A preparation method of terbutaline metabolite

Abstract

The invention discloses a method for preparing a terbutaline metabolite, comprising the following steps: (1) dissolving a raw material A in an organic solvent, adding a base, and then adding a raw material B to carry out a substitution reaction to obtain an intermediate product C; (2) dissolving the intermediate product C in an organic solvent, and then adding a reducing agent to carry out a reduction reaction to reduce the carbonyl group to obtain an intermediate product D; (3) dissolving the intermediate product D in a solvent, carrying out a deprotection reaction to remove the protecting groups X and R on the hydroxyl group to obtain a target product, a terbutaline metabolite E. The method adopts relatively cheap raw materials, undergoes three-step reactions, has mild reaction conditions, and has a high yield. The chemical purity of the obtained product E can reach more than 98.5%, and the product has great application research value in the metabolic process of terbutaline in a living body and clinical pharmacokinetics research.

Description

Technical Field

[0001] The invention relates to a method for preparing a compound, in particular to a method for preparing a terbutaline metabolite. Background Art

[0002] Terbutaline is also known as Bricanyl, terbutaline ... This product replaces the catechol ring with a meta-hydroxyphenol ring, and replaces the hydrogen atom of the amino group with a tert-butyl group on the ethanolamine side chain. This structural change makes it difficult to be inactivated by COMT, monoamine oxidase or sulfate kinase, and the action time is significantly prolonged, which is its most significant feature. This product can also excite the β2 receptors of the uterine myometrium and inhibit spontaneous uterine contraction or uterine contraction caused by oxytocin.

[0003] With the progress of the times and the improvement of scientific and technological levels, people have a more comprehensive understanding of the importance of scientific evaluation of the quality, safety and efficacy of drugs before they are put on the market. Therefore, it is essential to study the metabolic process of drugs in the body. The metabolic process of drugs has received more and more attention from medical workers in the process of drug development and research. A terbutaline metabolite obtained by the present invention provides a standard product for the study of the metabolic mechanism of terbutaline drugs, can be used to explore the metabolic process of the drug in vivo, and has great application research value in clinical pharmacokinetic research. At present, there is no literature report on the synthesis method of this metabolite. Summary of the invention

[0004] Purpose of the invention: The present invention aims to provide a method for preparing terbutaline metabolites for use in the study of terbutaline metabolism mechanism and clinical pharmacokinetics.

[0005] Technical solution: The method for preparing the terbutaline metabolite of the present invention comprises the following steps:

[0006] (1) dissolving raw material A in an organic solvent, adding a base, and then adding raw material B to carry out a substitution reaction to obtain an intermediate product C;

[0007] (2) Dissolving the intermediate C in an organic solvent, then adding a reducing agent to carry out a reduction reaction to reduce the carbonyl group and obtain the intermediate D;

[0008] (3) The intermediate product D is dissolved in a solvent and subjected to a deprotection reaction to remove the protecting groups X and R on the hydroxyl group to obtain the target product, terbutaline metabolite E;

[0009] The synthetic route is as follows:

[0010]

[0011] Wherein, X is a protective group for a hydroxyl group, and R is a protective group for a phenolic hydroxyl group or H.

[0012] Preferably, X is Bn (benzyl), Allyl (allyl), Acetyl (acetyl), Benzoyl (benzoyl) or TBDMS (tert-butyl dimethyl).

[0013] Preferably, when R is a protecting group for a phenolic hydroxyl group, it is selected from Bn (benzyl), Allyl (allyl), TBDMS (tert-butyl dimethyl), Acetyl (acetyl) or MOM (methoxymethyl ether).

[0014] The raw material A is obtained by reacting N-tert-butylhydroxylamine with a protecting agent, and the hydroxyl group is protected.

[0015] Wherein, when R is a protecting group of a phenolic hydroxyl group, the raw material B is obtained by reacting 2-bromo-1-(3,5-dihydroxyphenyl)-ethanone with a protecting agent, and the hydroxyl group is protected.

[0016] Preferably, in step (1), the temperature of the substitution reaction is 40 to 90° C., and the reaction time is 6 to 48 hours; the organic solvent is DMF, DMSO, acetonitrile, acetone, chloroform, methanol or ethanol; the base is an organic base or an inorganic base, wherein the organic base is triethylamine, DIPEA or DBU, and the inorganic base is sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, NaOH or KOH.

