CN112592342B - Preparation method of butorphanol acyclic butyl impurity compound - Google Patents
Preparation method of butorphanol acyclic butyl impurity compound Download PDFInfo
- Publication number
- CN112592342B CN112592342B CN202110056678.1A CN202110056678A CN112592342B CN 112592342 B CN112592342 B CN 112592342B CN 202110056678 A CN202110056678 A CN 202110056678A CN 112592342 B CN112592342 B CN 112592342B
- Authority
- CN
- China
- Prior art keywords
- compound
- concentrating
- butorphanol
- preparation
- tetrahydrofuran
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of organic synthesis, and provides a preparation method of a butorphanol acyclic butyl impurity compound. The invention can realize simple, convenient and efficient synthesis of the impurities, the compound 1 is catalyzed by strong Lewis acid and reacts with a reducing agent to prepare a butorphanol cyclobutylidene impurity intermediate (compound 2), and then the butorphanol cyclobutylidene impurity (compound 4) with high purity is obtained through cyclization reaction and demethoxylation reaction without column chromatography purification.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of a butorphanol acyclic butyl impurity compound.
Background
Butorphanol tartrate is a central analgesic developed by the American Behcet-Mitsui-Bao company in the United states, and is clinically used for relieving moderate to severe pain, such as postoperative pain, cancer pain and the like.
The impurity content of a drug is an important criterion for the effectiveness and safety of a drug. Impurities present in the drug directly affect the efficacy of the drug and may lead to non-therapeutically active toxic side effects that must be controlled. It was found that one particular impurity is produced during the preparation of butorphanol tartrate: (-) -3, 14-dihydroxymorphinan is a decylmethyl impurity compound of butorphanol, and the chemical structural formula is as follows:
in order to control the impurity content of the drug, i.e. limit the impurity content within a certain range, a proper impurity standard substance must be selected in the process of drug quality analysis. The butorphanol acyclic butyl impurity is not sold in the market at present, and only the compound can be synthesized.
Two reaction routes for preparing the butorphanol acyclic butyl impurity are reported in the literature which can be inquired at home and abroad at present, and are shown as follows.
Route 1: US patent US3775414
According to the patent scheme, 7-methoxy-1-tetralone is used as a raw material, and the butorphanol acyclic butyl impurity is prepared through 11 steps of reactions such as alkylation, reduction, protection, deprotection, epoxidation, acylation and the like, and has the advantages of complex reaction types, complex operation, low total yield of 2.9% and low implementation feasibility.
Route 2: journal of Org Chem,1984,49,2081-
The literature reports a method for removing nitrogen and an upper group, and researchers design a reaction route as follows according to the method reported by the literature:
according to a method for removing nitrogen and upper groups reported in a literature, butorphanol reacts with chloroformic acid chloroethyl ester, a cyclobutylmethyl is removed, and methanol is used for reflux reaction to obtain butorphanol decyclobutyl impurities, researchers find that the reaction raw materials in the first step are more and remained, the reaction thin-layer chromatography in the second step shows that a small amount of suspected target products are obtained, the target products are subjected to post-treatment extraction washing and column chromatography purification to obtain a small amount of impure target products, the yield is only 0.05%, the reaction yield is too low, and the preparation efficiency of the impurities is not ideal.
Disclosure of Invention
Against the background, the invention aims to provide a simple and efficient preparation method of a butorphanol acyclic butyl impurity compound.
