) -8-benzyloxy carbostyril (5A) in an alcohol solvent by using a reducing agent to obtain 5- (2-isopropylamine-1-hydroxy butyl) -8-benzyloxy carbostyril (6A);
step 3): the 5- (2-isopropylamine-1-hydroxy butyl) -8-benzyloxy quinolone (6A) is subject to hydrogenation reduction reaction under the catalysis of a catalyst, and then reacts with hydrochloric acid to form salt, so as to obtain procaterol hydrochloride.
Further, in the step 1), the molar ratio of the 5- (2-bromobutyryl) -8-benzyloxy carbostyril (4A) to the isopropylamine is 1: (10-25), preferably 1: (16-20).
Further, in the step 1), the mass-volume ratio of the 5- (2-bromobutyryl) -8-benzyloxy carbostyril (4A) to the tetrahydrofuran is 1:8-12, preferably 1:10-11.
Further, in the step 1), the reaction temperature of the 5- (2-bromobutyryl) -8-benzyloxyquinolone (4A) and isopropylamine is 30 to 60 ℃, preferably 40 to 50 ℃.
Further, in step 1), the reaction time of the 5- (2-bromobutyryl) -8-benzyloxy carbostyril (4A) and isopropylamine is 4 to 10 hours, preferably 6 to 8 hours.
Further, in step 1), the ammonolysis reaction is: stirring 5- (2-bromobutyryl) -8-benzyloxy carbostyril (4A), tetrahydrofuran and isopropylamine for reaction, concentrating, crystallizing by using a solvent, and finally filtering and drying; wherein the solvent is a mixed solvent of n-hexane, n-hexane and methyl tertiary butyl ether, and the volume of the n-hexane and the methyl tertiary butyl ether is 1-10: 1 (preferably 3:1).
Further, in step 2), the reducing agent is selected from sodium borohydride, sodium borohydride acetate or sodium cyanoborohydride.
Further, in step 2), the alcohol solvent is selected from methanol, ethanol or isopropanol.
Further, in the step 2), the molar ratio of the 5- (2-isopropylaminobutyl) -8-benzyloxy quinolone (5A) to the reducing agent is 1:2-4, preferably 1:2.5-3.
Further, in the step 2), the ratio of the 5- (2-isopropylaminobutyl) -8-benzyloxyquinolone (5A) to the solvent is 1g to (8-15) mL, preferably 1g to (10-12) mL.
Further, in the step 2), the reaction temperature is 10-40 ℃, preferably 15-25 ℃;
further, in step 2), the reaction time is 3 to 6, preferably 4 to 5 hours.
Further, in the step 3), the hydrogenation reduction reaction is carried out in a mixed solvent of alcohol and water under the catalysis of a catalyst by 5- (2-isopropylamine-1-hydroxybutyl) -8-benzyloxy quinolone (6A).
Further, in step 3), the catalyst is selected from Raney Ni and palladium on charcoal.
Further, in the step 3), the mass ratio of the 5- (2-isopropylamine-1-hydroxybutyl) -8-benzyloxy carbostyril (6A) to the catalyst is 1: (0.1-0.01), preferably 1: (0.04-0.02).
In the step 3), the mixed solvent is selected from a mixture of methanol and water, ethanol and water or isopropanol and water, and the volume ratio of the ethanol to the water is (90-99) to (10-1).
Further, in the step 3), the mass-volume ratio of the 5- (2-isopropylamine-1-hydroxybutyl) -8-benzyloxy carbostyril (6A) to the mixed solvent is 1: (5-12), preferably 1: (9-11).
Further, in step 3), the hydrogenation reduction reaction temperature is 25 to 80 ℃, preferably 35 to 40 ℃.
Further, in the step 3), the pressure of the hydrogenation reduction reaction is 0.8-3 MPa.
Further, in the step 3), the hydrogenation reduction reaction time is 4-6 hours.
Further, in the step 3), the concentration of the hydrochloric acid is 4-10 mol/L.
Further, in the step 3), the ratio of the 5- (2-isopropylamine-1-hydroxybutyl) -8-benzyloxy carbostyril (6A) to hydrochloric acid is 1g to (0.8-1.4) mL, preferably 1g to (1-1.2) mL.
The invention has the beneficial effects that:
the invention provides an intermediate for preparing procaterol hydrochloride and a preparation method thereof, 8-butyryloxy quinolone is adopted as a raw material, and the problems of unstable use, more side reactions caused by raw material 2-bromobutyryl chloride or 2-bromobutyryl bromide reagent, namely severe and difficult control of bromine bromination reaction conditions, poor process stability and reproducibility and inconvenient use are avoided, namely, the 3A raw material is mixed with the isomer 3B thereof without separation, the quality of the procaterol intermediate 4A is not affected, and the process is simple, safe to operate and suitable for large-scale amplification and production. When the method is used for preparing procaterol hydrochloride, the method has the advantages of simple and easily controlled synthesis process, improved efficiency and suitability for large-scale industrial production.
