CN114634514B - Method for removing impurities in noroxymorphone - Google Patents
Method for removing impurities in noroxymorphone Download PDFInfo
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- CN114634514B CN114634514B CN202210389978.6A CN202210389978A CN114634514B CN 114634514 B CN114634514 B CN 114634514B CN 202210389978 A CN202210389978 A CN 202210389978A CN 114634514 B CN114634514 B CN 114634514B
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- noroxymorphone
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- 239000012535 impurity Substances 0.000 title claims abstract description 73
- HLMSIZPQBSYUNL-IPOQPSJVSA-N Noroxymorphone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4 HLMSIZPQBSYUNL-IPOQPSJVSA-N 0.000 title claims abstract description 58
- 238000000034 method Methods 0.000 title claims abstract description 21
- 230000002378 acidificating effect Effects 0.000 claims abstract description 14
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 12
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims abstract description 12
- 239000004289 sodium hydrogen sulphite Substances 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 7
- 238000004321 preservation Methods 0.000 claims abstract description 7
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 51
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 239000003814 drug Substances 0.000 abstract description 8
- 230000002349 favourable effect Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- 239000000126 substance Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 229940079593 drug Drugs 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 4
- 239000000920 calcium hydroxide Substances 0.000 description 4
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 4
- 235000011116 calcium hydroxide Nutrition 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 229930013930 alkaloid Natural products 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 238000011020 pilot scale process Methods 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- QMFVIJMHPXUVOL-RCGDHTHDSA-N (4r,4as,7ar,12bs)-4a,9-dihydroxy-1,2,3,4,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;hydrochloride Chemical compound Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4 QMFVIJMHPXUVOL-RCGDHTHDSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229960005297 nalmefene Drugs 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- FQXXSQDCDRQNQE-VMDGZTHMSA-N thebaine Chemical class C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 FQXXSQDCDRQNQE-VMDGZTHMSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for removing impurities in noroxymorphone, which comprises the steps of adding sodium bisulphite into the noroxymorphone under an acidic condition, heating and stirring to 75-85 ℃, and measuring the single impurity content for 12.5min after heat preservation reaction; and when the content of single impurity is lower than 0.05%, cooling to room temperature, adding alkali to adjust the pH to be 9, crystallizing and filtering to obtain the noroxymorphone. The method is simple and has high yield (more than 95 percent), and provides a favorable guarantee for controlling the impurities of the raw material medicine of the noroxymorphone.
Description
Technical Field
The invention relates to the technical field of bulk drug impurity removal, in particular to a method for removing impurities in noroxymorphone.
Background
Any other component except the chemical entity of the drug in the bulk drug can be called as an impurity, and the existence of the impurity is always difficult and important for researching the quality of the drug and is also the source of the quality control of the bulk drug.
Noroxymorphone produced by Gansu province pharmaceutical alkali factories is a derivative of thebaine and morphine, and is also an important intermediate for synthesizing naloxone, naltrexone, nalmefene and other medicines. In the detection of substances related to the noroxymorphone product, the content of single impurities in the product for 12.5min is more than 0.1%, and the specific structure of the single impurities is not determined. Therefore, in order to improve the quality of noroxymorphone, it is highly desirable to control the factory requirements of single impurity related substances with the detection content less than 0.1%.
Disclosure of Invention
The invention aims to provide a method for removing impurities in noroxymorphone, which is simple and has high yield.
In order to solve the problems, the method for removing impurities in noroxymorphone is characterized by comprising the following steps: the method comprises the steps of adding sodium bisulphite with the mass of 0.03-0.4 times of that of noroxymorphone under an acidic condition, heating and stirring to 75-85 ℃, and measuring the single impurity content for 12.5min after heat preservation reaction; and when the content of single impurity is lower than 0.05%, cooling to room temperature, adding alkali to adjust the pH to be 9, crystallizing and filtering to obtain the noroxymorphone.
The acidic condition is acetic acid aqueous solution with volume concentration of 2-10%.
The heat preservation reaction time is 0.5-12 hours.
The alkali refers to ammonia water.
The crystallization time is 3-15 hours.
Compared with the prior art, the invention has the following advantages:
1. according to the related impurity removal method, a method for removing single impurities for 12.5min is found through experiments, the purpose of removing the impurities is achieved, and the delivery requirement that the detection content of the single impurity related substances is less than 0.1% is met.