The invention adopts the following technical scheme: the designed synthetic route is as follows:
a process for the preparation of a butorphanol acyclic butyl impurity compound, the process comprising the steps of:
a. in the presence of a reducing agent, (1R,9R,10S) -N-cyclobutylformyl-9, 10-dihydroxy-1-p-methoxybenzyl-decahydroisoquinoline is dissolved in tetrahydrofuran and reacts under the catalysis of strong Lewis acid;
b. quenching the reaction solution, decompressing, concentrating and drying, adding water, extracting and separating by using an organic solvent, adjusting the pH of a water phase by using an inorganic base, extracting and separating by using an organic phase solvent, and concentrating and drying to obtain a high-purity product (1R,9R,10S) -9, 10-dihydroxy-1-p-methoxybenzyl-decahydroisoquinoline;
c. complexing the high-purity product obtained in the previous step with a complexing reagent, and then carrying out cyclization reaction in the presence of phosphoric acid and phosphorus pentoxide to obtain (-) -14-hydroxy-3-methoxy morphinan;
d. and (2) reacting the (-) -14-hydroxy-3-methoxy morphinan obtained in the previous step with hydrobromic acid without separation, neutralizing with inorganic base, extracting and separating by using dichloromethane, and concentrating and refining an organic phase to obtain the (-) -3, 14-dihydroxy morphinan.
Further, in the preparation method of the butorphanol acyclic butyl impurity compound, the reaction temperature in the step a is 50-60 ℃; the temperature of the cyclization reaction in the step c is 80-100 ℃; the reaction temperature of the step d is 100-110 ℃.
Further, in the preparation method of the impurity compound for removing the cyclobutyls of butorphanol, the molar ratio of the reducing agent in the step a is (5.0-10.0): 1.
further, in the preparation method of the impurity compound for removing the cyclobutyls of butorphanol, the mol ratio of the complexing reagent in the step c is (3.0-5.0): 1.
further, in the preparation method of the butorphanol acyclic butyl impurity compound, the dosage of the phosphoric acid in the step c is 8-15 times of the weight ratio, and the dosage of the phosphorus pentoxide is 2-6 times of the weight ratio.
Further, in the preparation method of the butorphanol acyclic butyl impurity compound, in the step a, the reducing agent is selected from one or more of lithium aluminum hydride, borane dimethyl sulfide and borane tetrahydrofuran.
Further, in the preparation method of the impurity compound of the decylamine acyclic butyl, the strong lewis acid in the step a is one or more selected from aluminum trichloride, titanium tetrachloride and boron trifluoride tetrahydrofuran.
Further, in the preparation method of the impurity compound for removing the cyclobutyl of butorphanol, the organic solvent in the step b is one or two of dichloromethane, trichloromethane and toluene.
Further, in the preparation method of the butorphanol acyclic butyl impurity compound, the complexing agent in the step c is borane tetrahydrofuran or borane dimethyl sulfide.
Further, in the preparation method of the impurity compound for removing the n-butyl group of butorphanol, the refined solvent in the step d is one or two selected from ethyl acetate, n-hexane, methyl tert-butyl ether and toluene.
Further, in the preparation method of the impurity compound of the butorphanol acyclic butyl, the inorganic base in the step b or d is one or two of sodium hydroxide, sodium carbonate and sodium bicarbonate; adjusting the pH range and controlling the pH range to be 8-10.
