CN101759642A - Method for preparing high purity dimemorfan and phosphate - Google Patents
Method for preparing high purity dimemorfan and phosphate Download PDFInfo
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- CN101759642A CN101759642A CN200810241014A CN200810241014A CN101759642A CN 101759642 A CN101759642 A CN 101759642A CN 200810241014 A CN200810241014 A CN 200810241014A CN 200810241014 A CN200810241014 A CN 200810241014A CN 101759642 A CN101759642 A CN 101759642A
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- dimemorfan
- recrystallization
- reaction
- solvent
- highly purified
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- KBEZZLAAKIIPFK-NJAFHUGGSA-N dimemorfan Chemical compound C1C2=CC=C(C)C=C2[C@@]23CCN(C)[C@@H]1[C@H]2CCCC3 KBEZZLAAKIIPFK-NJAFHUGGSA-N 0.000 title claims abstract description 23
- 229960001056 dimemorfan Drugs 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 18
- 229910019142 PO4 Inorganic materials 0.000 title abstract 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title abstract 2
- 239000010452 phosphate Substances 0.000 title abstract 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 239000011541 reaction mixture Substances 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000001953 recrystallisation Methods 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000010977 jade Substances 0.000 claims description 3
- 125000006178 methyl benzyl group Chemical group 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 3
- 238000004821 distillation Methods 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 239000003434 antitussive agent Substances 0.000 abstract 1
- 229940124584 antitussives Drugs 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- 206010011224 Cough Diseases 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000001568 sexual effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010010774 Constipation Diseases 0.000 description 2
- 206010052804 Drug tolerance Diseases 0.000 description 2
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- 229960004126 codeine Drugs 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- MKXZASYAUGDDCJ-NJAFHUGGSA-N dextromethorphan Chemical compound C([C@@H]12)CCC[C@]11CCN(C)[C@H]2CC2=CC=C(OC)C=C21 MKXZASYAUGDDCJ-NJAFHUGGSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000026781 habituation Effects 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
- 230000011514 reflex Effects 0.000 description 2
- 210000001533 respiratory mucosa Anatomy 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000001932 glossopharyngeal nerve Anatomy 0.000 description 1
- 210000004704 glottis Anatomy 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 210000003105 phrenic nerve Anatomy 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000003019 respiratory muscle Anatomy 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 210000001032 spinal nerve Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 210000001186 vagus nerve Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing high-purity dimemorfan and phosphate, relating to a new method for preparing and purifying raw material dimemorfan of an antitussive drug and a relative intermediate. The invention aims to avoid high vacuum degree distillation operation in the preparation of an US3786054 step five intermediate (2-(p-methylbenzyl)-octahydro isoquinolined-(+)tartrate) so as to avoid the disadvantage that individual impurity can not be removed through column separation. The step five intermediate with high purity and high yield is obtained by using acetone and the like as solvents to recrystallize cyclized reaction mixture.
Description
Technical field
The present invention relates to a kind of non-habituation sexual centre cough medicine---preparation of dimemorfan bulk drug and intermediate of producing.
Background technology
Cough is a kind of frequently-occurring disease and common disease, and except that seasonal burst and influenza, trachitis, diseases such as old-slow-bronchial tube all are main clinic symptoms with the cough.China more than 50 years old middle-aged and old old-slow-bronchial tube sickness rate be about 15%-30%.Because environmental pollution has 400,000 newly-increased chronic bronchitis people every year.No matter be domestic or external, the cough patient occupies huge radix, and remarkably productive cough medicine is had the great market requirement forever.The shared market sales revenue maximum of cold cough medicine in the whole world nonprescription drugs (OTC) reaches 21.3%.
The genesis mechanism of cough is a kind of neuroprotective sexual reflex that produces after respiratory mucosa is upset.Respiratory mucosa imports the signal that is upset into the oblongata coughing centre through vagus nerve, glossopharyngeal nerve and trifacial Sensory fibre, will reflect impulsion respectively through nervus laryngeus inferior, phrenic nerve and spinal nerves again and be sent to pharynx flesh, glottis, diaphram and other respiratory muscles and cause the cough action.Physiological cough has protection and defense reaction to the respiratory tract part, can borrow the reflex cough with the foreign matter in the respiratory tract and gets rid of.When cough frequent repeatedly generation and when having influence on normal work and rest, coughing just becomes the pathologic symptom.Because cough is a kind of nervosa reflection, therefore the most effective cough medicine is exactly depressor of nerve centre or claims the nervus centralis blocker at present, comprises opium, morphine monomethyl ether, morphine etc., its effect highly significant.