[0017] Preferably, in step (2), the reducing agent is NaBH4, LiBH4, BH3-THF solution or SmI2 / MeOH, the reduction reaction temperature is 0-50°C, and the reaction time is 2-12 hours; the organic solvent is THF, methanol or ethanol; the amount of the reducing agent is 1-3 times the molar amount of compound C.

[0018] In step (3), the protective groups of hydroxyl and phenolic hydroxyl are removed by reaction. Preferably, in step (3), when X = Bn, R = H or Bn, the deprotection reaction uses a palladium catalyst and ammonium formate, reacts at a temperature of 20 to 80°C for 2 to 8 hours to remove the benzyl group, and obtains the target product E; when X = Allyl, R = Allyl, THF is used as a solvent, and tetrakistriphenylphosphine palladium and 1,3-dimethylbarbituric acid are used to remove the Allyl protective group; when X = TBDMS, R = MOM or TBDMS, hydrochloric acid or trifluoroacetic acid are used to remove the TBDMS and MOM protective groups; when X = R = TBDMS, tetrabutylammonium fluoride or hydrogen fluoride pyridine is used to remove TBDMS; when X = Acetyl or Benzoyl, R = Acetyl, ammonia-containing methanol or an inorganic base is used to remove the Acetyl and Benzoyl protective groups to obtain the target product (E).

[0019] Preferably, in step (3): when X = Bn, R = H or Bn, the solvent is methanol, ethanol, tetrahydrofuran or DMF, etc., the catalyst is palladium carbon, palladium hydroxide carbon, palladium dichloride, etc., the mass ratio of the catalyst to the compound D is 0.05-0.2:1, and the molar equivalent ratio of ammonium formate to the compound D is 3-10:1. When X = R = Allyl, THF is used as the solvent, tetrakistriphenylphosphine palladium and 1,3-dimethylbarbituric acid are used to remove the Allyl protecting group, tetrakistriphenylphosphine palladium is the catalytic equivalent, the mass ratio of the catalyst to the compound D is 0.05-0.1:1, and the molar equivalent ratio of 1,3-dimethylbarbituric acid to the compound D is 3-5:1. When X=R=TBDMS, the protecting group is removed by hydrochloric acid or trifluoroacetic acid, and the molar equivalent ratio of hydrochloric acid or trifluoroacetic acid to compound D is 3-5:1; or it is removed by tetrabutylammonium fluoride or hydrogen fluoride pyridine, and the molar equivalent ratio of tetrabutylammonium fluoride or hydrogen fluoride pyridine to compound D is 3-7:1. When X=Acetyl, Benzoyl; R=Acetyl, it can be removed by ammonia-containing methanol or inorganic base, and the volume ratio of ammonia-containing methanol to compound D is 5-10:1, and the inorganic base can be potassium carbonate, sodium carbonate, NaOH, KOH, etc., and the molar equivalent ratio of inorganic base to compound D is 3-5:1. When R=MOM, hydrochloric acid or trifluoroacetic acid is used to remove the R group, and the molar equivalent ratio of hydrochloric acid or trifluoroacetic acid to compound D is 2-4:1. Preferably, X=R=Bn, methanol is the solvent, palladium carbon is the catalyst, the molar equivalent ratio of ammonium formate to compound D is 5:1, and the reaction time is preferably 2 hours. The reaction is relatively clean and easy to handle, so this condition is preferred.

[0020] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The present invention provides a method for synthesizing terbutaline metabolites, using relatively cheap raw materials, undergoing three-step reactions, with mild reaction conditions and high yield, and the chemical purity of the obtained product E can reach more than 98.5%, which has great application research value in the metabolic process of terbutaline in vivo and clinical pharmacokinetics research; (2) The process design is reasonable, the operability is strong, the three wastes are small, and industrial production can be realized; (3) The method provides a reference method for similar nitrogen hydroxyl compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is a circuit diagram of the preparation method of the present invention;

[0022] Figure 2 This is the liquid phase diagram of product E of Example 1 of the present invention;

[0023] Figure 3 This is the H NMR spectrum of product E of Example 1 of the present invention;

[0024] Figure 4 This is the mass spectrum of product E in Example 1 of the present invention. DETAILED DESCRIPTION

[0025] The technical solution of the present invention is further described below in conjunction with embodiments.