Detailed Description
The invention provides a synthesis method of an intermediate for preparing procaterol hydrochloride, which can be implemented through the following steps:
step 1: reacting 8-butyryloxy quinolone shown in formula I with butyryl chloride in the presence of a catalyst to obtain a mixture of 5-butyryl-8-hydroxyquinolone (2A) and 7-butyryl-8-hydroxyquinolone (2B) shown in formula II;
step 2: reacting the non-isolated and benzyl bromide of formula II (mixture of 2A and 2B) under alkaline conditions to obtain a mixture of 5-butyryl-8-benzyloxyquinolone (3A) and 7-butyryl-8-benzyloxyquinolone (3B) of formula III;
step 3: reacting the non-isolated pyridinium tribromide of formula III (3A and 3B mixture) with a tetrahydrofuran solvent to obtain a 5- (2-bromobutyryl) -8-benzyloxyquinolone (4A) of formula IV;
the structural formulas in the steps are respectively as follows:
formula (I):
formula (II):
formula (iii):
formula (iv):
the synthetic route of the 3A synthetic intermediate is as follows:
the invention relates to a process for synthesizing an intermediate 4A by taking a mixture of 3A and 3B as a raw material, which has the following reaction general formula:
the 4A obtained by the invention can be further used for preparing procaterol hydrochloride, and then the step 3 is carried out, and the method further comprises the following steps:
step 4: carrying out ammonolysis reaction on the formula IV (4A) and isopropylamine in tetrahydrofuran solvent to obtain 5- (2-isopropylamine butyryl) -8-benzyloxy carbostyril (5A) shown in a formula V;
step 5: carrying out reduction reaction on the formula V (5A) in an alcohol solution by using a reducing agent to obtain 5- (1-hydroxy-2-isopropylaminobutyl) -8-benzyloxy carbostyril (6A) shown in a formula VI;
step 6: carrying out hydrogenation reduction reaction on the formula VI (6A) under the catalysis of a catalyst, and then carrying out salification reaction on the catalyst and hydrochloric acid to obtain procaterol hydrochloride shown in a formula VII;
the structural formulas in the steps are respectively as follows:
the following description of the embodiments of the present invention will be further described with reference to examples, and the present invention is not limited to the embodiments, but rather, the technical solutions of the embodiments of the present invention will be clearly and completely described below. It will be apparent that the embodiments described below are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 15 Synthesis of- (2-bromobutyryl) -8-benzyloxyquinolone
Sequentially adding 8-butyryloxy quinolone (54.43 g,0.26 mol) shown in formula I, chloroform (350.0 mL) and anhydrous aluminum trichloride (103.81 g,0.78 mol) into a reaction bottle, stirring uniformly at room temperature, then dropwise adding butyryl chloride (33.25 g,0.32 mol), heating to 80 ℃ for reacting for 8 hours, slowly adding the reactant into frozen hydrochloric acid (300.0 mL,5 mol/L), filtering, washing with 300mL deionized water, drying to obtain substances shown in formula II (a mixture of 2A and 2B, carrying out the next reaction without separation), obtaining 96.0% yield, and carrying out [ M+H ] of the two substances of LC-MS at 2.67min and 3.17min] + The nuclear to cytoplasmic ratio was 232.1.
215.0mL of water and potassium carbonate (63.45 g,0.46 mol) were added sequentially to the reaction flask, and 325.0mL of acetonitrile and a mixture of 2A and 2B represented by formula II (54.00 g,0.23 mol) were added with stirring, and benzyl bromide (47.95 g,0.28 mol) was added dropwise to react for 3 hours while heating to 80 ℃. The reaction mixture was added with 100.0mL of water, extracted with 150.0mL of ethyl acetate, concentrated, crystallized with a mixed solvent of n-hexane and ethyl acetate, and dried to obtain a mixture of 3A and 3B of the formula III, which was subjected to the next reaction without separation, and the yield was 93.5%.