Further, the preparation method of the butorphanol acyclic butyl impurity compound comprises the following specific steps:
a. dissolving 0.05-0.1 times of Lewis acid catalyst and (1R,9R,10S) -N-cyclobutylformyl-9, 10-dihydroxy-1-p-methoxybenzyl-decahydroisoquinoline in tetrahydrofuran according to the weight ratio, and then adding the mixture according to the molar ratio of (5.0-10.0): 1, controlling the temperature to be 50-60 ℃, and stirring for reaction for 4-8 h;
b. cooling the reaction liquid to 0-10 ℃, dropwise adding a quenching agent in a weight ratio of 5-20 times for quenching, concentrating and drying after adding, adding water in a weight ratio of 5-15 times, adding an extraction solvent in a weight ratio of 15-30 times to extract other components except the target product in the reaction liquid into an organic phase, regulating the pH value of the rest water phase to 8-10 by using inorganic base after layering, extracting by using an extraction solvent in a weight ratio of 15-30 times, and concentrating and drying the organic phase to obtain the high-purity (1R,9R,10S) -9, 10-dihydroxy-1-p-methoxybenzyl-decahydro-isoquinoline;
c. and (3.0-5.0) mixing the compounds 2 obtained in the previous step: 1, concentrating and drying after complexing by using a complexing reagent, adding 8-15 times of phosphoric acid and 4-6 times of phosphorus pentoxide, performing cyclization reaction for 5-10 h at 80-100 ℃, adjusting the pH to be neutral by using ammonia water, adding dichloromethane for extraction and liquid separation, and concentrating an organic phase to obtain (-) -14-hydroxy-3-methoxy morphinan;
d. the preparation method comprises the steps of reacting (-) -14-hydroxy-3-methoxy morphinan with 10-20 times of hydrobromic acid at the temperature of 100-110 ℃ for 1.0-3.0 h, cooling, neutralizing with inorganic base, extracting and separating dichloromethane, concentrating an organic phase, drying, adding a refining solvent, pulping at the temperature of 50-70 ℃ for refining for 1-3 h, cooling in an ice bath, filtering, and drying in vacuum to obtain the target compound (-) -3, 14-dihydroxy morphinan.
Further, the butorphanol acyclic butyl impurity compound obtained by the preparation method is used as a reference substance or used for controlling the quality of the butorphanol tartrate.
The invention has the beneficial effects.
1. Provides a reliable preparation method for obtaining a high-purity reference substance of the butorphanol acyclic butyl impurities, and the purity of a liquid phase is more than or equal to 95 percent.
2. Under the condition that the prior butorphanol acyclic butyl impurity compound has no market sale, a convenient and reliable acquisition way is provided for impurity research of the tartaric acid butorphanol. The synthetic reaction material is easy to obtain, the reaction route is short, the operation is simple and convenient, the material cost is low, the impurity preparation cost is greatly reduced, and the method has great promotion effect on the further research on the safety, reliability and stability of the butorphanol tartrate medicine and the quality control in the production process.
3. The method has positive guiding effect on consistency evaluation of localization of butorphanol tartrate.
Drawings
FIG. 1: liquid phase diagram of compound 2 synthesized in inventive example 1.
FIG. 2 is a drawing: the nuclear magnetic hydrogen spectrum of the compound 2 synthesized in the example 1 of the invention.
FIG. 3: mass spectra of compound 2 synthesized in inventive example 1.
FIG. 4 is a drawing: liquid phase diagram of compound 4 synthesized in inventive example 4.
FIG. 5: the nuclear magnetic hydrogen spectrum of the compound 4 synthesized in the example 4 of the invention.
FIG. 6: mass spectrum of compound 4 synthesized in example 4 of the present invention.
FIG. 7: synthetic route map designed by the invention
The specific implementation mode is as follows: the invention is further described in connection with the following specific examples, which are intended to be illustrative of the invention and are not to be construed as limiting the invention.
A reaction route for the preparation of butorphanol acyclic butyl impurity compounds according to the present invention.
Example 1 (preparation of Compound 2)
a. 10g of the compound 1((1R,9R,10S) -N-cyclobutylformyl-9, 10-dihydroxy-1-p-methoxybenzyl-decahydroisoquinoline) and 60g of tetrahydrofuran are added into a 250ml three-necked flask, then 0.5g of aluminum trichloride is added, 17.2g (5.18eq) of 10M borane dimethylsulfide solution is slowly added under stirring, and after the addition is finished, the temperature is raised to 50-60 ℃ for reaction for 4 hours.
b. Cooling the reaction solution to 0-20 ℃, dropwise adding 50g of methanol to quench the reaction, after the addition is finished, evaporating an organic phase at 50 ℃ under reduced pressure, adding 50g of drinking water, extracting and separating by using 75g of 2 trichloromethane, combining the organic phases, discarding, adjusting the pH of a water phase to 8-9 by using a 10% sodium carbonate aqueous solution, adding 150g of trichloromethane, extracting and separating, and evaporating an organic phase at 40 ℃ under reduced pressure to obtain 2.35g of a pale yellow solid, namely the butorphanol acyclic butyl impurity intermediate (compound 2), wherein the yield is 30.1% and the HPLC purity is 97.5%. FIG. 1, FIG. 2 and FIG. 3 are the liquid phase purity chart, nuclear magnetic hydrogen spectrum chart and mass spectrum chart, respectively.
