CN112279776B - Method for synthesizing arformoterol free alkali - Google Patents
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- CN112279776B CN112279776B CN202011201831.7A CN202011201831A CN112279776B CN 112279776 B CN112279776 B CN 112279776B CN 202011201831 A CN202011201831 A CN 202011201831A CN 112279776 B CN112279776 B CN 112279776B
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- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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Abstract
The invention discloses a method for synthesizing arformoterol free alkali, which comprises the following steps: (1) taking a compound shown as a formula SM1 as a raw material, carrying out carbonyl chiral reduction reaction in a first solvent to obtain a reaction solution containing the compound shown as a formula M1, and concentrating and drying; (2) dissolving the material obtained in the step (1) by using a second solvent, carrying out hydrogenation reaction to obtain a reaction solution containing a compound shown as a formula M2, filtering the reaction solution, and cooling the filtrate; (3) performing formylation reaction on the cooled filtrate in the step (2) to obtain a reaction solution containing a compound shown as a formula M3, and concentrating and drying; (4) dissolving the material obtained in the step (3) by using a third solvent, performing cyclization reaction to obtain a reaction solution containing a compound shown as a formula M4 and free SM2, filtering, and concentrating and drying the filtrate; (5) and (3) dissolving the material obtained in the step (4) by using a fourth solvent, carrying out condensation reaction to obtain an arformoterol precursor shown as a formula M5, and carrying out hydrogenation and debenzylation on M5 to obtain the arformoterol.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a method for synthesizing arformoterol free alkali.
Background
The arformoterol is a long-acting beta 2-adrenergic receptor stimulant, is a common medicine for treating severe chronic bronchial asthma, has high pharmacological activity, quick response and long action time, has obvious anti-inflammatory effect, is used for treating the chronic bronchial asthma, is used together with glucocorticoid, and is used for treating the severe asthma. The arformoterol molecule has two chiral centers and four optical isomers exist, and pharmacological studies show that the pharmacological activity of (R, R) -formoterol is 1000 times that of (S, S) configuration, and the arformoterol molecule shows less toxicity. In the literature, the synthetic method of arformoterol has a long route, for example, as shown in fig. 1, the synthetic route uses a raney nickel inflammable material, the danger is greatly increased in the operation process, and a separation column is used for separating isomers, so that the production cost is greatly increased.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to solve the technical problems of long reaction route, harsh reaction conditions, complex operation and the like in the prior art and provides a method for synthesizing arformoterol free alkali.
The technical problem to be solved by the present invention is to provide the use of the above arformoterol free base in the synthesis of arformoterol.
In order to solve the first technical problem, the invention discloses a method for synthesizing arformoterol free alkali, wherein the intermediate in each step does not need to be separated into solid, each step of reaction is subjected to simple post-treatment and directly subjected to the next step of reaction, so that the link of separating and purifying the intermediate is omitted, a large amount of reagents and time are saved, and the production cost is reduced, and the method specifically comprises the following steps:
(1) dissolving a compound (3 '-nitro-4' -benzyloxy-2-bromoacetophenone) shown as a formula SM1 in a first solvent together with (1R,2S) -1-amino-2-indanone, cooling under nitrogen, adding borane dimethyl sulfide, performing carbonyl chiral reduction reaction to obtain a reaction solution containing the compound shown as a formula M1, quenching with methanol, and concentrating to dryness;
(2) stirring and dissolving the material obtained in the step (1) by using a second solvent, carrying out hydrogenation reaction on the material and a reduction catalyst under hydrogenation to obtain a reaction liquid containing a compound shown as a formula M2, filtering the reaction liquid to remove the reduction catalyst, and cooling the filtrate to directly carry out the next reaction;
(3) adding a pre-prepared mixed solution of formic acid and acetic anhydride into the filtrate obtained after the temperature reduction in the step (2), performing formylation reaction to obtain a reaction solution containing a compound shown as a formula M3, and concentrating and drying to obtain an oily substance of the compound shown as a formula M3;
(4) stirring and dissolving the material obtained in the step (3) by using a third solvent, performing cyclization reaction with potassium carbonate and a compound shown as a formula SM2 to obtain a reaction liquid containing the compound shown as a formula M4 and a free-state SM2, filtering the reaction liquid to remove potassium carbonate, and concentrating and drying the filtrate to obtain a mixture of free-state SM2 and oily compounds shown as a formula M4;
(5) stirring and dissolving the oily material obtained in the step (4) by using a fourth solvent, and carrying out condensation reaction to obtain a compound (arformoterol precursor) shown as a formula M5;
in the step (1), the first solvent is any one or a combination of several of anhydrous tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane.