Dimemorfan is a kind of non-habituation sexual centre cough medicine, can directly suppress the oblongata coughing centre and produces antitussive effect.The antibechic effect is about the twice of morphine monomethyl ether, its structure and the similar Dextromethorphane Hbr of effect, and the antibechic effect slightly is better than Dextromethorphane Hbr.Advantage is that toxicity is low, and security is big, and therapeutic dose does not suppress to breathe, and does not have the constipation side effect.Therapeutic dose does not cause respiration inhibition and constipation, is applicable to the cough that a variety of causes causes.Preparation has tablet spray etc.
The present invention improves on the US3786054 basis, is that raw material is produced dimemorfan with the tetrahydroisoquinoline, controls for the 5th step intermediate temperature of reaction and reaction times, and reaction mixture dimemorfan content is between 75-95%.With acetone is solvent recrystallization, obtains highly purified the 5th step intermediate.Adopt recrystallization method to obtain to meet the officinal qualified product after adding the phosphoric acid salify.
By retrieval, do not see about produce highly purified dimemorfan intermediate 5 and phosphatic pertinent literature and patent report with the method for recrystallization.
Summary of the invention
Produce highly purified dimemorfan and phosphatic method, the present invention relates to the novel method of producing and purifying of a kind of cough medicine bulk drug dimemorfan and relevant intermediate.The object of the invention is to avoid the condition of high vacuum degree distillation procedure of US3786054 the 5th step intermediate (2-(to methyl-benzyl)-octahydro different quinoline beautiful jade d-(+) tartrate) when producing, and has avoided post to separate the shortcoming that indivedual impurity can't be removed.With solvent not such as acetone, to becoming the reaction mixture recrystallization behind the ring, method obtain the 5th step intermediate of high purity, high yield.
The present invention is that raw material is when producing dimemorfan with the tetrahydroisoquinoline, the 5th goes on foot reaction control temperature 120-135 ℃ of intermediate (2-(to methyl-benzyl)-octahydro different quinoline beautiful jade d-(+) tartrate), reaction times 68-100 hour, reaction mixture dimemorfan content was between 75-95%.Preferred 135 ℃ of temperature of reaction, the reaction times was at 60-90 hour.
When the present invention produces phosphoric acid salt with dimemorfan,, obtain highly purified phosphoric acid dimemorfan by the method for recrystallization.By the method for recrystallization, the preferred acetone of recrystallisation solvent and other polarity mixed solvent such as the propyl alcohol methyl alcohol etc. about 5.4.
Adopt the method for recrystallization directly to obtain highly purified dimemorfan, solvent preferred alcohol, methyl alcohol etc.
Embodiment
Come the present invention is produced highly purified dimemorfan and phosphatic method by following example
Do further specifying, but be not limited in following examples.
Embodiment 1
Tartrate 51.8g after the fractionation adds 28% ammoniacal liquor to PH=9, with ethyl acetate extraction three times, merges organic phase, wash three times, revolve to steam to desolventize, white moisture oily matter, add dehydrated alcohol 30mL, 70 ℃ of extremely anhydrous outflows of steamings, liquid 30.51g.The phosphatase 11 30Ml of adding 85%, 135-140 ℃ of induction stirring heating, reaction 70h, change reaction mixture over to frozen water, add ammoniacal liquor, merge the washing decompression for three times with extracted with diethyl ether and remove solvent to alkalescence, get the yellow pale brown look oily matter that arrives, 29.28g adds acetone 10ml, vibrate homogeneous liquid, put into refrigerator crystallization (spending the night) and get light yellow crystal, get above-mentioned crystal and do liquid chromatography, peak face area percentage 99.5%, to the solid acetone recrystallization, the general peak area per-cent 99.98% of Dry Sack.