A mixture of 3A and 3B (53.97 g,0.17 mol), tetrahydrofuran (530.0 mL, 10V), onium tribromopyridinium (64.53 g,0.20 mol) and boron trifluoride diethyl ether (12.01 g,0.08 mol) of the formula III were successively charged into a reaction flask, and reacted at room temperature with stirring for 4 hours, followed by filtration. The filtrate was washed with 200.0mL of saturated brine and concentrated to give a crude product. The crude product is added with 150.0mL of ethyl acetate for pulping, filtered and dried to obtain the formula IV (namely 4A:5- (2-bromobutyryl) -8-benzyloxy carbostyril), the yield is 50.4%, and the purity is more than 98% by HPLC detection.
Nuclear magnetic resonance hydrogen spectrum detection result of 5- (2-bromobutyryl) -8-benzyloxy carbostyril: 1 H NMR(400MHz,DMSO-d 6 )δ：11.08(s,1H,H1),8.38(d,J＝10.1Hz,1H,H3),7.86(d,J＝8.2Hz,1H,H4),7.60(d,J＝7.0Hz,2H,H7),7.38(d,J＝7.4Hz,2H,H8),7.31(dd,J＝14.9,7.6Hz,2H,H9,H5),6.68(d,J＝10.1Hz,1H,H2),5.66(s,1H,H10),5.43(s,2H,H6),2.22–1.85(m,2H,H11),1.01(t,J＝6.9Hz,3H,H12)。
nuclear magnetic resonance carbon spectrum detection result of 5- (2-bromobutyryl) -8-benzyloxy carbostyril: 13 C NMR(400MHz,DMSO-d 6 )δ：195.04,161.14,148.27,137.67,136.48,130.82,128.88,128.57,128.44,125.48,125.32,124.99,118.54,111.17,70.59,53.58,27.12,12.14。
mass spectrometry detection result of 5- (2-bromobutyryl) -8-benzyloxy carbostyril: ESI-MS, m/z (C) 20 H 18 BrNO 3 )[M+H] + Theoretical 401.3, found 401.1.
Example 25 Synthesis of- (2-bromobutyryl) -8-benzyloxyquinolone:
8-butyryloxy-quinolone (54.43 g,0.26 mol) shown in formula I, dichloroethane (450.0 mL) and anhydrous aluminum trichloride (109.1 g,0.82 mol) were sequentially added into a reaction flask, butyryl chloride (37.41 g,0.36 mol) was added dropwise after stirring at room temperature, then the temperature was raised to 85 ℃ for reaction for 9 hours, the reaction mixture was slowly added into frozen hydrochloric acid (300.0 mL,5 mol/L), filtered, washed with 300mL of deionized water, and dried to obtain formula II (a mixture of 2A and 2B, the next reaction was carried out without separation), and the yield was 96.5%.
215.0mL of water and potassium carbonate (63.45 g,0.46 mol) were added sequentially to the reaction flask, and 325.0mL of acetonitrile and a mixture of 2A and 2B of formula II (54.00 g,0.23 mol) were added with stirring, and heated to 80℃to react with benzyl bromide (51.37 g,0.30 mol) dropwise. The reaction mixture was added with 100.0mL of water, extracted with 150.0mL of ethyl acetate, concentrated, crystallized from a mixed solvent of n-hexane and ethyl acetate, and dried to give the compound of formula III (3A and 3B, a mixture was carried out without isolation for the next reaction) in a yield of 93.0%.
A reaction flask was charged with the mixture of formula III (53.97 g,0.17 mol), tetrahydrofuran (530.0 mL, 10V), phosphonium tribromide (70.98 g,0.22 mol) and boron trifluoride diethyl ether (12.01 g,0.08 mol), followed by stirring at 50℃for 5 hours and filtering. The filtrate was washed with 200.0mL of saturated brine and concentrated to give a crude product. The crude product is added with 150.0mL of ethyl acetate for pulping, filtered and dried to obtain the formula IV (namely 4A:5- (2-bromobutyryl) -8-benzyloxy carbostyril), the yield is 48.6%, and the purity is more than 98.5% by HPLC detection.
Example 3
Otherwise, as in example 1, 3A (53.0 g) was used instead of the blend of 3A and 3B, and finally procaterol intermediate 4A was also obtained with a purity of 99.6%.
Comparative example 1
The first (Fries rearrangement) and second (8-hydroxy protection) steps of the process for preparing 5- (2-bromobutyryl) -8-benzyloxyquinolone are reversed, i.e. the following synthetic route is followed:
215.0mL of water and potassium carbonate (63.45 g,0.46 mol) were added sequentially to the reaction flask, 325.0mL of acetonitrile and 8-hydroxyquinolone (37.00 g,0.23 mol) were added with stirring, and benzyl bromide (47.95 g,0.28 mol) was added dropwise thereto to react for 3 hours while heating to 80 ℃. 100.0mL of water is added into the reaction, 150.0mL of ethyl acetate is used for extraction, concentration and crystallization are carried out by using a mixed solvent of n-hexane and ethyl acetate, and 8-benzyloxy carbostyril is obtained after drying, and the yield is 96.2%.