In the step (1), the ratio of the first solvent to the compound shown as the formula SM1 is 10-20 mL: 1g of the total weight of the composition.
In the step (1), the mass ratio of the compound shown as the formula SM1 to the (1R,2S) -1-amino-2-indanone is 50: 1-1.5, preferably 50: 1.45.
In the step (1), the temperature is reduced to 5-10 ℃ under the protection of nitrogen.
In the step (1), the dosage ratio of the compound shown as the formula SM1 to borane dimethylsulfide is 50 g: 0.12 mol.
In the step (1), the temperature of the chiral reduction reaction of the carbonyl is 5-10 ℃.
In the step (1), the time of the chiral reduction reaction of the carbonyl is 1 h.
In the step (2), the second solvent is a mixed solution of tetrahydrofuran and toluene, and the volume ratio of the tetrahydrofuran to the toluene is 0.5-1: 1.
In the step (2), the dosage ratio of the second solvent to the compound shown as the formula M1 is 10-20 mL: 1g, preferably 10 mL: 1g of the total weight of the composition.
In the step (2), the reduction catalyst is platinum dioxide and/or platinum carbon, preferably platinum dioxide.
In the step (2), the mass ratio of the reduction catalyst to the compound shown as the formula SM1 is 0.05: 1.
in the step (2), the hydrogen pressure is 2.0 MPa.
In the step (2), the reaction temperature of the nitro hydrogenation reaction is 30-35 ℃.
In the step (2), the reaction time of the nitro hydrogenation reaction is 12 h.
In the step (2), the temperature is reduced to 5-10 ℃.
In the step (3), the mass ratio of formic acid to acetic anhydride is 15: 18; preferably, it is used after stirring for 30 min.
In the step (3), the addition of formic acid and acetic anhydride (acetic anhydride) is finished within 30-60 min; dropwise addition is preferred.
In the step (3), the feeding ratio of formic acid to acetic anhydride is as follows: formic acid: acetic anhydride: SM1 was 15 g: 18 g: 50 g.
In the step (3), the formamide reaction is carried out at 5-10 ℃ for 10-20 min.
In the step (4), the third solvent is a mixed solution of tetrahydrofuran and methanol, and the volume ratio of the tetrahydrofuran to the methanol is 0.5-1: 1, preferably 1: 1.
In the step (4), the dosage ratio of the third solvent to the compound shown as the formula M3 is 10-20 mL: 1g of the total weight of the composition.
In the step (4), the dosage ratio of potassium carbonate, the compound shown as the formula SM2 and the compound shown as the formula SM1 is 35-50: 40: 50.
in the step (4), the cyclization reaction is carried out for 5-8 hours at the temperature of 30-40 DEG C
In the step (5), the fourth solvent is any one or a combination of toluene, n-heptane and n-hexane.
In the step (5), the dosage ratio of the fourth solvent to the compound shown as the formula M4 is 10-20 mL: 1g of the total weight of the composition.
In the step (5), the reaction temperature of the condensation reaction is 60-80 ℃.
In the step (5), the reaction time of the condensation reaction is 12-24 h.
In the step (5), after the reaction was completed, the reaction solution was concentrated to obtain M5.
In order to solve the second technical problem, the invention also discloses the application of the M5 in synthesizing arformoterol, and the reaction route is shown in figure 2.
Wherein, after the reaction solution containing the compound shown as the formula M5 is concentrated and dried, a fifth solvent is added, the mixture is stirred, palladium carbon is added, and the reaction solution containing the free base of the arformoterol is obtained by reaction under the hydrogen pressure.
Wherein, the fifth solvent is methanol.
Wherein the ratio of the fifth solvent to the compound shown as the formula M5 is 10-20 mL: 1g of the total weight of the composition.
Wherein the concentration of palladium carbon is 5-7.5 mg/mL.
Wherein the hydrogen pressure is 2.0 to 3.0 MPa.