[0026] Example 1

[0027] The preparation method of the terbutaline metabolite of the present invention, X=R=Bn, the synthesis route is as follows:

[0028]

[0029] (1) 10.00 g of raw material A-1 was dissolved in 100 mL of DMF, 7.71 g of potassium carbonate was added at room temperature, and then 22.94 g of raw material B-1 was added, and then reacted at 50° C. for 6 hours; TLC monitored the complete reaction of the raw materials, filtered the reaction solution, the filtrate was dried, 200 mL of water was added, extracted with ethyl acetate, the ethyl acetate phase was concentrated, and purified by column chromatography to obtain 22.10 g of intermediate (C-1) as a yellow oil with a yield of 77.73%;

[0030] (2) 10.00 g of intermediate C-1 was dissolved in 50 mL of ethanol, and 0.74 g of sodium borohydride was added under ice bath conditions. The reaction was carried out at room temperature for 4 hours to obtain a yellow solution. The TLC plate showed that the raw material had reacted completely. Under ice bath conditions, 100 mL of water was slowly added to the reaction solution, and the mixture was extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain 9.10 g of intermediate D-1 as a light yellow oil with a yield of 90.64%.

[0031] (3) Dissolve 5.00 g of intermediate D-1 in 50 mL of methanol, then evacuate with nitrogen, add 0.25 g of palladium carbon, then add 3.08 g of ammonium formate, and react at 40° C. for 2 hours; TLC spot plate monitoring shows that the raw material is completely reacted, filter the palladium carbon, concentrate the filtrate, and purify it by column chromatography to obtain 1.80 g of the target product E as a white solid with a yield of 76.34%.

[0032] The final product E was characterized by HPLC, NMR and mass spectrometry.

[0033] Depend on Figure 2 It was obtained that the purity of compound E was 99.7161%.

[0034] Depend on Figure 3 The NMR of compound E is obtained: 1 H NMR (400MHz, DMSO-d6): δ9.04(s,2H),7.63(s,1H),6.20(d,2H),6.05(d,1H),4.51(m,1H),4.41(brs,1H),2.54(m,2H),0.99(s,9H).

[0035] Depend on Figure 4 Compound E MS: 242.2 [M+1] + .

[0036] Example 2

[0037] The preparation method of the terbutaline metabolite of the present invention, X=R=Allyl, the synthesis route is as follows:

[0038]

[0039] (1) 10.00 g of raw material A-2 was dissolved in 100 mL of ethanol, 12.00 g of DIPEA was added at room temperature, and then 24.10 g of raw material B-2 was added, and then reacted at 50° C. for 5 hours; TLC monitored the complete reaction of the raw materials, filtered the reaction solution, the filtrate was dried, 200 mL of water was added, extracted with ethyl acetate, the ethyl acetate phase was concentrated, and purified by column chromatography to obtain 20.50 g of intermediate C-2 as a yellow oil with a yield of 73.68%;

[0040] (2) 5.00 g of intermediate C-2 was dissolved in 50 mL of THF, and 0.76 g of lithium borohydride was added under ice bath conditions. The mixture was reacted at 50° C. for 2 hours to obtain a white suspension. The TLC plate showed that the reaction of the raw material was complete. Under ice bath conditions, 100 mL of water was slowly added dropwise to the reaction solution until there were no bubbles in the reaction solution. Then, THF was dried by spin drying, the reaction solution was concentrated, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain 4.10 g of intermediate D-2 as a light yellow oil with a yield of 81.54%.

[0041] (3) 4.00 g of intermediate D-2 was dissolved in 40 mL of THF, and then 0.20 g of tetrakistriphenylphosphine palladium and 5.18 g of 1,3-dimethylbarbituric acid were added and reacted at room temperature for 4 hours. After the reaction was completed, the reaction was concentrated and purified by column chromatography to obtain 1.90 g of the target product E as a white solid with a yield of 71.16%.

[0042] The NMR and mass spectrometry data of compound E were the same as those in Example 1, and the HPLC purity was 99.0023%.