Example 2 (preparation of Compound 2)
a. 10g of the compound 1((1R,9R,10S) -N-cyclobutylformyl-9, 10-dihydroxy-1-p-methoxybenzyl-decahydroisoquinoline) and 60g of tetrahydrofuran were added to a 1000ml three-necked flask, then 1.0g of titanium tetrachloride was added, and finally 167g (7.0eq) of 1M borane tetrahydrofuran solution was slowly added with stirring, and after the addition, the temperature was raised to 50-60 ℃ for reaction for 8 hours.
b. Cooling the reaction solution to 0-20 ℃, dropwise adding 200g of methanol to quench the reaction, after the addition is finished, evaporating an organic phase at 50 ℃ under reduced pressure, adding 150ml of drinking water, extracting and separating liquid by using 150g of 2-dichloromethane, combining organic phases, discarding, adjusting the pH of an aqueous phase to 9-10 by using a 10% sodium hydroxide aqueous solution, adding 300g of dichloromethane, extracting and separating liquid, and evaporating the organic phase at 40 ℃ under reduced pressure to obtain 1.88g of light yellow solid, namely the compound 2, wherein the yield is 24.1%.
Example 3 (preparation of Compound 2)
a. Adding 10g of compound 1((1R,9R,10S) -N-cyclobutylformyl-9, 10-dihydroxy-1-p-methoxybenzyl-decahydroisoquinoline) and 100g of tetrahydrofuran into a 500ml three-necked flask, then adding 0.75g of boron trifluoride tetrahydrofuran, protecting with nitrogen, cooling to 0-10 ℃, slowly adding 9.8g (9.7eq) of lithium aluminum hydride, and slowly heating to 50-60 ℃ to react for 6 hours after the addition is finished.
b. Cooling the reaction solution to 0-20 ℃, slowly dropping 60g of ice water to quench the reaction, after the addition, evaporating the reaction solution at 60 ℃ under reduced pressure, adding 100g of drinking water, extracting and separating by using 150g of 2 trichloromethane, combining organic phases, discarding, adjusting the pH of a water phase to 8-9 by using a 5% sodium bicarbonate aqueous solution, adding 200g of toluene, extracting and separating, and evaporating the organic phase at 60 ℃ under reduced pressure to obtain 2.03g of light yellow solid, namely the compound 2, wherein the yield is 26.0%.
Example 4 (preparation of Compound 4)
c. Adding 1.5g of compound 2 and 15g of tetrahydrofuran into a 100ml three-neck flask, adding 13.9g (3.0eq) of 1M borane tetrahydrofuran solution, reacting at 20-30 ℃ for 1h after the addition is finished, concentrating the dried tetrahydrofuran at 40 ℃ under reduced pressure, adding 12.0g of 85% phosphoric acid and 6.0g of phosphorus pentoxide, reacting at 90-100 ℃ for 6h, cooling to 30-40 ℃, adjusting the pH to be neutral by using ammonia water, adding 200g of dichloromethane for extraction and liquid separation, discarding the water phase, and concentrating the organic phase at 40 ℃ under reduced pressure to obtain a compound 3.
d. Adding 15.0g of hydrobromic acid into the oily compound 3 obtained in the previous step, heating to 100-110 ℃, reacting for 1.5h, cooling to 20-30 ℃, dropwise adding a 10% sodium hydroxide aqueous solution, adjusting the pH value to be neutral, adding 200g of dichloromethane for extraction and liquid separation, concentrating and drying an organic phase, adding 1.5g of ethyl acetate and 6.0g of n-hexane, pulping at 50-60 ℃, refining for 2h, cooling to 0-10 ℃ in an ice bath, filtering, and drying under reduced pressure to obtain 0.88g of light yellow solid, namely the butorphanol cyclobutylidene impurity (compound 4), wherein the yield is 61.8%, and the purity is 99.0%. FIG. 4, FIG. 5 and FIG. 6 are the liquid phase purity chart, nuclear magnetic hydrogen spectrum chart and mass spectrum chart, respectively.