8-Benzyloxy-quinolone (27.20 g,0.13 mol), chloroform 175.0mL and anhydrous aluminum trichloride (50.65 g,0.39 mol) were sequentially added to the reaction flask, butyryl chloride (16.50 g,0.16 mol) was added dropwise after stirring at room temperature, then the temperature was raised to 80℃for reaction for 8 hours, the reaction mass was slowly added to frozen hydrochloric acid (150.0 mL,5 mol/L), filtered, washed with 150mL of deionized water, and dried to give a mixture of formula III (3A and 3B), which was analyzed as a mixture of unreacted 8-benzyloxyquinolone, debenzolized 8-hydroxyquinolone and 8-butyroxyquinolone.
The result of the reaction is that the first reaction is smooth, the second reaction does not give the expected formula III (3A and 3B), the actual reaction results are as follows:
it can be seen that comparative example 1 failed to prepare 5- (2-bromobutyryl) -8-benzyloxyquinolone.
Comparative example 2
Preparation of 5- (2-bromobutyryl) -8-benzyloxyquinolone by the rie rearrangement reaction with butyric anhydride instead of butyryl chloride: the procedure and conditions were the same as in the schemes of example 1 and example 2, except that butyryl chloride was replaced with butyric anhydride, and as a result, it was found that butyric anhydride did not react with formula I (8-butyryloxyquinolone), and a mixture of formula II (2A and 2B) was not obtained, and comparative example 2 failed to prepare 5- (2-bromobutyryl) -8-benzyloxyquinolone.
Comparative example 3
Preparation of 5- (2-bromobutyryl) -8-benzyloxyquinolone by the rie rearrangement reaction with butyryl bromide instead of butyryl chloride: the reaction procedure and conditions were the same as in the schemes of example 1 and example 2, except that butyryl chloride was replaced with butyryl bromide, and as a result, butyryl bromide was found to react with formula I (8-butyryloxyquinolone), but the byproducts were more difficult to separate and purify.
Comparative example 4
Preparation of 5- (2-bromobutyryl) -8-benzyloxyquinolone with liquid bromine instead of tribromopyridinium: the procedure and conditions were the same as in example 1 and example 2 except that the solution bromine was used instead of the tribromopyridinium salt, and as a result, it was found that the solution bromine was complicated with the reaction product of the formula III, the objective compound was very small and difficult to separate and purify, and thus the preparation of 5- (2-bromobutyryl) -8-benzyloxyquinolone scheme of comparative example 4 failed.
Comparative example 5
Preparation of 5- (2-bromobutyryl) -8-benzyloxyquinolone with other solvents instead of tetrahydrofuran solvent: the reaction procedure was the same as in the schemes of example 1 and example 2 except that the tetrahydrofuran solvent in the step of preparing 4A using a mixture of 3A and 3B was replaced with methylene chloride, chloroform, dioxane, ethanol or dichloroethane, and as a result, it was found that the onium tribromopyridinium was either not reacted with formula III or was by-produced in a large amount, and the desired product could not be isolated, so that the scheme of preparing 5- (2-bromobutyryl) -8-benzyloxyquinolone in comparative example 5 failed in practice.
Example 45 Synthesis of- (2-isopropylaminobutyl) -8-benzyloxyquinolone
The reaction flask was charged with the formula IV (30.00 g,0.075 mol), tetrahydrofuran 300.0mL and isopropylamine (88.50 g,1.5 mol) obtained in example 1, stirred at 50deg.C for 8h, concentrated, crystallized with a mixed solvent of 180.0mL n-hexane and 60.0mL methyl tert-butyl ether, filtered, and dried to give 25.3g of formula V (5A: 5- (2-isopropylaminobutyl) -8-hydroxyquinolone) with a yield of 89.2% and a purity of more than 97% as measured by HPLC.
Nuclear magnetic resonance hydrogen spectrum of 5- (2-isopropylamine butyryl) -8-benzyloxy carbostyril: 1 H NMR(400MHz,DMSO-d 6 ) Delta: 11.22 (s, 1H, H1), 8.57 (d, j=10.0 hz,1H, H3), 8.11 (d, j=8.7 hz,1H, H4), 7.68-7.55 (m, 2H, H7), 7.44-7.37 (m, 2H, H8), 7.36-7.30 (m, 2H, H9 and H5), 6.74 (t, j=8.9 hz,1H, H2), 5.50-5.37 (m, 2H, H6), 4.02 (q, j=7.1 hz,1H, H10), 3.27 (s, 1H, H14), 1.98 (s, 1H, H13), 1.29 (dt, j=28.9, 14.4hz,6H, H15), 1.20-1.13 (m, 2H, H11), 0.77 (t, j=7.5 hz, H12).