[0043] Example 3

[0044] The preparation method of the terbutaline metabolite of the present invention, X=R=TBDMS, the synthesis route is as follows:

[0045]

[0046] (1) 10.00 g of raw material A-3 was dissolved in 100 mL of acetonitrile, 10.19 g of potassium carbonate was added at room temperature, and then 34.85 g of raw material B-3 was added, and then the reaction was carried out at 40° C. for 8 hours; TLC monitored the complete reaction of the raw materials, filtered the reaction solution, the filtrate was dried, 200 mL of water was added, extracted with ethyl acetate, the ethyl acetate phase was concentrated, and purified by column chromatography to obtain 21.50 g of intermediate C-3 as a yellow oil with a yield of 75.13%;

[0047] (2) 5.00 g of intermediate C-3 was dissolved in 50 mL of THF. Under ice bath conditions, 10.3 mL of 1 M borane solution in THF was added. The mixture was reacted at room temperature for 2 hours to obtain a colorless solution. The reaction of the raw material was complete according to TLC. Under ice bath conditions, 30 mL of methanol was slowly added dropwise to the reaction solution until there were no bubbles in the reaction solution. Then, THF and methanol were removed by spinning. The reaction solution was concentrated and extracted with ethyl acetate. After concentration and purification by column chromatography, 4.00 g of intermediate D-3 was obtained as a light yellow oil with a yield of 79.72%.

[0048] (3) 4.00 g of intermediate D-3 was dissolved in 40 mL of THF, and then 20 mL of 3N HCl was added. The reaction was carried out at room temperature for 4 hours. The reaction of the raw materials was completed. The THF was concentrated to remove the THF, and the pH was adjusted to 7 with concentrated ammonia water. The mixture was extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain 1.10 g of the target product E as a white solid. The yield was 66.57%.

[0049] The NMR and mass spectrometry data of compound E were the same as those in Example 1, and the HPLC purity was 98.9162%.

[0050] Example 4

[0051] The preparation method of the terbutaline metabolite of the present invention, X = Benzoyl, R = Acetyl, the synthesis route is as follows:

[0052]

[0053] (1) 10.00 g of raw material A-4 was dissolved in 100 mL of acetonitrile, 9.45 g of DBU (1,8-diazobisspiro[5.4.0]undec-7-ene) was added at room temperature, and then 19.57 g of raw material B-4 was added, and then reacted at 45° C. for 9 hours; TLC monitored the complete reaction of the raw material, 200 mL of water was added, and the mixture was extracted with ethyl acetate, the ethyl acetate phase was concentrated, and column chromatography was performed to obtain 14.60 g of intermediate C-4 as a yellow oil with a yield of 66.01%;

[0054] (2) 5.00 g of intermediate C-4 was dissolved in 50 mL of THF, and 17.5 mL of 1 MBH3-THF solution was added under ice bath conditions. The reaction was allowed to react at room temperature for 1 hour to obtain a light yellow solution. The TLC plate showed that the reaction of the raw materials was complete. Under ice bath conditions, 30 mL of methanol was slowly added dropwise to the reaction solution until there were no bubbles in the reaction solution. Then, THF and methanol were spun off, the reaction solution was concentrated, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain 3.90 g of intermediate D-4 as a light yellow oil with a yield of 77.63%;

[0055] (3) 3.00 g of intermediate D-4 was dissolved in 30 mL of methanol, and then 30 mL of 4 M ammonia-containing methanol was added. The reaction was carried out at room temperature for 8 hours. The raw materials were reacted completely, and the methanol was removed by concentration. 50 mL of water was added, and the mixture was extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain 1.15 g of the target product E as a white solid. The yield was 68.23%.

[0056] The NMR and mass spectrometry data of compound E were the same as those in Example 1, and the HPLC purity was 99.2016%.

[0057] Example 5

[0058] The preparation method of the terbutaline metabolite of the present invention, X=Bn, R=H, the synthesis route is as follows:

[0059]

[0060] (1) 10.00 g of raw material A-5 was dissolved in 100 mL of acetonitrile, 8.47 g of triethylamine was added at room temperature, and then 12.90 g of raw material B-5 was added, and then the reaction was carried out at 40° C. for 12 hours; TLC monitored the complete reaction of the raw materials, the reaction solution was filtered, the filtrate was spin-dried, 200 mL of water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate phase was concentrated and purified by column chromatography to obtain 11.10 g of intermediate C-5 as a yellow oil with a yield of 60.41%;

[0061] (2) 10.00 g of intermediate C-5 was dissolved in 50 mL of THF, and 91.1 mL of 1 MBH3-THF solution was added under ice bath conditions. The mixture was reacted at room temperature for 2 hours to obtain a light yellow solution. The TLC plate showed that the reaction of the raw materials was complete. Under ice bath conditions, 100 mL of methanol was slowly added to the reaction solution. When no bubbles were generated in the reaction solution, the reaction solution was concentrated and purified by column chromatography to obtain 8.00 g of intermediate D-5 as a light yellow oil with a yield of 79.51%.