Example 5 (preparation of compound 4).
c. Adding 1.0g of compound 2 and 10g of tetrahydrofuran into a 100ml three-neck flask, adding 1.75g (4.0eq) of 10M borane dimethyl sulfide solution, reacting for 2 hours at 20-30 ℃, concentrating the dried tetrahydrofuran under reduced pressure at 40 ℃, adding 12.0g of 85% phosphoric acid and 6.0g of phosphorus pentoxide, reacting for 8 hours at 80-90 ℃, cooling to 30-40 ℃, adjusting the pH to be neutral by using ammonia water, adding 200g of dichloromethane for extraction and liquid separation, discarding the water phase, and concentrating the organic phase under reduced pressure at 40 ℃ to obtain a compound 3.
d. Adding 15.0g of hydrobromic acid into the oily compound 3 obtained in the previous step, heating to 100-110 ℃, reacting for 3 hours, cooling to 20-30 ℃, dropwise adding 10% sodium hydroxide aqueous solution, adjusting the pH value to be neutral, adding 200g of dichloromethane for extraction and liquid separation, concentrating and drying an organic phase, adding 5.0g of methyl tert-butyl ether, pulping at 50-60 ℃, refining for 3 hours, cooling to 0-10 ℃ in an ice bath, filtering, and drying under reduced pressure to obtain 0.65g of light yellow solid, namely the compound 4, wherein the yield is 68.4%.
Example 6 (preparation of Compound 4)
c. Adding 1.0g of compound 2 and 10g of tetrahydrofuran into a 100ml three-neck flask, adding 2.2g (5.0eq) of 10M borane dimethyl sulfide solution, reacting for 2 hours at 20-30 ℃, concentrating the dried tetrahydrofuran under reduced pressure at 40 ℃, adding 15.0g of 85% phosphoric acid and 6.0g of phosphorus pentoxide, reacting for 10 hours at 80-90 ℃, cooling to 30-40 ℃, adjusting the pH to be neutral by using ammonia water, adding 200g of dichloromethane for extraction and liquid separation, discarding the water phase, and concentrating the organic phase under reduced pressure at 40 ℃ to obtain a compound 3.
d. Adding 20.0g of hydrobromic acid into the oily compound 3 obtained in the previous step, heating to 100-110 ℃, reacting for 1h, cooling to 20-30 ℃, dropwise adding 10% sodium hydroxide aqueous solution, adjusting the pH value to be neutral, adding 200g of dichloromethane, extracting, separating, concentrating and drying an organic phase, adding 5.0g of toluene, pulping at 60-70 ℃, refining for 1h, cooling to 0-10 ℃ in an ice bath, filtering, and drying under reduced pressure to obtain 0.50g of light yellow solid, namely the compound 4, wherein the yield is 52.6%.
Example 7
The structure of compound 2 obtained in example 1 was confirmed by analyzing the compound by hydrogen spectroscopy and mass spectrometry, respectively.
(1) Nuclear magnetic resonance spectroscopy hydrogen spectroscopy
Instrument model and test condition
The instrument model is as follows: bruker 600MHz avance III HD type nuclear magnetic resonance spectrometer;
and (3) testing conditions are as follows: CDCl3(solvent); TMS (internal standard);
hydrogen spectrum data and analysis result
A. Chemical structural formula labeled with atomic position:
B. test data and attribution
③ analysis
The nuclear magnetic resonance hydrogen spectrum shows that the structure of the test article is consistent with that of the compound 2.
