CN107827819A - A kind of pentazocine crystal formation and preparation method thereof - Google Patents
A kind of pentazocine crystal formation and preparation method thereof Download PDFInfo
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- CN107827819A CN107827819A CN201711031811.8A CN201711031811A CN107827819A CN 107827819 A CN107827819 A CN 107827819A CN 201711031811 A CN201711031811 A CN 201711031811A CN 107827819 A CN107827819 A CN 107827819A
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- Prior art keywords
- crystal formation
- pentazocine
- preparation
- present
- butanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/26—Benzomorphans
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to medical science technical field, especially a kind of pentazocine crystal formation and preparation method thereof, crystal formation XRPD collection of illustrative plates has characteristic diffraction peak at 2 θ=5.646,10.325,11.215,13.019,14.733,15.019,15.394,16.808,17.182,17.996,18.452,19.389,20.524,21.616,22.714,24.400,24.995,25.783,26.744,27.606,28.191,28.894,30.166,30.803,36.233,37.220.Present invention also offers the preparation method of this pentazocine crystal formation.The crystal formation high income of gained of the invention, purity is good, have good stability, and synthesis technique produces under the conditions of factory GMP, suitable industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to (2RS, 6RS, 11RS) -1,2,3,4,5,6- hexahydros 6,11- bis-
Methyl -3- (3- methyl-2-butenes base) -2,6- methylene -3- benzo azocine -8- alcohol is pentazocine crystal formation and its preparation side
Method.
Background technology
Chemical name is (2RS, 6RS, 11RS) -1,2,3,4,5,6- hexahydros 6,11- dimethyl -3- (3- methyl-2-butenes
Base) -2,6- methylene -3- benzo azocine -8- alcohol, structural formula is as follows：
Pentazocine is the derivative of artificial synthesized opiates medicine benzmorphan, is the Agonistic-antagonistic of opiate receptor
Agent, for Postoperative analgesia, definite effect, clinical application has obvious treatment advantage：It is additive minimum, than other opioid drugs
Small, parenteral administration produces quick strong analgesic activity, and central inhibitory action is light, particularly in respiration inhibition and nausea and vomiting side
Face is all lighter than other opiate drug things；Many countries are classified as non-narcotic medicine and are managed；Analgesic activity is rapid-action, 15 points
Clock works, shorter than morphine, Sauteralgyl；There is no hypotension；Do not sway the emotion；Half-life period is moderate to be consequently adapted to various operations
Deng；Operation aftereffect eliminates rapidly in addition；Thus pentazocine parenteral solution has certain advantage in terms of curative effect, security.
Patent US3073837A and US3644373A and document Analytical.profiles of drug
Substances volume 13.p361~411, J.Org.Chem.24,116；1432,1435, (1959)；27,245；
2144, (1962)；28,2470, (1963) report the synthetic method of pentazocine, and some uses methanol crystallization, some uses
Acetone crystallizes, but does not carry out the research of crystal formation to it.
It is well known that the different crystal forms of same medicine, its stability and bioavilability etc. may exist bright
Significant difference is different, the effect of so as to influence medicine and use range.Therefore, research and development are more conducive to use in medicine processing and pharmaceutical composition
Pentazocine novel crystal forms, and for solid drugs the effect of research provide more qualitative, quantitative information have it is very important
Meaning.
At present, the pentazocine prepared with prior art easily produces the pentazocine of cis-isomer and de- side chain, should
Two kinds of materials clinically easily cause the adverse reaction of medicine.The present invention is by largely putting into practice creative work, unexpected hair
It is existing, pentazocine is prepared into certain crystallization can stabilize it while pharmaceutical purity also greatly improves, and prior art does not have yet
There is any research on pentazocine crystal formation to report, therefore, the invention provides a kind of crystal formation of new pentazocine.
The content of the invention
It is an object of the invention to overcome the deficiencies of the prior art and provide a kind of new pentazocine crystal formation, obtained crystalline substance
Type purity height (>=99.7%), stability is good, the fine powder good fluidity obtained after drying, easily stored and pharmaceutical preparation to make
With.
Another object of the present invention is to provide a kind of preparation method of above-mentioned new pentazocine crystal formation, with existing preparation
Method is simple compared to its technique, preparation condition is gentle, high income, and being easy to industrialization production and meet clinical injection level raw material will
Ask.