5- (2-isopropylamine butyryl) -8-benzyloxy carbostyril carbon spectrum: 13 C NMR(400MHz,DMSO-d 6 )δ：197.22,161.07,149.29,137.20,136.34,131.12,128.90,128.62,128.48,127.69,125.60,123.75,118.27,111.20,70.75,60.46,49.82,24.26,19.82,19.22,9.21。
mass spectrometry of 5- (2-isopropylaminobutyl) -8-benzyloxyquinolone: ESI-MS, m/z (C) 23 H 26 N 2 O 3 )[M+H] + Theoretical 379.5, found 379.5.
Example 55 Synthesis of- (2-isopropylaminobutyl) -8-benzyloxyquinolone
The reaction flask was charged with the formula IV (30.00 g,0.075 mol), tetrahydrofuran 300.0mL and isopropylamine (66.10 g,1.12 mol) obtained in example 2, stirred at 50deg.C for 8h, concentrated, crystallized with a mixed solvent of 180.0mL n-hexane and 60.0mL methyl tert-butyl ether, filtered, and dried to give 25.3g of formula V (5A: 5- (2-isopropylaminobutyl) -8-hydroxyquinolone) with a yield of 89.2% and a purity of more than 97% as measured by HPLC.
Nuclear magnetic resonance hydrogen spectrum of 5- (2-isopropylamine butyryl) -8-benzyloxy carbostyril: 1 H NMR(400MHz,DMSO-d 6 ) Delta: 11.22 (s, 1H, H1), 8.57 (d, j=10.0 hz,1H, H3), 8.11 (d, j=8.7 hz,1H, H4), 7.68-7.55 (m, 2H, H7), 7.44-7.37 (m, 2H, H8), 7.36-7.30 (m, 2H, H9 and H5), 6.74 (t, j=8.9 hz,1H, H2), 5.50-5.37 (m, 2H, H6), 4.02 (q, j=7.1 hz,1H, H10), 3.27 (s, 1H, H14), 1.98 (s, 1H, H13), 1.29 (dt, j=28.9, 14.4hz,6H, H15), 1.20-1.13 (m, 2H, H11), 0.77 (t, j=7.5 hz, H12).
Nuclear magnetic resonance carbon spectrum of 5- (2-isopropylamine butyryl) -8-benzyloxy carbostyril: 13 C NMR(400MHz,DMSO-d 6 )δ：197.22,161.07,149.29,137.20,136.34,131.12,128.90,128.62,128.48,127.69,125.60,123.75,118.27,111.20,70.75,60.46,49.82,24.26,19.82,19.22,9.21。
mass spectrometry of 5- (2-isopropylaminobutyl) -8-benzyloxyquinolone: ESI-MS, m/z (C) 23 H 26 N 2 O 3 )[M+H] + Theoretical 379.5, found 379.5.
Comparative example 6
Preparation of 5- (2-isopropylaminobutyl) -8-benzyloxy quinolone using other solvents instead of the example 3 or example 4 protocol: the reaction procedure was the same as in example 3 and example 4 except that tetrahydrofuran was replaced with ethyl acetate, methylene chloride, chloroform, dioxane, ethanol or dichloroethane, and as a result, it was found that isopropylamine was either unreactive with formula iv or the product was complex, dark in color and unable to be isolated and purified, and thus comparative example 6 failed to prepare 5- (2-isopropylamine butyryl) -8-benzyloxy quinolone scheme.
Comparative example 7
Comparative example 7 was prepared using other solvents instead of the example 3 or example 4 protocol to prepare 5- (2-isopropylaminobutyl) -8-benzyloxyquinolone: the reaction procedure was the same as in the schemes of example 3 and example 4, except that the solvent mixture of n-hexane and methyl t-butyl ether used in the beating procedure was replaced with ethyl acetate, methylene chloride, chloroform, dioxane, ethanol, dichloroethane or methyl t-butyl ether, and as a result, it was found that only a yellow clear solution could be obtained, and that the separation and purification of 5- (2-isopropylaminobutyl) -8-benzyloxyquinolone failed.