(2) Mass spectrometry
Instrument model
AB-TRIPLR-QuAD 4500
② test conditions
An ionization mode: ESI
Scanning range: 200-330m/z
Third test data and attribution
Analysis: mass spectrum data show that the molecular weight of the test sample is consistent with the structure of the compound 2.
(3) Conclusion
The mass spectrum of the sample confirms that the formula weight of M + H excimer ions is M/z =292.4, and the structure of the compound 2 is met
②1The H-NMR spectrum confirmed that the type and position of the hydrogen atom of the sample corresponded to the structure of Compound 2.
In summary, the following steps: the structure of the test sample is consistent with that of the compound 2 (intermediate of butorphanol demethoxylate).
Example 8 the structure of compound 4 obtained in example 4 was confirmed by analyzing the compound by hydrogen spectroscopy and mass spectrometry, respectively.
(1) Nuclear magnetic resonance spectroscopy hydrogen spectroscopy
Instrument model and test condition
The instrument model is as follows: bruker 600MHz avance III HD type nuclear magnetic resonance spectrometer;
and (3) testing conditions are as follows: deuterated DMSO (solvent); TMS (internal standard);
hydrogen spectrum data and analysis result
C. Chemical structural formula labeled with atomic position:
D. test data and attribution
③ analysis
The nuclear magnetic resonance hydrogen spectrum shows that the structure of the test article is consistent with that of the compound 4.
(2) Mass spectrometry
Instrument model AB-TRIPLR-QUAD 4500
Testing the ionization mode under the condition: ESI scan range: 100-310m/z
Third test data and attribution
Analysis: mass spectrum data show that the molecular weight of the test sample is consistent with the structure of the compound 4.
(3) The conclusion is that the mass spectrum of the test sample confirms that the formula weight of M + H excimer ions is M/z =260.1, and the structure of the compound 4 is met; ② 1H-NMR spectrum confirms that the hydrogen atom type and position of the sample accord with the structure of the compound 4.
In summary, the following steps: the structure of the test sample is consistent with that of a compound 4 (butorphanol acyclic butyl impurity). The invention is confirmed to successfully prepare the high-purity butorphanol acyclic butyl impurity, provides a convenient and reliable obtaining way for research of the butorphanol acyclic butyl impurity, and has great promotion effect on more deeply researching the quality of the tartaric acid butorphanol and the related medication safety, reliability and stability and quality control in the production process.
It is to be understood that the above description is not intended to limit the present invention, and the present invention is not limited to the above examples, and those skilled in the art may make modifications, discoveries, additions and substitutions within the spirit and scope of the present invention.
Claims (5)
1. A process for the preparation of a butorphanol acyclic butyl impurity compound which is (-) -3, 14-dihydroxymorphinan, the process comprising the steps of:
a. in the presence of a reducing agent, (1R,9R,10S) -N-cyclobutylformyl-9, 10-dihydroxy-1-p-methoxybenzyl-decahydroisoquinoline is dissolved in tetrahydrofuran and reacts under the catalysis of strong Lewis acid;
b. quenching the reaction solution, decompressing, concentrating and drying, adding water, extracting and separating by using an organic solvent, adjusting the pH of a water phase by using an inorganic base, extracting and separating by using an organic phase solvent, and concentrating and drying to obtain a high-purity product (1R,9R,10S) -9, 10-dihydroxy-1-p-methoxybenzyl-decahydroisoquinoline;
c. complexing the high-purity product obtained in the previous step with a complexing reagent, and then carrying out cyclization reaction in the presence of phosphoric acid and phosphorus pentoxide to obtain (-) -14-hydroxy-3-methoxy morphinan;
d. reacting the (-) -14-hydroxy-3-methoxy morphinan obtained in the previous step with hydrobromic acid without separation, neutralizing with inorganic base, extracting and separating with dichloromethane, concentrating and refining the organic phase to obtain (-) -3, 14-dihydroxy morphinan,
wherein, the reducing agent in the step a is selected from one or more of lithium aluminum hydride, borane dimethyl sulfide and borane tetrahydrofuran, the strong Lewis acid is selected from one or two of aluminum trichloride, titanium tetrachloride and boron trifluoride tetrahydrofuran, and the complexing reagent in the step c is borane tetrahydrofuran or borane dimethyl sulfide.