2. The method is simple and has high yield (more than 95 percent), and provides a favorable guarantee for controlling the impurities of the raw material medicine of the noroxymorphone.
Drawings
The following describes the embodiments of the present invention in further detail with reference to the drawings.
Fig. 1 shows an external standard 50.18% of sodium hydroxide noroxymorphone. Wherein the peak area occupied by impurity 1 is 0.06% about 12.5 min; impurity 2 occupies 33.07% of the peak area at about 38.7 min.
Figure 2 is an external standard 88.48% of aqueous ammonia noroxymorphone. Wherein: about 12.5min, the peak area occupied by impurity 1 is 0.68%.
Fig. 3 is a sodium bicarbonate noroxymorphone external standard 95.19%. Wherein: about 12.5min, the peak area of impurity 1 is 0.69%.
Fig. 4 shows a 75.84% external standard for calcium hydroxide noroxymorphone. Wherein: about 12.5min, the peak area occupied by impurity 1 is 0.48%.
Figure 5 is noroxymorphone hydrochloride external standard 62.45%. Wherein: about 12.5min, the peak area occupied by impurity 1 is 0.28%.
Figure 6 is a 96.13% external standard of noroxymorphone acetate according to the invention. Wherein: about 12.5min, the peak area occupied by impurity 1 is 0.01%.
FIG. 7 shows the yields of noroxymorphone from various acetic acid concentrations in accordance with the present invention.
FIG. 8 shows the yields of noroxymorphone from various sodium bisulphite quality factors of the present invention.
FIG. 9 shows the yields of noroxymorphone from various reaction times of the present invention.
FIG. 10 shows the yields of noroxymorphone from various crystallization times according to the present invention.
FIG. 11 is a pilot scale-up experiment of the present invention.
Detailed Description
A method for removing impurities in noroxymorphone, which comprises the following steps: under an acidic condition, sodium bisulphite with the mass of 0.03-0.4 times of that of the noroxymorphone is added into the noroxymorphone, and the mixture is heated and stirred to 75-85 ℃ and reacts for 0.5-12 hours under heat preservation, and then the single impurity content is measured for 12.5 min; and when the single impurity content is lower than 0.05%, cooling to room temperature, adding ammonia water to adjust the pH to be 9, crystallizing for 3-15 hours, filtering to obtain a filter cake, and pumping and washing the filter cake with softened water with the mass of 0.5 times to obtain the noroxymorphone.
Wherein: the acidic condition is an aqueous acetic acid solution with a volume concentration of 2-10%.
[ Material ]
Instrument and reagent:
waters e2695 high performance liquid chromatograph (Waters); RCTB S025 magnetic stirrer (IKA); DH-101-3BS oven (Tianjin middle ring laboratory circuits Co., ltd.).
Analytically pure sodium bisulfite (Shanghai Bobo chemical Co., ltd.); analytically pure acetic acid (Shanghai Bobo chemical Co., ltd.).
[ Experimental methods ]
The method comprises the steps of removing impurities from noroxymorphone under alkaline conditions:
sequentially weighing 5g of noroxymorphone (with the external standard content of 87.28%, the card-type moisture of 11.3% and the impurity content of 0.69% in the detection of related substances of 12.5 min), putting into a three-mouth bottle, respectively adding 25ml of softened water to select sodium hydroxide, ammonia water, sodium bicarbonate and calcium hydroxide as alkali, adding 0.1 time of sodium bisulphate, reacting for 30 minutes at the system temperature of 75-85 ℃, crystallizing for 12 hours at the system pH=9, and then filtering and drying. And detecting the external standard content of related substances and normorphone by using a high performance liquid chromatograph.
Removing impurities from the noroxymorphone under the acidic condition:
sequentially weighing 5g of noroxymorphone (with the external standard content of 87.28%, the card-type moisture of 11.3% and the impurity content of 0.69% in the detection of related substances for 12.5 min), putting into a three-mouth bottle, respectively adding 25ml of softened water, hydrochloric acid or acetic acid as acid, adding 0.1 times of sodium bisulphite, reacting for 30 minutes at the system temperature of 75-85 ℃, crystallizing for 12 hours at the system pH=9, and then filtering and drying. And detecting the external standard content of related substances and normorphone by using a high performance liquid chromatograph.