Wherein the reaction is carried out at 30-40 ℃ for 5-10 h.
Preferably, after the reaction is finished, filtering the reaction solution to remove palladium carbon, concentrating the filtrate, adding isopropanol into the concentrated filtrate to dissolve the filtrate, then adding L-tartaric acid, stirring for crystallization, cooling and filtering, and drying the obtained solid to obtain the tartrate of the arformoterol.
In the present invention, the stirring is not particularly required.
Has the advantages that: compared with the prior art, the invention has the following advantages:
the method has mild reaction conditions, no solid is separated in the intermediate step, the production time is saved, the usage amount of the solvent is greatly reduced, the total yield of the arformoterol free alkali is about 50%, the ee value of the product is higher than 95%, the yield is higher than 30% of the yield of the prior art, and the production cost is lower than that of the prior synthesis process.
Drawings
The foregoing and/or other advantages of the invention will become more apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.
Fig. 1 is a schematic diagram of a synthesis method of arformoterol in the prior art.
Fig. 2 is a schematic diagram of a synthetic method of arformoterol of the present invention.
FIG. 3 shows the mass spectrum M1.
FIG. 4 shows the mass spectrum M2.
FIG. 5 shows the mass spectrum M3.
FIG. 6 shows the mass spectrum M5.
Figure 7 is a mass spectrum of arformoterol free base.
Figure 8 is the arformoterol tartrate hydrogen spectrum.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the methods of the embodiments of the present invention are given by way of illustration only and not by way of limitation, and therefore all simple modifications of the methods of the present invention are within the scope of the claimed invention.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
Example 1
(1) 50g of 3 '-nitro-4' -benzyloxy-2-bromoacetophenone (SM1) and 1.45g of (1R,2S) -1-amino-2-indanone are added into a reaction bottle, 500mL of anhydrous tetrahydrofuran solvent is added and stirred for dissolving, nitrogen is used for protection, the temperature is reduced to 5-10 ℃, 12mL of borane dimethyl sulfide solution (the solvent is dimethyl sulfide) of 10mol/L is added dropwise, the temperature is kept for 5-10 ℃ for reaction for 1h, and M1 is generated by dot-panel display.
(2) Directly concentrating the M1 reaction solution to about 55g, adding 300mL of tetrahydrofuran and 300mL of toluene, stirring, dissolving, adding into an autoclave, adding 2.5g of platinum dioxide, replacing with hydrogen for 2 times in the autoclave, pressurizing to 2.0MPa, heating to 30-35 ℃, reacting for 12h, and displaying the point plate to generate M2.
(3) Filtering the M2 reaction liquid to remove platinum dioxide, cooling the filtrate to 5-10 ℃, dropping a mixed solution of 15g formic acid/18 g acetic anhydride (prepared 1h in advance) for 30min, preserving the temperature for 5-10 ℃, reacting for 20min, and spotting to show that M3 is generated. The M3 reaction was concentrated to dryness to give 65g of M3 as an oil.
(4) Adding 350mL of methanol and 350mL of tetrahydrofuran into the M3 material, stirring and dissolving, adding 35g of potassium carbonate and 40g of SM2 material, heating to 35 ℃, and carrying out heat preservation reaction for 5 hours, wherein a dot plate shows that SM2 free state and M4 are generated.
(5) The SM2 and M4 reaction liquid is filtered to remove potassium carbonate solid filtrate, the solid filtrate is concentrated to be dry to obtain about 100g of free SM2 and M4 oily substances, 1000mL of toluene is added to be stirred and dissolved, the temperature is increased to 80 ℃, the reaction is kept for 12 hours, and the point plate shows that M5 is generated.
(6) Concentrating the M5 reaction solution to be about 95g dry, adding 1000mL of methanol into an autoclave with stirring, adding 6g of palladium-carbon, replacing for 2 times with hydrogen, pressurizing to 2.0MPa, keeping the temperature at 40 ℃ for 5 hours, adding a dot plate to show that arformoterol is generated, filtering to remove the palladium-carbon, concentrating the filtrate to be dry, adding 500mL of isopropanol, stirring and dissolving, adding 20g of L-tartaric acid, stirring at 40 ℃ to form salt and crystallization for 3 hours, cooling to room temperature, filtering, drying and weighing to obtain 34g, wherein the total yield is 50%, the purity is 96%, and the ee value is 96%. The synthetic mass spectrograms of the obtained products are shown in figures 3 to 8.