2. The preparation method according to claim 1, wherein the organic solvent in step b is one or two selected from dichloromethane, chloroform and toluene.
3. The preparation method according to claim 1, wherein the inorganic base in step b or d is one or two selected from sodium hydroxide, sodium carbonate and sodium bicarbonate; adjusting the pH range and controlling the pH range to be 8-10.
4. The method according to claim 1, wherein the refining in step d is carried out in a solvent selected from one or two of ethyl acetate, n-hexane, methyl t-butyl ether and toluene.
5. A preparation method of a butorphanol acyclic butyl impurity compound is characterized by comprising the following steps:
a. dissolving a strong Lewis acid catalyst and (1R,9R,10S) -N-cyclobutylformyl-9, 10-dihydroxy-1-p-methoxybenzyl-decahydroisoquinoline in a weight ratio of 0.05-0.1 times to tetrahydrofuran, and then adding the mixture in a molar ratio of (5.0-10.0): 1, controlling the temperature to be 50-60 ℃, and stirring for reaction for 4-8 h;
b. cooling the reaction liquid to 0-10 ℃, dropwise adding a quenching agent in a weight ratio of 5-20 times for quenching, concentrating and drying after adding, adding water in a weight ratio of 5-15 times, adding an extraction solvent in a weight ratio of 15-30 times to extract other components except the target product in the reaction liquid into an organic phase, regulating the pH value of the rest water phase to 8-10 by using inorganic base after layering, extracting by using an extraction solvent in a weight ratio of 15-30 times, and concentrating and drying the organic phase to obtain the high-purity (1R,9R,10S) -9, 10-dihydroxy-1-p-methoxybenzyl-decahydro-isoquinoline;
c. and (3.0-5.0) mixing the compounds 2 obtained in the previous step: 1, concentrating and drying after complexing by using a complexing reagent, adding 8-15 times of phosphoric acid and 4-6 times of phosphorus pentoxide, performing cyclization reaction for 5-10 h at 80-100 ℃, adjusting the pH to be neutral by using ammonia water, adding dichloromethane for extraction and liquid separation, and concentrating an organic phase to obtain (-) -14-hydroxy-3-methoxy morphinan;
d. reacting (-) -14-hydroxy-3-methoxy morphinan with 10-20 times of hydrobromic acid at the temperature of 100-110 ℃ for 1.0-3.0 h, cooling, neutralizing with inorganic base, extracting and separating with dichloromethane, concentrating and drying an organic phase, adding a refining solvent, pulping and refining at the temperature of 50-70 ℃ for 1-3 h, cooling in an ice bath, filtering, and drying in vacuum to obtain a target compound (-) -3, 14-dihydroxy morphinan;
wherein, the reducing agent in the step a is selected from one or more of lithium aluminum hydride, borane dimethyl sulfide and borane tetrahydrofuran, the strong Lewis acid is selected from one or two of aluminum trichloride, titanium tetrachloride and boron trifluoride tetrahydrofuran, and the complexing reagent in the step c is borane tetrahydrofuran or borane dimethyl sulfide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110056678.1A CN112592342B (en) | 2021-01-15 | 2021-01-15 | Preparation method of butorphanol acyclic butyl impurity compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110056678.1A CN112592342B (en) | 2021-01-15 | 2021-01-15 | Preparation method of butorphanol acyclic butyl impurity compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112592342A CN112592342A (en) | 2021-04-02 |
| CN112592342B true CN112592342B (en) | 2022-02-22 |
Family
ID=75207314