Embodiment 2
Tartrate 134.52g after the fractionation, the ammoniacal liquor of adding 28% use ethyl acetate extraction three times to PH=9, merge organic phase, wash three times, revolve steaming and desolventize, get white moisture oily matter, add dehydrated alcohol 80mL, 70 ℃ of steamings are to anhydrous outflows, liquid 78.51g.The phosphoric acid 380Ml of adding 85%, 135-140 ℃ of induction stirring heating, reaction 70h, change reaction mixture over to frozen water, add ammoniacal liquor, merge the washing decompression for three times with extracted with diethyl ether and remove solvent to alkalescence, get the yellow pale brown look oily matter that arrives, 76.28g adds acetone 30ml, vibrate homogeneous liquid, put into refrigerator crystallization (spending the night) and get light yellow crystal, get above-mentioned crystal and do liquid chromatography, peak face area percentage 99.46%, to the solid acetone recrystallization, the general peak area per-cent 99.98% of Dry Sack.
Embodiment 3
Tartrate 48.8g after the fractionation adds 28% ammoniacal liquor to PH=9, with ethyl acetate extraction three times, merges organic phase, wash three times, revolve to steam to desolventize, white moisture oily matter, add dehydrated alcohol 30mL, 70 ℃ of extremely anhydrous outflows of steamings, liquid 28.51g.The phosphatase 11 30Ml of adding 85%, 135-140 ℃ of induction stirring heating, reaction 70h, change reaction mixture over to frozen water, add ammoniacal liquor, merge the washing decompression for three times with extracted with diethyl ether and remove solvent to alkalescence, get the yellow pale brown look oily matter that arrives, 29.28g adds acetone 10ml, vibrate homogeneous liquid, put into refrigerator crystallization (spending the night) and get light yellow crystal, get above-mentioned crystal and do liquid chromatography, peak face area percentage 99.58%, to the solid acetone recrystallization, the general peak area per-cent 99.96% of Dry Sack.
Embodiment 4
Get the step recrystallization and get yellow crystals 14.57g and be dissolved in 150ml acetone, add 85% phosphoric acid 8.08g, the agitation and filtration washing and drying gets the 19.94g solid.Liquid content 99.2%, titrimetry content 93%, ultimate analysis N:3.67%, C:56.18%, H:7.62% gets above-mentioned solid 5g and adds anhydrous methanol 40ml, reflux 20min, filtered while hot, filtrate is placed crystallization, white solid, dry solid 4.2g, content 99.98%, titrimetry content 99%, 101%.
Claims (6)
1. the present invention is that raw material is when producing dimemorfan with the tetrahydroisoquinoline, the 5th goes on foot reaction control temperature 120-135 ℃ of intermediate (2-(to methyl-benzyl)-octahydro different quinoline beautiful jade d-(+) tartrate), reaction times 68-100 hour, reaction mixture dimemorfan content was between 75-95%.
2. the 5th step intermediate adopts the method for recrystallization directly to obtain in the claim 1.
3. when dimemorfan is produced phosphoric acid salt in the claim 1,, obtain highly purified phosphoric acid dimemorfan by the method for recrystallization.
4. preferred 135 ℃ of temperature of reaction in the claim 1, the reaction times was at 60-90 hour.
5. in the claim 2 during purification dimemorfan intermediate 5, by the method for recrystallization, the preferred acetone of recrystallisation solvent and other polarity mixed solvent such as the propyl alcohol methyl alcohol etc. about 5.4.
6. adopt the method for recrystallization directly to obtain highly purified dimemorfan, solvent preferred alcohol, methyl alcohol etc. in the claim 3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810241014A CN101759642A (en) | 2008-12-24 | 2008-12-24 | Method for preparing high purity dimemorfan and phosphate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810241014A CN101759642A (en) | 2008-12-24 | 2008-12-24 | Method for preparing high purity dimemorfan and phosphate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101759642A true CN101759642A (en) | 2010-06-30 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810241014A Pending CN101759642A (en) | 2008-12-24 | 2008-12-24 | Method for preparing high purity dimemorfan and phosphate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101759642A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241630A (en) * | 2011-05-20 | 2011-11-16 | 杭州保灵集团有限公司 | Preparation method of dimethylmorphinan phosphate used as cough medicine |
| CN104086486A (en) * | 2014-07-02 | 2014-10-08 | 杭州澳医保灵药业有限公司 | Preparation method of dimemorfan phosphate |
-
2008
- 2008-12-24 CN CN200810241014A patent/CN101759642A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241630A (en) * | 2011-05-20 | 2011-11-16 | 杭州保灵集团有限公司 | Preparation method of dimethylmorphinan phosphate used as cough medicine |
| CN104086486A (en) * | 2014-07-02 | 2014-10-08 | 杭州澳医保灵药业有限公司 | Preparation method of dimemorfan phosphate |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20100630 |