The purpose of the present invention is achieved through the following technical solutions：A kind of pentazocine crystal formation, the fusing point of its crystal formation for 148~
150 DEG C, X- powder diagram modal datas are as follows：
The preparation method of the new crystal formation of pentazocine of the present invention, comprises the following steps：
(1) pentazocine is dissolved in what n-butanol, being heated to 50~55 DEG C is completely dissolved it, it is subsequently cooled to 30~
35℃；
(2) it is slowly added in ethyl acetate to step 1, continues to be heated to 50~55 DEG C of insulation 40min；
(3) room temperature 3~4h of crystallization is naturally cooled to, is filtered, the dry 6~7h of 70~75 DEG C of vacuum obtains white crystalline powder
As pentazocine crystal formation.Wherein, the ratio of the pentazocine described in step 1 and n-butanol addition therebetween for 1g: 5~
6ml, the volume ratio of ethyl acetate and n-butanol amount described in step 2 is 2: 1.
Those of ordinary skill in the art can be carried out according to its knowledge and experience to the dosage of the inventive method agents useful for same
Adjustment, including scale up or reduce raw material dosage and adjust solvent load, the scheme of these adjustment is also contained in the present invention
Method in.
A kind of pentazocine crystal formation proposed by the present invention and preparation method thereof, beneficial effect is：Spray provided by the invention
Ta Zuoxinxin crystal formation, high income, purity is good, has good stability, and synthesis technique produces under the conditions of factory GMP
, it is adapted to industrialized production；The qualitative, quantitative information provided simultaneously, there is weight the effect of to further studying such solid drugs
The meaning wanted.
Brief description of the drawings
Fig. 1 is the powder X-ray diffraction collection of illustrative plates (XRPD) of pentazocine crystal formation of the present invention；
Fig. 2 is that the DSC of pentazocine crystal formation of the present invention schemes；
Fig. 3 is that the TG of pentazocine crystal formation of the present invention schemes；
Fig. 4 is the infrared spectrogram of pentazocine crystal formation of the present invention；
Fig. 5 is that the HPLC of pentazocine crystal formation of the present invention schemes.
Embodiment
The present invention can be further described for the following examples, however, these embodiments should not be used as to this
The limitation of invention scope.
Embodiment 1
In 30g pentazocines (purity 97.6%) dissolving what 150ml n-butanols, being heated to 50~55 DEG C makes it completely molten
Solution, is subsequently cooled to 30~35 DEG C, is slowly added to 300ml ethyl acetate, continues to be heated to 50~55 DEG C of insulation 40min, nature
Room temperature 3~4h of crystallization is cooled to, filters, the dry 7h of 70~75 DEG C of vacuum, obtains 27.6g white crystalline powders, mp：148~150
DEG C, yield 92.0%, purity 99.7%, the crystal formation powder X-ray diffraction spectrogram of gained, DSC spectrograms, TG spectrograms, infrared spectrogram
And HPLC spectrograms are shown in Fig. 1, Fig. 2, Fig. 3, Fig. 4 and Fig. 5 respectively.
Embodiment 2
In 30g pentazocines (purity 95.8%) dissolving what 180ml n-butanols, being heated to 50~55 DEG C makes it completely molten
Solution, is subsequently cooled to 30~35 DEG C, is slowly added to 360ml ethyl acetate, continues to be heated to 50~55 DEG C of insulation 40min, nature
Room temperature 3~4h of crystallization is cooled to, filters, the dry 7h of 70~75 DEG C of vacuum, obtains 25.8g white crystalline powders, mp：148~150
DEG C, yield 86.0%, purity 99.8%.
Embodiment 3
Stability of crystal form investigates experiment
Study condition：
Result of study：
The chemical property of the pentazocine crystal formation of the present invention is very stable it can be seen from result above.
The foregoing is only a preferred embodiment of the present invention, but protection scope of the present invention be not limited thereto,
Any one skilled in the art the invention discloses technical scope in, technique according to the invention scheme and its
Inventive concept is subject to equivalent substitution or change, should all be included within the scope of the present invention.
Claims (3)
1. a kind of pentazocine crystal formation, it is characterised in that the fusing point of the crystal formation is 148~150 DEG C, crystal formation X- powder diagrams
Modal data is as follows：
A kind of 2. method of the pentazocine crystal formation prepared described in claim 1, it is characterised in that：Comprise the following steps：
(1) pentazocine is dissolved in what n-butanol, being heated to 50~55 DEG C is completely dissolved it, is subsequently cooled to 30~35
℃；
(2) it is slowly added in ethyl acetate to step 1, continues to be heated to 50~55 DEG C of insulation 40min；
(3) room temperature 3~4h of crystallization is naturally cooled to, is filtered, the dry 6~7h of 70~75 DEG C of vacuum obtains white crystalline powder and is
Pentazocine crystal formation.