[0062] (3) 5.00 g of D-5 intermediate was dissolved in 50 mL of ethanol, then evacuated with nitrogen, 0.25 g of palladium hydroxide on carbon was added, and then 2.85 g of ammonium formate was added, and the reaction was carried out at room temperature for 3 hours; TLC spot plate monitoring showed that the raw material reaction was complete, the palladium on carbon was filtered, the filtrate was dried, concentrated, and purified by column chromatography to obtain 2.60 g of the target product E as a white solid, with a yield of 71.42%;

[0063] The NMR and mass spectrometry data of compound E were the same as those in Example 1, and the HPLC purity was 99.3763%.

[0064] Experimental conclusion: Through a large number of experiments, it was found that when R=H, there may be side reactions in the second step, and the phenolic hydroxyl group may react with bromine, so the yield of this step is relatively low; when X is not equal to R, R=Allyl, TBDMS, Acetyl, MOM, the last step is to remove the R group first, so it is more troublesome than X=R, but the overall yield is very high. The experiment prefers X=R=Bn, and the product is directly debenzylated in the last step.

Claims

1. A method for preparing a terbutaline metabolite, characterized in that: The following steps are involved: (1) Dissolve the raw material A in an organic solvent, add a base, and then add the raw material B to carry out a substitution reaction to obtain an intermediate product C; (2) Dissolve the intermediate product C in an organic solvent, then add a reducing agent to carry out a reduction reaction to reduce the carbonyl group and obtain the intermediate product D; (3) The intermediate product D is dissolved in a solvent and subjected to a deprotection reaction to remove the protecting groups X and R on the hydroxyl group to obtain the target product, terbutaline metabolite E; The synthetic route is as follows: ； Wherein, X is a protecting group for a hydroxyl group, R is a protecting group for a phenolic hydroxyl group or H; X is Bn, Allyl, Acetyl, Benzoyl or TBDMS; when R is a protecting group for a phenolic hydroxyl group, it is selected from Bn, Allyl, TBDMS, Acetyl or MOM.

2. The method for preparing a terbutaline metabolite according to claim 1, characterized in that: In step (1), the temperature of the substitution reaction is 40-90° C., and the reaction time is 6-48 hours.

3. The method for preparing a terbutaline metabolite according to claim 1, characterized in that: In step (2), the reducing agent is NaBH4, LiBH4, BH3-THF solution or SmI2 / MeOH, the reduction reaction temperature is 0-50°C, and the reaction time is 2-12 hours.

4. The method for preparing a terbutaline metabolite according to claim 1, characterized in that: In step (3), when X=Bn, R=H or Bn, the deprotection reaction uses a palladium catalyst and ammonium formate, and the reaction is carried out at a temperature of 20-80°C for 2-8 hours to remove the benzyl group to obtain the target product E; when X=Allyl and R=Allyl, THF is used as the solvent, and tetrakistriphenylphosphine palladium and 1,3-dimethylbarbituric acid are used to remove the Allyl protecting group; when X=TBDMS, R=MOM or TBDMS, hydrochloric acid or trifluoroacetic acid is used to remove the TBDMS and MOM protecting groups; when X=R=TBDMS, tetrabutylammonium fluoride or hydrogen fluoride pyridine is used to remove TBDMS; when X=Acetyl or Benzoyl, R=Acetyl, ammonia-containing methanol or an inorganic base is used to remove the Acetyl and Benzoyl protecting groups to obtain the target product E.

5. The method for preparing a terbutaline metabolite according to claim 1, characterized in that: In step (1), the organic solvent is DMF, DMSO, acetonitrile, acetone, chloroform, methanol or ethanol; the base is an organic base or an inorganic base, wherein the organic base is triethylamine, DIPEA or DBU, and the inorganic base is sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, NaOH or KOH.

6. The method for preparing a terbutaline metabolite according to claim 1, characterized in that: In step (2), the organic solvent is THF, methanol or ethanol.

7. The method for preparing a terbutaline metabolite according to claim 1, characterized in that: In step (2), the amount of the reducing agent used is 1 to 3 times the molar amount of compound C.

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