Example 65 Synthesis of- (1-hydroxy-2-isopropylaminobutyl) -8-benzyloxyquinolone
5A (15.0 g,0.04 mol) obtained in example 4 and 150mL of isopropanol were added to a three-necked flask, sodium borohydride (3.78 g,0.1 mol) was added three times, the reaction was stirred at 20℃for 4 hours, 100.0mL of water was added to quench the reaction, extraction was performed twice with 200mL of ethyl acetate, and the mixture was concentrated to give formula VI (6A: 5- (1-hydroxy-2-isopropylaminobutyl) -8-benzyloxyquinolone) in a yield of 91.5% and a purity of more than 99% by HPLC detection.
Nuclear magnetic resonance hydrogen spectrum of 5- (1-hydroxy-2-isopropylaminobutyl) -8-benzyloxyquinolone: 1 H NMR(400MHz,DMSO-d 6 ) Delta/ppm: 10.60 (s, 1H, H1), 8.16 (d, j=10.0 hz,1H, H3), 7.60-7.50 (m, 2H, H7), 7.41-7.34 (m, 2H, H8), 7.34-7.27 (m, 1H, H9), 7.22-7.13 (m, 2H, H4 and H5), 6.55 (t, j=8.6 hz,1H, H2), 5.29 (s, 2H, H6), 4.92 (s, 1H, H10), 1.42 (tdd, j=20.6, 12.4,8.4hz,1H, H16), 1.29-1.14 (m, 2H, H13), 0.87 (t, j=7.6 hz,3H, H14), 0.80-0.67 (m, 6H, H17);
nuclear magnetic resonance carbon spectrum of 5- (1-hydroxy-2-isopropylaminobutyl) -8-benzyloxyquinolone: 13 C NMR(100MHz,DMSO-d 6 )，δ/ppm：161.34,143.34,137.58,137.17,133.80,129.62,128.76,128.29,121.84,120.78,117.54,112.47,71.62,70.33,61.81,45.85,24.04,23.46,23.11,10.99。
mass spectrum of 5- (1-hydroxy-2-isopropylaminobutyl) -8-benzyloxyquinolone: ESI-MS, m/z (C) 23 H 28 N 2 O 3 )[M+H] + Theoretical 380.2, measured 381.2.
Example 75 Synthesis of- (1-hydroxy-2-isopropylaminobutyl) -8-benzyloxyquinolone
5A (15.0 g,0.04 mol) obtained in example 5, 170mL of ethanol and sodium borohydride acetate (11.5 g,0.12 mol) are sequentially added into a three-necked flask, the mixture is stirred at 25 ℃ for reaction for 5 hours, 100.0mL of water is added for quenching reaction, 200mL of ethyl acetate is used for extraction and twice combination, concentration is carried out, and the yield is 90.3%, and the purity detected by HPLC is more than 98%.
EXAMPLE 8 Synthesis of procaterol hydrochloride
After charging the material of formula VI obtained in example 6 (10.00 g,26.3 mmol), 95.0mL of methanol, 5mL of water and palladium on carbon (1.00 g,10% wt) into a reaction vessel, H was introduced 2 The pressure in the kettle is kept at 1.5MPa, and the reaction is carried out for 4 hours at 40 ℃. Filtering, adding hydrochloric acid (24 g,5 mol. L) -1 ) Filtering, washing with 95% methanol water solution at 0deg.C, and drying to obtain procaterol hydrochloride of formula VII, 69.4%, with purity of more than 99% detected by HPLC.
Nuclear magnetic resonance hydrogen spectrum of procaterol hydrochloride: 1 H NMR(400MHz,DMSO-d 6 )，δ/ppm：8.15(d,J＝9.9Hz,1H,H3),7.10(d,J＝8.2Hz,1H,H5),6.92(dd,J＝8.0,3.9Hz,1H,H4),6.50(d,J＝9.9Hz,1H,H2),4.92(d,J＝5.3Hz,1H,H6),2.59(dd,J＝12.1,6.0Hz,1H,H8),2.56–2.51(m,1H,H9),1.55–1.33(m,1H,H13),1.33–0.96(m,2H,H10),0.87(t,J＝7.4Hz,3H,H11),0.77(t,J＝6.9Hz,6H,H14)。
nuclear magnetic resonance carbon spectrum of procaterol hydrochloride: 13 C NMR(100MHz,DMSO-d 6 ，δ/ppm)，161.28,143.14,137.62,131.45,128.82,121.57,121.12,117.65,114.31,71.42,61.77,46.00,23.81,23.30,22.82,11.07。
nuclear magnetic resonance mass spectrometry of procaterol hydrochloride: ESI-MS, m/z (C) 16 H 22 N 2 O 3 )[M+H] + Theoretical 290.2 and measured 291.2.