Example 2
(1) Feeding 100g of 3 '-nitro-4' -benzyloxy-2-bromoacetophenone (SM1) and 2.90g of (1R,2S) -1-amino-2-indanone into a reaction bottle, adding 1000mL of anhydrous tetrahydrofuran solvent, stirring and dissolving, cooling to 5-10 ℃ under the protection of nitrogen, dropwise adding 24mL of 10mol/L borane dimethyl sulfide solution (the solvent is dimethyl sulfide), keeping the temperature for 5-10 ℃ and reacting for 1h, and displaying a dot plate to generate M1.
(2) Directly concentrating the M1 reaction solution to be about 105g, adding 600mL of tetrahydrofuran and 600mL of toluene, stirring, dissolving, adding into an autoclave, adding 5.0g of platinum dioxide, replacing with hydrogen for 2 times in the autoclave, pressurizing to 2.0MPa, heating to 30-35 ℃, reacting for 12h, and displaying the point plate to generate M2.
(3) Filtering the M2 reaction liquid to remove platinum dioxide, cooling the filtrate to 5-10 ℃, dropping 30g formic acid/36 g acetic anhydride mixed solution (prepared 1h ahead) for 30min, keeping the temperature at 5-10 ℃ for reaction for 20min, and spotting to show that M3 is generated. The M3 reaction was concentrated to dryness to give 125g of M3 as an oil.
(4) The M3 material is added with 700mL of methanol and 700mL of tetrahydrofuran to be stirred and dissolved, 70g of potassium carbonate and 80g of SM2 material are added, the temperature is raised to 35 ℃, the reaction is kept for 5 hours, and the point plate shows that SM2 free state and M4 are generated.
(5) The SM2 and M4 reaction liquid is filtered to remove potassium carbonate solid filtrate, the solid filtrate is concentrated to be dry to obtain about 205g of free SM2 and M4 oily substances, 2000mL of toluene is added to be stirred and dissolved, the temperature is increased to 80 ℃, the reaction is kept for 12 hours, and the point plate shows that M5 is generated.
(6) Concentrating the M5 reaction solution to be about 200g dry, adding 2000mL of methanol stirring solvent into an autoclave, adding 12g of palladium carbon, replacing 2 times with hydrogen, pressurizing to 2.0MPa, keeping the temperature at 40 ℃ for 5 hours, adding a dot plate to show that arformoterol is generated, filtering to remove the palladium carbon, concentrating the filtrate, adding 1000mL of isopropanol, stirring, dissolving, adding 40g of L-tartaric acid, stirring at 40 ℃ to form salt, crystallizing for 3 hours, cooling to room temperature, filtering, drying and weighing to obtain 70g, wherein the total yield is 49%, the purity is 95%, and the ee value is 95%.
Example 3
(1) Feeding 200g of 3 '-nitro-4' -benzyloxy-2-bromoacetophenone (SM1) and 5.8g of (1R,2S) -1-amino-2-indanone into a reaction bottle, adding 2000mL of anhydrous tetrahydrofuran solvent, stirring and dissolving, cooling to 5-10 ℃ under the protection of nitrogen, dropwise adding 48mL of borane dimethyl sulfide solution (the solvent is dimethyl sulfide) of 10mol/L, keeping the temperature at 5-10 ℃ and reacting for 1h, and displaying a point plate to generate M1.
(2) Directly concentrating the M1 reaction solution to about 205g, adding 1000mL of tetrahydrofuran and 1000mL of toluene, stirring, dissolving, adding into an autoclave, adding 10g of platinum dioxide, replacing with hydrogen for 2 times in the autoclave, pressurizing to 2.0MPa, heating to 30-35 ℃, reacting for 12h, and spotting to show that M2 is generated.
(3) Filtering the M2 reaction liquid to remove platinum dioxide, cooling the filtrate to 5-10 ℃, dropwise adding a mixed solution of 60g formic acid/72 g acetic anhydride (prepared 1h in advance) for 30min, preserving the temperature for 5-10 ℃, reacting for 20min, and spotting to show that M3 is generated. The M3 reaction was concentrated to dryness to give 255g of M3 as an oil.