Under the acidic condition, the concentration of acetic acid, the mass multiple of sodium bisulfite, the impurity removal reaction time and the crystallization time are examined:
(1) the experiment method is the same, the acetic acid concentration is 2%, 4%, 6%, 8% and 10%, and the yield of normorphone is calculated.
(2) The experimental method is the same, the mass multiples of sodium bisulphite are respectively 0.03, 0.06, 0.09, 0.2 and 0.4, and the yield of normorphone is calculated.
(3) The experimental method is the same, the impurity removal reaction and heat preservation time is respectively 0.5, 2, 8, 10 and 12 hours, and the yield of the normorphone is calculated.
(4) And (3) the experimental method is the same, the crystallization time is 3, 6, 9, 12 and 15 hours respectively, and the yield of the normorphone is calculated.
Pilot scale up experiment:
amplifying the feeding amount of noroxymorphone by 100 times, adding sodium bisulphite with the mass of 0.06 times into 6% acetic acid aqueous solution with the mass of 5.5 times, heating and stirring the system to 75-85 ℃ and preserving heat for reaction for 10 hours, cooling the system to 20 ℃, adding ammonia water for alkali adjustment to pH=9, crystallizing the system at 10-20 ℃ for 8-12 hours, filtering, pumping and washing a filter cake with softened water with the mass of 0.5 times, and detecting the external standard content of related substances and the normorphone by using a high performance liquid chromatograph.
Results and discussion
The method comprises the steps of removing impurities from noroxymorphone under alkaline conditions:
because noroxymorphone belongs to alkaloids, alkaloid is easy to dissolve in acid-base solution, and the impurity structure is considered to be destroyed under the acid and alkaline conditions, the property of the noroxymorphone is obviously different from that of main products, so that the noroxymorphone is further separated.
Under the condition of NaOH as alkali, the noroxymorphone can be completely dissolved after alkali adjustment, and the external standard 50.18 percent of sodium hydroxide noroxymorphone is obtained in 52.46 percent of yield. As shown in fig. 1, impurity 1 occupies a peak area of 0.06% for about 12.5min, and impurity 2 occupies a peak area of 33.07% for about 38.7 min. Namely: single impurities of 12.5min can be eliminated, but 38min of impurities are newly generated.
Further exploration was carried out by using other commonly used alkaline reagents in a laboratory, ammonia water, sodium bicarbonate and calcium hydroxide were tried as bases, and the bases were adjusted after the addition of the system, but noroxymorphone could not be dissolved, and impurities could not be released into the system for removal. Ammonia water noroxymorphone external standard 88.48%, yield 90.38%, as shown in figure 2, the peak area occupied by impurity 1 about 12.5min is 0.68%; sodium bicarbonate noroxymorphone external standard 95.19%, yield 97.28%, as shown in fig. 3, impurity 1 occupies about 12.5min with peak area 0.69%; the external standard of the calcium hydroxide noroxymorphone is 75.84 percent, the yield is 83.42 percent, and as shown in fig. 4, the peak area occupied by the impurity 1 is 0.48 percent about 12.5 min.
In conclusion, when sodium hydroxide is a dissolution system, the system is completely dissolved, the yield is low, and new impurities are generated about 38.7min, namely, the instability of the noroxymorphone can be destroyed; under other alkaline conditions, the dissolution system is incomplete, and impurities about 12.5min are not obviously reduced. Therefore, the conditions are not suitable for the production of noroxymorphone for impurity removal and purification.
Removing impurities from the noroxymorphone under the acidic condition:
the ability to remove this impurity under acidic conditions allows for better stability of noroxymorphone under acidic conditions. Hydrochloric acid and acetic acid were tried as dissolution systems. As shown in fig. 5, hydrochloric acid is used as an acidic condition, and the external standard of noroxymorphone is 62.45%, and the peak area occupied by impurity 1 about 12.5min is 0.28%, namely: the content of relevant substances of the noroxymorphone impurity for 12.5min is 0.28 percent, and the yield is 70.73 percent. As shown in fig. 6, acetic acid was used as an external standard of noroxymorphone at 96.13% and impurity 1 at about 12.5min was present at a peak area of 0.01%, namely: the content of relevant substances of the noroxymorphone impurity for 12.5min is 0.05, and the yield is 95.16%. From this, it was found that acetic acid was more effective in removing impurities than hydrochloric acid and was high in yield.
Under the acidic condition, the concentration of acetic acid, the mass multiple of sodium bisulfite, the impurity removal reaction time and the crystallization time are examined:
as can be seen from fig. 7 to 10, sodium bisulphite with the mass of 0.06 times is added into 6% acetic acid aqueous solution to react for 10 hours, the single impurity is reduced to below 0.05%, the crystallization is carried out for 12 hours when the crystallization ph=9, and the system crystallization is more complete.
Pilot scale up experiment:
in pilot scale-up experiments and parallel experiments, impurity 1 of noroxymorphone occupies 0.04% of peak area (see fig. 11) about 12.5min, the external standard is 95.02%, the yield is 95.00%, the moisture on card is 4.76%, and the dry matter content is 99.06%. The data show that the experimental method can effectively remove single impurities for 12.5min, and achieve the aim of impurity removal.
[ DOMINATION ] A method for producing a polypeptide
The impurity removal effect of the noroxymorphone under the conditions of an alkali and acid system is researched through different alkali and acid dissolving reagents, and the condition is found that single impurities in an aqueous solution of acetic acid can be removed within 12.5min, and the yield is higher. And then, the influences of different acetic acid concentrations, impurity removal reaction time and crystallization time on impurity removal and yield are examined, and the optimal condition for optimally removing the impurities is that the single impurity is reduced to below 0.05% in a reaction system for 10 hours, and the crystallization is carried out for 12 hours when the crystallization pH=9, so that the crystallization of the system is complete.
For the stability of the process, 500g of the process is added in an amplified manner, and the product with the external standard of 95.02%, the yield of 95.00%, the card-type moisture of 4.76%, the dry content of 99.06% and the single impurity of 0.05% is obtained.
In conclusion, the process method for purifying the noroxymorphone product has the advantages of good effect, simple purification mode, high yield and the like.
Claims (1)
1. A method for removing impurities in noroxymorphone, which is characterized by comprising the following steps: the method comprises the steps of adding sodium bisulphite with the mass of 0.06 times of that of noroxymorphone under an acidic condition, heating and stirring to 75-85 ℃, and measuring the single impurity content for 12.5min after heat preservation reaction; when the single impurity content is lower than 0.05%, cooling to room temperature, adding alkali to adjust the pH to be 9, crystallizing for 12-15 hours, and filtering to obtain the noroxymorphone; the acidic condition is acetic acid aqueous solution with volume concentration of 6%, and the dosage of the acetic acid aqueous solution is 5.5 times of the mass of the noroxymorphone; the alkali refers to ammonia water; the heat preservation reaction time is 10-12 hours.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101395159A (en) * | 2006-03-02 | 2009-03-25 | 马林克罗特公司 | Processes for preparing morphinan-6-one products with low levels of alpha, beta-unsaturated ketone compounds |
| WO2016187522A1 (en) * | 2015-05-20 | 2016-11-24 | Noramco, Inc. | Process for the preparation of oxymorphone freebase |
| CN112194664A (en) * | 2020-03-17 | 2021-01-08 | 国药集团工业有限公司 | A kind of preparation method and application of oxymorphone impurity |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101652369A (en) * | 2006-12-04 | 2010-02-17 | 诺拉姆科有限公司 | Reduce the method for impurity in the oxycodone base |
| EP3495371A1 (en) * | 2017-12-05 | 2019-06-12 | Siegfried AG | Synthesis of noroxymorphone |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101395159A (en) * | 2006-03-02 | 2009-03-25 | 马林克罗特公司 | Processes for preparing morphinan-6-one products with low levels of alpha, beta-unsaturated ketone compounds |
| WO2016187522A1 (en) * | 2015-05-20 | 2016-11-24 | Noramco, Inc. | Process for the preparation of oxymorphone freebase |
| CN112194664A (en) * | 2020-03-17 | 2021-01-08 | 国药集团工业有限公司 | A kind of preparation method and application of oxymorphone impurity |
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