EXAMPLE 9 Synthesis of procaterol hydrochloride
After adding the formula VI (10.00 g,26.3 mmol) obtained in example 7, 110mL of ethanol, 5.8mL of water and 1.20g of Raney nickel to a reaction vessel, H was introduced 2 The pressure in the kettle is kept at 2.5MPa, and the reaction is carried out for 5 hours at 60 ℃. Filtering, adding hydrochloric acid (24 g, 6mol.L) -1 ) Filtering, washing with 95% methanol water solution at 0deg.C, and drying to obtain procaterol hydrochloride of formula VII, 68.6%, with purity of more than 99% detected by HPLC.
In this embodiment, the nickel metal residue meets the ICH guidelines.
Claims (11)
1. An intermediate, characterized in that the structural formula of the intermediate is shown as the following formula:
2. the process for preparing an intermediate according to claim 1, comprising the following steps in order:
step 1: performing Fries rearrangement reaction on 8-butyryloxy quinolone, butyryl chloride and a catalyst in an organic solvent to obtain a mixture of 5-butyryl-8-hydroxyquinolone and 7-butyryl-8-hydroxyquinolone;
step 2: directly reacting the mixture of 5-butyryl-8-hydroxyquinolone and 7-butyryl-8-hydroxyquinolone obtained in step 1 with a benzyl compound and a base without separation to obtain a mixture of 5-butyryl-8-benzyloxy quinolone and 7-butyryl-8-benzyloxy quinolone;
step 3: reacting the mixture of 5-butyryl-8-benzyloxy quinolone and 7-butyryl-8-benzyloxy quinolone obtained in step 2 without separation with pyridinium tribromide in tetrahydrofuran to obtain 5- (2-bromobutyryl) -8-benzyloxy quinolone; or:
reacting the 5-butyryl-8-benzyloxy quinolone obtained in step 2 with pyridinium tribromide in tetrahydrofuran to obtain 5- (2-bromobutyryl) -8-benzyloxy quinolone.
3. The process for producing an intermediate according to claim 2, wherein in step 2, the molar ratio of the mixture of 5-butyryl-8-hydroxyquinolone and 7-butyryl-8-hydroxyquinolone to the benzyl compound is 1:1.1 to 1.4;
the mol ratio of the mixture to the alkali is 1:1.5-3.0;
the reaction temperature is 60-100 ℃;
the reaction time of the mixture and the benzyl compound is 2-5 h;
the alkali is potassium carbonate or sodium carbonate;
the benzyl compound is selected from: benzyl bromide, benzyl chloride, benzyl p-toluenesulfonate, benzyl benzenesulfonate or benzyl p-nitrobenzenesulfonate.
4. A process for the preparation of an intermediate according to claim 2 or 3, characterized in that in step 3 the molar ratio of the mixture of 5-butyryl-8-benzyloxyquinolone and 7-butyryl-8-benzyloxyquinolone to pyridinium tribromide is between 1:1 and 1.3;
when only 5-butyryl-8-benzyloxy quinolone is used, the molar ratio of 5-butyryl-8-benzyloxy quinolone to pyridinium tribromide is 1:1-1.3;
the ratio of the mixture of the 5-butyryl-8-benzyloxy carbostyril and the 7-butyryl-8-benzyloxy carbostyril to tetrahydrofuran is 1g to 8-12 mL;
when only 5-butyryl-8-benzyloxy carbostyril is used, the ratio of 5-butyryl-8-benzyloxy carbostyril to tetrahydrofuran is 1 g:8-12 mL;
the reaction temperature is 10-70 ℃;
the reaction time is 2-6 h.
5. The process for preparing an intermediate according to claim 2, wherein in step 1, the molar ratio of 8-butyryloxy quinolone to butyryl chloride is 1:1 to 1.6;
the molar ratio of the 8-butyryloxy quinolone to the catalyst is 1:2-5;
the catalyst is Lewis acid;
the organic solvent for Fries rearrangement reaction is chloroform, carbon disulfide, 1, 2-dichloroethane or dioxane;
the ratio of the 8-butyryloxy quinolone to the organic solvent is 1g to 8-14 mL;
the Fries rearrangement reaction temperature is 60-120 ℃;
the Fries rearrangement reaction time is 5-14 h.
6. The process for preparing an intermediate according to claim 5, wherein the catalyst is anhydrous aluminum trichloride.