(4) The M3 material is added with 1500mL of methanol and 1500mL of tetrahydrofuran to be stirred and dissolved, 140g of potassium carbonate and 160g of SM2 material are added, the temperature is raised to 35 ℃ for 5 hours of heat preservation reaction, and the point plate shows that SM2 free state and M4 are generated.
(5) The SM2 and M4 reaction liquid is filtered to remove potassium carbonate solid filtrate, the solid filtrate is concentrated to be dry, about 408g of free SM2 and M4 oily matters are obtained, 4000mL of methylbenzene are added and stirred to be dissolved, the temperature is increased to 80 ℃, the reaction is kept for 12 hours, and the point plate shows that M5 is generated.
(6) Concentrating the M5 reaction solution to be dry about 398g, adding 4000mL of methanol stirring solvent into an autoclave, adding 24g of palladium carbon, replacing for 2 times by hydrogen, pressurizing to 2.0MPa, keeping the temperature at 40 ℃ for 5 hours, adding a point plate to show that arformoterol is generated, filtering to remove the palladium carbon, concentrating and dissolving the filtrate by adding 2000mL of isopropanol, adding 80g of L-tartaric acid, stirring at 40 ℃ to form salt crystallization for 3 hours, cooling to room temperature, filtering, drying and weighing to obtain 142g, wherein the total yield is 50%, the purity is 96%, and the ee value is 97%.
Example 4: the prior art is compared with the invention:
note: the prior art mentioned above is the prior art mentioned in the background, namely the prior art corresponding to fig. 1.
Claims (6)
1. A method for synthesizing arformoterol free base, comprising the steps of:
(1) dissolving a compound (3 '-nitro-4' -benzyloxy-2-bromoacetophenone) shown as a formula SM1 in a first solvent together with (1R,2S) -1-amino-2-indanone, cooling under nitrogen, adding borane dimethyl sulfide, performing carbonyl chiral reduction reaction to obtain a reaction solution containing the compound shown as a formula M1, quenching with methanol, and concentrating to dryness;
(2) dissolving the material obtained in the step (1) by using a second solvent, carrying out hydrogenation reaction on the material and a reduction catalyst under hydrogenation to obtain a reaction liquid containing a compound shown as a formula M2, filtering the reaction liquid, and cooling the filtrate;
(3) adding a mixed solution of formic acid and acetic anhydride into the filtrate subjected to temperature reduction in the step (2), performing formylation reaction to obtain a reaction solution containing a compound shown as a formula M3, and concentrating and drying;
(4) dissolving the material obtained in the step (3) by using a third solvent, performing cyclization reaction with potassium carbonate and a compound shown as a formula SM2 to obtain a reaction solution containing a compound shown as a formula M4 and free SM2, filtering, and concentrating and drying the filtrate;
(5) dissolving the material obtained in the step (4) by using a fourth solvent, and performing condensation reaction to obtain an arformoterol precursor containing a formula M5, and performing hydrogenation and debenzylation on M5 to obtain arformoterol free alkali;
in the step (1), the first solvent is tetrahydrofuran;
in the step (2), the second solvent is a mixed solution of tetrahydrofuran and toluene, and the volume ratio of the tetrahydrofuran to the toluene is 0.5-1: 1;
in the step (4), the third solvent is a mixed solution of tetrahydrofuran and methanol, and the volume ratio of the tetrahydrofuran to the methanol is 0.5-1: 1;
in the step (5), the fourth solvent is any one or a combination of several of toluene, n-heptane and n-hexane;
2. the method according to claim 1, wherein in the step (1), the ratio of the first solvent to the compound represented by the formula SM1 is 10-20 mL: 1g of the total weight of the composition.
3. The method according to claim 1, wherein in the step (2), the ratio of the second solvent to the compound represented by the formula M1 is 10-20 mL: 1 g.
4. The method of claim 1, wherein in step (2), the reduction catalyst is platinum dioxide and/or platinum carbon.
5. The method according to claim 1, wherein in the step (4), the ratio of the third solvent to the compound represented by the formula M3 is 10-20 mL: 1g of the total weight of the composition.
6. The method according to claim 1, wherein in the step (5), the ratio of the fourth solvent to the compound represented by the formula M4 is 10-20 mL: 1g of the total weight of the composition.
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