3. preparation method according to claim 2, it is characterised in that both pentazocines and n-butanol described in step 1
Between the ratio of addition be 1g: 5~6ml, the volume ratio of the ethyl acetate described in step 2 and n-butanol amount is 2: 1.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711031811.8A CN107827819A (en) | 2017-10-30 | 2017-10-30 | A kind of pentazocine crystal formation and preparation method thereof |
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| CN201711031811.8A CN107827819A (en) | 2017-10-30 | 2017-10-30 | A kind of pentazocine crystal formation and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111217749A (en) * | 2020-03-13 | 2020-06-02 | 安徽省逸欣铭医药科技有限公司 | Deuterated pentazocine, preparation method, medical composition and application |
| CN113845477A (en) * | 2021-10-28 | 2021-12-28 | 华润双鹤药业股份有限公司沧州分公司 | Refining method of pentazocine |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3634433A (en) * | 1967-06-07 | 1972-01-11 | Sumitomo Chemical Co | Process for producing 6 7-benzomorphane derivatives of amine type useful as analgesics |
| US3644373A (en) * | 1968-12-06 | 1972-02-22 | Grelan Pharmaceutical Co | Method for the production of 3-substituted-1 2 3 4 5 6-hexahydro-6 11-dimethyl-8-hydroxy-2 6-methano-3-benzazocines |
| US3686167A (en) * | 1968-02-09 | 1972-08-22 | Takeda Chemical Industries Ltd | Benzazocine derivatives |
| GB1330464A (en) * | 1969-11-20 | 1973-09-19 | Grindstedvaerket As | Method for the production of derivatives of 1,2,3,4,5,6- hexahydro-2,6-methano-3-benzazocine |
| CA963012A (en) * | 1972-03-31 | 1975-02-18 | Fumio Satoh | Method for preparing a heterocyclic compound |
| CA969939A (en) * | 1971-08-24 | 1975-06-24 | Hisao Yamamoto | Process for preparing benzomorphan derivatives and salts thereof |
| US4105659A (en) * | 1960-12-01 | 1978-08-08 | Sterling Drug Inc. | 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines |
-
2017
- 2017-10-30 CN CN201711031811.8A patent/CN107827819A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4105659A (en) * | 1960-12-01 | 1978-08-08 | Sterling Drug Inc. | 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines |
| US3634433A (en) * | 1967-06-07 | 1972-01-11 | Sumitomo Chemical Co | Process for producing 6 7-benzomorphane derivatives of amine type useful as analgesics |
| US3686167A (en) * | 1968-02-09 | 1972-08-22 | Takeda Chemical Industries Ltd | Benzazocine derivatives |
| US3644373A (en) * | 1968-12-06 | 1972-02-22 | Grelan Pharmaceutical Co | Method for the production of 3-substituted-1 2 3 4 5 6-hexahydro-6 11-dimethyl-8-hydroxy-2 6-methano-3-benzazocines |
| GB1330464A (en) * | 1969-11-20 | 1973-09-19 | Grindstedvaerket As | Method for the production of derivatives of 1,2,3,4,5,6- hexahydro-2,6-methano-3-benzazocine |
| CA969939A (en) * | 1971-08-24 | 1975-06-24 | Hisao Yamamoto | Process for preparing benzomorphan derivatives and salts thereof |
| CA963012A (en) * | 1972-03-31 | 1975-02-18 | Fumio Satoh | Method for preparing a heterocyclic compound |
Non-Patent Citations (2)
| Title |
|---|
| TETSUJI KAMETANI,等: "A Novel Cleavage of Aryl Benzyl Ethers and Allyl Aryl Ethers by Sodium Bis(2-methoxyethoxy)aluminum Hydride. An Alternative Synthesis of Pentazocine", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| TETSUJI KAMETANI,等: "Studies on the syntheses of heterocyclic compounds.DCLXVIII.Studies on the syntheses of analgesics.XLVI.An abnormal Hofmann degradation of N-(4-hydroxybenzyl)-3-benzazocinium halides", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111217749A (en) * | 2020-03-13 | 2020-06-02 | 安徽省逸欣铭医药科技有限公司 | Deuterated pentazocine, preparation method, medical composition and application |
| WO2021180081A1 (en) * | 2020-03-13 | 2021-09-16 | 安徽恒星制药有限公司 | Deuterated pentazocine, preparation method therefor and use thereof |
| CN113845477A (en) * | 2021-10-28 | 2021-12-28 | 华润双鹤药业股份有限公司沧州分公司 | Refining method of pentazocine |
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Application publication date: 20180323 |