7. A process for the preparation of procaterol hydrochloride from an intermediate according to claim 1 or from a process according to any one of claims 2 to 6; and the process for preparing procaterol hydrochloride from the intermediate comprises the steps of:
step 1): ammonolysis reaction is carried out on the intermediate and isopropylamine in tetrahydrofuran to obtain 5- (2-isopropylamine butyryl) -8-benzyloxy carbostyril;
step 2): reducing 5- (2-isopropylamine butyryl) -8-benzyloxy carbostyril with a reducing agent in an alcohol solvent to obtain 5- (2-isopropylamine-1-hydroxy butyl) -8-benzyloxy carbostyril;
step 3): the 5- (2-isopropylamine-1-hydroxy butyl) -8-benzyloxy quinolone is subject to hydrogenation reduction reaction under the catalysis of a catalyst, and then reacts with hydrochloric acid to form salt, thus obtaining procaterol hydrochloride.
8. A process for the preparation of procaterol hydrochloride according to claim 7, wherein in step 1) the molar ratio of intermediate to isopropylamine is from 1:10 to 25;
the mass-volume ratio of the intermediate to the tetrahydrofuran is 1:8-12;
the reaction temperature of the intermediate and the isopropylamine is 30-60 ℃;
the reaction time of the intermediate and the isopropylamine is 4-10 h.
9. A process for the preparation of procaterol hydrochloride as claimed in claim 8, wherein in step 1), the ammonolysis reaction is: stirring the intermediate, tetrahydrofuran and isopropylamine for reaction, concentrating, crystallizing by using a solvent, and finally filtering and drying; wherein the solvent is a mixed solvent of n-hexane and methyl tertiary butyl ether, and the volume of the n-hexane and the methyl tertiary butyl ether is 1-10: 1.
10. a process for the preparation of procaterol hydrochloride according to claim 7, wherein in step 2) the reducing agent is selected from sodium borohydride, sodium borohydride acetate or sodium cyanoborohydride;
the alcohol solvent is selected from methanol, ethanol or isopropanol;
the molar ratio of the 5- (2-isopropylamine butyryl) -8-benzyloxy carbostyril to the reducing agent is 1:2-4;
the ratio of the 5- (2-isopropylamine butyryl) -8-benzyloxy carbostyril to the alcohol solvent is 1g to 8-15 mL;
the reaction temperature is 10-40 ℃;
the reaction time is 4-5 h.
11. A process for the preparation of procaterol hydrochloride as claimed in claim 7, wherein in step 3), the hydrogenation reduction is carried out in a mixed solvent of alcohol and water under the catalysis of a catalyst of 5- (2-isopropylamine-1-hydroxybutyl) -8-benzyloxyquinolone;
the catalyst is selected from Raney Ni and palladium carbon;
the mass ratio of the 5- (2-isopropylamine-1-hydroxybutyl) -8-benzyloxy carbostyril to the catalyst is 1:0.1-0.01;
the mixed solvent is selected from a mixture of methanol and water, ethanol and water or isopropanol and water, and the ratio of the ethanol to the water is 90-99:10-1;
the mass volume ratio of the 5- (2-isopropylamine-1-hydroxybutyl) -8-benzyloxy carbostyril to the mixed solvent is 1:5-12;
the temperature of the hydrogenation reduction reaction is 25-80 ℃;
the pressure of the hydrogenation reduction reaction is 0.8-3 MPa;
the hydrogenation reduction reaction time is 4-6 h;
the concentration of the hydrochloric acid is 4-10 mol/L;
the ratio of the 5- (2-isopropylamine-1-hydroxybutyl) -8-benzyloxy carbostyril to the hydrochloric acid is 1g to 0.8-1.4 mL.
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| JP2008031067A (en) * | 2006-07-27 | 2008-02-14 | Otsuka Pharmaceut Co Ltd | Method for preparing carbostyryl derivative |
| CN111103372A (en) * | 2019-12-31 | 2020-05-05 | 成都惟邦药业有限公司 | Method for detecting related substances of procaterol hydrochloride intermediate |
| CN111217746A (en) * | 2020-03-10 | 2020-06-02 | 佛山市隆信医药科技有限公司 | Preparation method of procaterol hydrochloride |
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| CN113121430A (en) * | 2021-05-08 | 2021-07-16 | 岳阳新华达制药有限公司 | Preparation method of 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone |
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| JP2008031067A (en) * | 2006-07-27 | 2008-02-14 | Otsuka Pharmaceut Co Ltd | Method for preparing carbostyryl derivative |
| CN111103372A (en) * | 2019-12-31 | 2020-05-05 | 成都惟邦药业有限公司 | Method for detecting related substances of procaterol hydrochloride intermediate |
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| CN113121430A (en) * | 2021-05-08 | 2021-07-16 | 岳阳新华达制药有限公司 | Preparation method of 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone |
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