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110056678.1A Active CN112592342B (en) | 2021-01-15 | 2021-01-15 | Preparation method of butorphanol acyclic butyl impurity compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112592342B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116818928B (en) * | 2023-04-28 | 2024-04-19 | 杭州沐源生物医药科技有限公司 | Separation detection method for impurities in butorphanol tartrate injection |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3775414A (en) * | 1972-05-10 | 1973-11-27 | Bristol Myers Co | Process for the preparation of 14-hydroxymorphinan derivatives |
| CZ20003558A3 (en) * | 2000-09-26 | 2002-05-15 | Ivax-Cr A. S. | Process for preparing (-)-N-cyclobutylmethyl-14{beta]-hydroxy-3-methoxymorphinate |
-
2021
- 2021-01-15 CN CN202110056678.1A patent/CN112592342B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3775414A (en) * | 1972-05-10 | 1973-11-27 | Bristol Myers Co | Process for the preparation of 14-hydroxymorphinan derivatives |
| CZ20003558A3 (en) * | 2000-09-26 | 2002-05-15 | Ivax-Cr A. S. | Process for preparing (-)-N-cyclobutylmethyl-14{beta]-hydroxy-3-methoxymorphinate |
Non-Patent Citations (1)
| Title |
|---|
| Profiling impurities and degradants of butorphanol tartrate using liquid chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry substructural techniques;Kevin J. Volk et al.;《Journal of Pharmaceutical and Biomedical Analysis》;19961231;第14卷;第1663-1674页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112592342A (en) | 2021-04-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109438488A (en) | A kind of preparation method of liquid Lithium bis (oxalate) borate salt | |
| CN112592342B (en) | Preparation method of butorphanol acyclic butyl impurity compound | |
| CN112300212A (en) | Use of borane-pyridine complexes for the preparation of NK-1 receptor antagonists | |
| CN109942593A (en) | A kind of total synthesis method of racemization hanfangchin A | |
| CN111995565B (en) | Preparation method of (S) -2-piperidinecarboxylic acid | |
| CN113061077B (en) | Alpha, alpha-dideuteroalcohol compounds, deuterated drugs and preparation method thereof | |
| CN112679363B (en) | Method for preparing pentazocine intermediate | |
| CN110724084B (en) | Synthesis method of (S) -3-hydroxy-1-benzylpyrrolidine | |
| CN113999126A (en) | Preparation method of trimebutine | |
| CN110862421B (en) | Synthetic method of nitrogenous heterocyclic ferrocene derivative | |
| CN113999164A (en) | Preparation method of halofuginone intermediate trans-N-benzyloxycarbonyl- (3-hydroxy-2-piperidyl) -2-acetone | |
| CN113105319A (en) | Preparation method of biparidic acid | |
| CN109734737B (en) | Preparation method and application of gem-diboron compound | |
| CN113461643A (en) | Synthesis method of 4-methylbenzenesulfonic acid [ (3-fluoro-oxetan-3-yl) methyl ] ester | |
| CN112552345A (en) | Preparation method of NK-1 receptor antagonist | |
| CN112047842A (en) | 1, 4-diene compound and preparation method and application thereof | |
| CN105175355A (en) | Preparation method of 2-cyanophenothiazine | |
| CN106317064B (en) | The preparation method of methylnaltrexone bromide | |
| CN115093391B (en) | Synthesis method of 3-thietane hydrochloride | |
| CN115677579B (en) | Preparation method of tetrahydropapaverine and intermediate thereof | |
| CN113354573B (en) | Method for large-scale production of alpha, alpha-terpyridine | |
| CN102329291A (en) | Method for preparing 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-formaldehyde | |
| CN108863812B (en) | Purification method of N-ethyl-3-phenylpropylamine | |
| CN113979835B (en) | Synthesis method of pazopanib trimer impurity intermediate | |
| CN112794837B (en) | Synthesis method of heterochroman compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |