CN112159356A - Racemization recovery method of dextromethorphan hydrobromide intermediate byproduct - Google Patents
Racemization recovery method of dextromethorphan hydrobromide intermediate byproduct Download PDFInfo
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- CN112159356A CN112159356A CN202011072036.2A CN202011072036A CN112159356A CN 112159356 A CN112159356 A CN 112159356A CN 202011072036 A CN202011072036 A CN 202011072036A CN 112159356 A CN112159356 A CN 112159356A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
Abstract
A racemization recovery method of a dextromethorphan hydrobromide intermediate byproduct comprises the following steps of 1) mother liquor treatment: distilling under reduced pressure under stirring until methanol is basically evaporated; when the temperature of the concentrated mother liquor is lower than 40 ℃, adding a sodium hydroxide solution, stirring, standing, detecting the pH value to be higher than 12, then layering, recovering mandelic acid from a water phase, concentrating an oil phase under reduced pressure until toluene is evaporated completely, and then cooling to 65-80 ℃; 2) n-chlorination: adding isopropanol, and dropwise adding a sodium hypochlorite solution; 3) racemization: adding liquid alkali into a reaction system, stirring for reaction, and 4) reducing: dropwise adding a sodium borohydride solution, and reacting completely; 5) chiral resolution, namely adding methanol and D-mandelic acid into a toluene solution of the compound (I) to perform chiral resolution; 6) mother liquor refining: treating the mother liquor obtained in the step 5) as a raw material according to the treatment methods of the steps 1) to 4) to obtain a mother liquor, preparing a compound (I) toluene solution, and adding oxalic acid for refining.
Description
Technical Field
The present invention relates to a method for producing heterocyclic compounds of isoquinoline series, particularly to a racemization and chiral resolution method thereof.
Background
Dextromethorphan is a dextroisomer of morphine levorphan methylether and exerts a central antitussive effect by inhibiting the medullary cough center. It has antitussive effectThe degree is comparable to or slightly stronger than codeine. Has no analgesic effect, and has no tolerance and addiction after long-term application. The therapeutic dose did not inhibit breathing. Currently, clinically applied dextromethorphan hydrobromide, namely dextromethorphan hydrobromide, is an important intermediate which is needed to pass through in a synthetic route of dextromethorphan: l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl]Isoquinoline (I) (molecular formula is
CAS number 51072-36-7), the intermediate is racemic mixture, chiral resolution is required to enter the subsequent preparation process, and chiral by-product (S) -l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl) obtained by resolution is]Isoquinoline (II) (molecular formula is
) Can not be used for directly synthesizing dextromethorphan, and needs racemization treatment to convert the dextromethorphan into the compound (I) and then chiral resolution for full recycling. Chinese patent CN106083717A discloses a racemization recovery processing method of compound (II), which adopts a method that the compound (II) is oxidized to prepare 1- (4-methoxybenzyl) -3,4,5,6,7, 8-hexahydroisoquinoline, and then the compound (I) is obtained by reduction. However, in the redox reaction of the compound (II), it is necessary to purify the compound (II) from the crystallization mother liquor after the resolution reaction before the compound (II) is put into the reduction reaction as a raw material, and the crystallization mother liquor cannot be directly operated, and a pure product is required to be put into each step, which is not suitable for industrial production in the prior art. The methanol solution of the compound (II) is mainly contained in the crystallization mother liquor after chiral resolution of the compound (I) and the toluene added during washing crystallization, and because various solvents are mixed in the mother liquor, the compound (II) obtained by recrystallization in a conventional mode can cause loss of raw materials, a large amount of waste liquor is generated, the production cost is increased, and the environment is polluted. The oxidation reaction needs to be carried out in a toluene solvent, a large amount of waste liquid is generated, the cost is further increased, and therefore, the method becomes the prior art by improving the reaction route on the basis of racemization recovery of the existing compound (II), simplifying the operation, improving the production efficiency, meeting the requirement of industrial production and meeting the requirement of the prior artThe problem to be solved is urgent.
Disclosure of Invention
In view of the above problems in the prior art, the present invention provides a method for racemizing and recovering a mother liquor of chiral resolution crystallization of l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (I).
In order to achieve the purpose, the technical scheme provided by the invention is as follows:
a racemization recovery method of dextromethorphan hydrobromide intermediate by-products is characterized by comprising the following steps
1) Mother liquor treatment: the mother liquor to be treated is a crystallization mother liquor containing (S) -l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (II) and a washing liquid, and organic solvents in the mother liquor to be treated are methanol and toluene; the mother liquor treatment mode is as follows: distilling under reduced pressure under stirring until methanol is basically evaporated; when the temperature of the concentrated mother liquor is lower than 40 ℃, adding sodium hydroxide solution, stirring, standing, detecting the pH value to be higher than 12, then layering, recovering mandelic acid from the water phase, concentrating the oil phase under reduced pressure until toluene is evaporated completely, and then cooling to 65-80 ℃. To obtain (S) -l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (II); the weight percentage concentration of the sodium hydroxide solution is 12-15%,
2) n-chlorination: adding isopropanol into (S) -l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (II) obtained in the step 1), cooling to-5-8 ℃, dropwise adding a sodium hypochlorite solution, keeping the temperature of a reaction system at 0-6 ℃, and carrying out chlorination reaction to obtain chloride (III), wherein the volume weight ratio of the isopropanol to the compound (II) is 1.5-2.5: 1, the mass percentage concentration of the sodium hypochlorite solution is 8-13%, and the weight of the sodium hypochlorite to the compound (II) is 3-4: 1.
3) Racemization: adding liquid caustic soda into a reaction system for completing the reaction in the step 2), stirring for reaction, keeping the liquid temperature at 47-60 ℃ to complete racemization reaction to obtain 1- (4-methoxybenzyl) -3,4,5,6,7, 8-hexahydroisoquinoline (IV); the liquid alkali is a sodium hydroxide solution with the mass percent of 40-60%, and the weight ratio of the liquid alkali to the compound (II) is 1.0-1.3: 1; .
4) Reduction: cooling the reaction system after the reaction in the step 3) to 25-30 ℃, dropwise adding a sodium borohydride solution, controlling the temperature of the reaction system to 25-30 ℃, keeping the temperature of the reaction system at 40-50 ℃ after dropwise adding is finished, and reacting completely; distilling under reduced pressure to remove isopropanol, adding water, stirring, heating to 70-85 ℃, standing for layering, separating oil phase and water phase, adding toluene for dilution in the oil phase, distilling the water phase to remove the undissociated isopropanol, adding toluene and water for extraction, and standing for layering; combining all oil phases, heating to 70-85 ℃, and washing the oil phases with water; after standing and layering, concentrating the oil phase under reduced pressure, and evaporating partial toluene to obtain a toluene solution of l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (I); the weight ratio of the sodium borohydride to the compound (II) is 0.5-1: 1; the sodium borohydride solution is a water solution with the mass percentage concentration of 10-15%; the volume-to-volume ratio of the added toluene to the compound (II) is 2-3: 1, and the weight-to-volume ratio of the compound (I) to the toluene in the toluene solution of the compound (I) in the 1, 2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (I) is 0.38-0.42: 1;
5) chiral resolution, namely adding methanol and D-mandelic acid into a toluene solution of l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (I), stirring, controlling the temperature to be 40-60 ℃, keeping the temperature, slowly cooling and crystallizing to 0-minus 10 ℃, and curing for 8-10 hours at the temperature of 0-minus 10 ℃. Centrifugal filtration, washing with ice toluene, crystallizing and drying, directly putting the (R) -l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline-D-mandelate (V) which is successfully recovered into the production of dextromethorphan, and refining the mother liquor in the step 6), wherein the volume-weight ratio of methanol to the compound (I) is 2-5: 1, and the weight ratio of mandelic acid to the compound (I) is 7-11: 1
6) Mother liquor refining: treating the mother liquor obtained in the step 5) as a raw material according to the treatment methods of the steps 1) to 4) to obtain a mother liquor compound (I) toluene solution, concentrating under reduced pressure until toluene is evaporated, cooling to 25-30 ℃, adding acetone, starting stirring, heating to 35-45 ℃, stopping heating, adding oxalic acid dihydrate in batches, cooling to + 5-0 ℃ when the temperature rises to 50-60 ℃, obtaining oxalate solid, preserving heat and curing for 3 hours, filtering and collecting the oxalate solid, and washing the oxalate solid with glacial acetone to obtain an oxalate wet product; adding the wet oxalate product into a toluene and purified water mixed system, slowly adding potassium hydroxide solid while stirring until the pH is more than 12, continuing stirring until solid particles disappear, standing for layering, evaporating partial toluene from an oil phase at 60-80 ℃ under reduced pressure to obtain a refined toluene solution of the compound (I), and adding the refined toluene solution of the step 5).
The volume weight ratio of the acetone to the compound (I) is 2-10: 1, the volume weight ratio of toluene to the compound (I) is 2-10: 1, the volume weight ratio of purified water to the compound (I) is 2-10: 1, and the weight ratio of oxalic acid dihydrate to the compound (I) is 0.4-0.6: 1.
According to the racemization recovery method for the dextromethorphan hydrobromide intermediate byproduct, provided by the invention, the mother liquor after chiral separation can be directly racemized and recovered by optimizing the reaction route and conditions, and in the recovery process, multiple steps of processes can adopt one-pot reaction, namely, the processes can be directly performed in the reaction system after the previous step of reaction is completed, and extraction and refining of various intermediate products are not needed, so that the process flow is simplified, the reaction efficiency is improved, the production cost is reduced, the production period is shortened, and the method is suitable for industrial production.
Detailed Description
In order to better explain the invention, the following further illustrate the main content of the invention in connection with specific examples, but the content of the invention is not limited to the following examples. Moreover, in the following description, descriptions of well-known structures and techniques are omitted so as to not unnecessarily obscure the concepts of the present invention.
The invention provides a racemization recovery method of a dextromethorphan hydrobromide intermediate byproduct, which has the following process flow
Example 1
A racemization recovery method of dextromethorphan hydrobromide intermediate by-products specifically comprises the following steps
1) Mother liquor treatment: the mother liquor to be treated is a crystallization mother liquor and a washing liquor containing (S) -l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (II), 45Kg of compound (II) is contained in the mother liquor to be treated, and the organic solvent in the mother liquor to be treated is methanol and toluene; the treatment mode of the mother liquor to be treated is as follows: under the condition of stirring, controlling the liquid temperature at 40 ℃, distilling under reduced pressure until methanol is basically evaporated, and keeping the liquid temperature at 40 ℃; when the temperature of the concentrated mother liquor is lower than 40 ℃, adding a sodium hydroxide solution, stirring for 5min, standing for 1h, detecting the pH value to be higher than 12, then layering, recovering mandelic acid from a water phase, concentrating an oil phase under reduced pressure until toluene is evaporated completely, and then cooling to 70 ℃. To obtain (S) -l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (II); the weight percentage concentration of the sodium hydroxide solution is 12-15%. Prepared by purified water and NaOH (liquid caustic soda) with the concentration of 50 percent by mass,
2) n-chlorination: adding 6.6L of isopropanol into (S) -L,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (II) in a reaction container in the step 1) to form slurry, cooling to 25 ℃, adding 78.6L of isopropanol, cooling to-5-8 ℃, dropwise adding a sodium hypochlorite solution precooled to 0 ℃, keeping the temperature of a reaction system at 0-6 ℃, and carrying out chlorination reaction to obtain chloride (III), wherein the mass percentage concentration of the sodium hypochlorite solution is 8-13%, and the weight of the sodium hypochlorite and the compound (II) is 3.16.
3) Racemization: rapidly adding NaOH (liquid caustic soda) with the concentration of 50 percent by mass into a reaction container for completing the reaction in the step 2), stirring and reacting for 60-90 min, and keeping the liquid temperature at 47-60 ℃ to complete racemization reaction to obtain 1- (4-methoxybenzyl) -3,4,5,6,7, 8-hexahydroisoquinoline (IV); the weight ratio of the liquid alkali to the compound (II) is 1.1: 1.
4) reduction: cooling the reaction system in the reaction container for completing the reaction in the step 3) to 25-30 ℃, dropwise adding a sodium borohydride solution, controlling the temperature of the reaction system to be 28-30 ℃, keeping the temperature of the reaction system to be 45-47 ℃ after dropwise adding is completed, and reacting till the reaction is completed; distilling at 50-55 ℃ under reduced pressure to remove isopropanol, adding 53.3L of purified water, stirring, heating to 75 ℃, standing for layering, separating oil phase and water phase, adding toluene for diluting oil phase, distilling water phase to remove unseparated isopropanol, adding 95.9L of toluene and 76.5L of purified water, extracting, standing for layering; mixing all oil phases, and heating to 80 deg.C; washing the oil phase with 20L of purified water for 15min, standing for 1h for layering, concentrating the oil phase under reduced pressure, and evaporating to remove part of toluene to obtain a toluene solution of L,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (I); the weight ratio of the sodium borohydride to the compound (II) is 0.55:1, the sodium borohydride solution is a water solution with the mass percentage concentration of 10-15%, and the weight volume ratio of the compound (I) to the toluene in the toluene solution of the l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (I) is 0.4:1
5) Chiral resolution, namely adding methanol and D-mandelic acid into the toluene solution of the l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (I) obtained in the step 4), stirring, controlling the temperature to be 40-60 ℃ to completely dissolve solids, keeping the temperature for 10min, slowly cooling and crystallizing to-5 ℃, and curing for 8-10 h at-5 ℃. Centrifugal filtration, washing with ice toluene which is pre-cooled by ice brine water, crystallizing and drying to recover successful (R) -l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline-D-mandelate (V), directly putting into production of dextromethorphan, refining the mother liquor in the step 6), wherein the volume-weight ratio of methanol to the compound (I) is 4:1, and the weight ratio of mandelic acid to the compound (I) is 9:1.
6) Mother liquor refining: treating the mother liquor obtained in the step 5) as a raw material according to the treatment methods of the steps 1) to 4) to obtain a mother liquor compound (I) toluene solution, concentrating under reduced pressure until toluene is evaporated, cooling to 25-30 ℃, adding acetone, starting stirring, heating to 35-45 ℃, stopping heating, adding oxalic acid dihydrate in batches, cooling to + 5-0 ℃ when the temperature rises to 50-60 ℃, obtaining oxalate solid, preserving heat and curing for 3 hours, filtering and collecting the oxalate solid, and washing the oxalate solid with glacial acetone to obtain an oxalate wet product; adding the wet oxalate product into a toluene and purified water mixed system, slowly adding potassium hydroxide solid while stirring until the pH is more than 12, continuing stirring until solid particles disappear, standing for layering, evaporating partial toluene from an oil phase at 60-80 ℃ under reduced pressure to obtain a refined toluene solution of the compound (I), and adding the refined toluene solution of the step 5).
The volume weight ratio of acetone to compound (I) was 6:1, the volume weight ratio of toluene to compound (I) was 6:1, the volume weight ratio of the purified water to the compound (I) is 6:1, and the weight ratio of the oxalic acid dihydrate to the compound (I) is 0.5: 1.
In this example, 45Kg of compound (II) in the mother liquor to be treated in step 1) was treated in steps 1) to 4) and purified in the mother liquors in steps 5) and 6), to obtain 29.5Kg of compound (I) in a molar yield of 72.9%.
Claims (4)
1. A racemization recovery method of dextromethorphan hydrobromide intermediate by-products is characterized by comprising the following steps
1) Mother liquor treatment: the mother liquor to be treated is a crystallization mother liquor containing (S) -l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (II) and a washing liquid, and organic solvents in the mother liquor to be treated are methanol and toluene; the mother liquor treatment mode is as follows: distilling under reduced pressure under stirring until methanol is basically evaporated; when the temperature of the concentrated mother liquor is lower than 40 ℃, adding a sodium hydroxide solution, stirring, standing, detecting the pH value to be higher than 12, then layering, recovering mandelic acid from a water phase, concentrating an oil phase under reduced pressure until toluene is evaporated completely, and then cooling to 65-80 ℃; to obtain (S) -l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (II); the weight percentage concentration of the sodium hydroxide solution is 12-15%;
2) n-chlorination: adding isopropanol into (S) -l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (II) obtained in the step 1), cooling to-5-8 ℃, dropwise adding a sodium hypochlorite solution, keeping the temperature of a reaction system at 0-6 ℃, and carrying out chlorination reaction to obtain chloride (III), wherein the volume weight ratio of the isopropanol to the compound (II) is 1.5-2.5: 1, the mass percentage concentration of the sodium hypochlorite solution is 8-13%, and the weight of the sodium hypochlorite to the compound (II) is 3-4: 1;
3) racemization: adding liquid caustic soda into a reaction system for completing the reaction in the step 2), stirring for reaction, keeping the liquid temperature at 47-60 ℃ to complete racemization reaction to obtain 1- (4-methoxybenzyl) -3,4,5,6,7, 8-hexahydroisoquinoline (IV); the liquid alkali is a sodium hydroxide solution with the mass percent of 40-60%, and the weight ratio of the liquid alkali to the compound (II) is 1.0-1.3: 1;
4) reduction: cooling the reaction system after the reaction in the step 3) to 25-30 ℃, dropwise adding a sodium borohydride solution, controlling the temperature of the reaction system to 25-30 ℃, keeping the temperature of the reaction system at 40-50 ℃ after dropwise adding is finished, and reacting completely; distilling under reduced pressure to remove isopropanol, adding water, stirring, heating to 70-85 ℃, standing for layering, separating oil phase and water phase, adding toluene for dilution in the oil phase, distilling the water phase to remove the undissociated isopropanol, adding toluene and water for extraction, and standing for layering; combining all oil phases, heating to 70-85 ℃, and washing the oil phases with water; after standing and layering, concentrating the oil phase under reduced pressure, and evaporating partial toluene to obtain a toluene solution of l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (I); the weight ratio of the sodium borohydride to the compound (II) is 0.5-1: 1;
5) chiral resolution, namely adding methanol and D-mandelic acid into a toluene solution of l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (I), stirring, controlling the temperature to be 40-60 ℃, keeping the temperature, slowly cooling and crystallizing to 0-minus 10 ℃, and curing for 8-10 hours at the temperature of 0-minus 10 ℃; centrifugal filtration, washing with ice toluene, crystallizing and drying, directly putting the (R) -l,2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline-D-mandelate (V) for production of dextromethorphan for successful recovery, and refining the mother liquor in the step 6);
6) mother liquor refining: treating the mother liquor obtained in the step 5) as a raw material according to the treatment methods of the steps 1) to 4) to obtain a mother liquor compound (I) toluene solution, concentrating under reduced pressure until toluene is evaporated, cooling to 25-30 ℃, adding acetone, starting stirring, heating to 35-45 ℃, stopping heating, adding oxalic acid dihydrate in batches, cooling to + 5-0 ℃ when the temperature rises to 50-60 ℃, obtaining oxalate solid, preserving heat and curing for 3 hours, filtering and collecting the oxalate solid, and washing the oxalate solid with glacial acetone to obtain an oxalate wet product; adding the wet oxalate product into a toluene and purified water mixed system, slowly adding potassium hydroxide solid while stirring until the pH is more than 12, continuing stirring until solid particles disappear, standing for layering, evaporating partial toluene from an oil phase at 60-80 ℃ under reduced pressure to obtain a refined toluene solution of the compound (I), and adding the refined toluene solution of the step 5).
2. The racemization recovery method of dextromethorphan hydrobromide intermediate byproduct according to claim 1, wherein in the step 4), the sodium borohydride solution is an aqueous solution with a mass percentage concentration of 10% -15%; the volume-to-volume ratio of the added toluene to the compound (II) is 2-3: 1, and the weight-to-volume ratio of the compound (I) to the toluene in the toluene solution of the compound (I), 2,3,4,5,6,7, 8-octahydro-1- [ (4-methoxyphenyl) methyl ] isoquinoline (I), is 0.38-0.42: 1.
3. The racemization recovery method of dextromethorphan hydrobromide intermediate byproduct according to claim 1, wherein in the step 5), the volume-to-weight ratio of methanol to the compound (I) is 2-5: 1, and the weight ratio of mandelic acid to the compound (I) is 7-11: 1.
4. The racemization recovery method of dextromethorphan hydrobromide intermediate byproduct according to claim 1, wherein the volume-to-weight ratio of acetone to compound (I) in step 6) is 2-10: 1, the volume weight ratio of toluene to the compound (I) is 2-10: 1, the volume weight ratio of purified water to the compound (I) is 2-10: 1, and the weight ratio of oxalic acid dihydrate to the compound (I) is 0.4-0.6: 1.
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| CN115368233A (en) * | 2022-09-06 | 2022-11-22 | 启东东岳药业有限公司 | Method for recovering R-mandelic acid from dextromethorphan intermediate waste liquid |
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Application publication date: 20210101 |