CN101468945A - Technique for synthesizing vitacampher - Google Patents
Technique for synthesizing vitacampher Download PDFInfo
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- CN101468945A CN101468945A CNA2008100507078A CN200810050707A CN101468945A CN 101468945 A CN101468945 A CN 101468945A CN A2008100507078 A CNA2008100507078 A CN A2008100507078A CN 200810050707 A CN200810050707 A CN 200810050707A CN 101468945 A CN101468945 A CN 101468945A
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- vitacampher
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- oxycamphor
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 6
- BZFVGPPELIFTQP-FKTZTGRPSA-N (1r,4r,7r)-4,7-dimethyl-3-oxobicyclo[2.2.1]heptane-7-carbaldehyde Chemical compound C1C[C@@H]2CC(=O)[C@@]1(C)[C@]2(C)C=O BZFVGPPELIFTQP-FKTZTGRPSA-N 0.000 title claims description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 90
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 45
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000007788 liquid Substances 0.000 claims abstract description 30
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 29
- 238000002425 crystallisation Methods 0.000 claims abstract description 27
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 22
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 21
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 21
- 230000008025 crystallization Effects 0.000 claims abstract description 19
- 238000000605 extraction Methods 0.000 claims abstract description 19
- 239000000047 product Substances 0.000 claims abstract description 16
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims abstract description 15
- 241000723346 Cinnamomum camphora Species 0.000 claims abstract description 15
- 229930008380 camphor Natural products 0.000 claims abstract description 15
- 229960000846 camphor Drugs 0.000 claims abstract description 15
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 238000005893 bromination reaction Methods 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 238000000354 decomposition reaction Methods 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 7
- 230000018044 dehydration Effects 0.000 claims abstract description 6
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 6
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- 229960001701 chloroform Drugs 0.000 claims description 37
- 239000000243 solution Substances 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 26
- 238000013019 agitation Methods 0.000 claims description 25
- AXMKZEOEXSKFJI-UHFFFAOYSA-N 2-hydroxy-4,7,7-trimethylbicyclo[2.2.1]heptan-3-one Chemical compound C1CC2(C)C(=O)C(O)C1C2(C)C AXMKZEOEXSKFJI-UHFFFAOYSA-N 0.000 claims description 22
- 238000001816 cooling Methods 0.000 claims description 22
- 235000017550 sodium carbonate Nutrition 0.000 claims description 21
- OFAQZCPBQBALHS-UHFFFAOYSA-N 2,2-dibromo-4,7,7-trimethylbicyclo[2.2.1]heptan-3-one Chemical compound C1CC2(C)C(=O)C(Br)(Br)C1C2(C)C OFAQZCPBQBALHS-UHFFFAOYSA-N 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 229960000583 acetic acid Drugs 0.000 claims description 13
- 239000012362 glacial acetic acid Substances 0.000 claims description 13
- 239000000843 powder Substances 0.000 claims description 13
- JHWIEAWILPSRMU-UHFFFAOYSA-N 2-methyl-3-pyrimidin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=N1 JHWIEAWILPSRMU-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000000284 extract Substances 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000009835 boiling Methods 0.000 claims description 10
- 235000011194 food seasoning agent Nutrition 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 7
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 7
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 7
- 239000001110 calcium chloride Substances 0.000 claims description 7
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229930182817 methionine Natural products 0.000 claims description 7
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- VLOHNGJRIFIHMO-UHFFFAOYSA-N chloromethane;hydrate Chemical compound O.ClC VLOHNGJRIFIHMO-UHFFFAOYSA-N 0.000 claims description 5
- 235000019628 coolness Nutrition 0.000 claims description 5
- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 claims description 5
- 238000007599 discharging Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- 230000003068 static effect Effects 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 238000007259 addition reaction Methods 0.000 claims description 2
- 238000004140 cleaning Methods 0.000 claims description 2
- 238000004042 decolorization Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 4
- 238000002347 injection Methods 0.000 abstract description 4
- 239000007924 injection Substances 0.000 abstract description 4
- 230000003647 oxidation Effects 0.000 abstract description 4
- 230000031709 bromination Effects 0.000 abstract description 3
- 239000007795 chemical reaction product Substances 0.000 abstract description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical class [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000460 chlorine Substances 0.000 abstract description 2
- 229910052801 chlorine Inorganic materials 0.000 abstract description 2
- 229930008384 Oxocamphor Natural products 0.000 abstract 4
- DLKVHFJZTKTFRS-UHFFFAOYSA-N Oxocamphor Chemical compound C1CC2(C=O)C(=O)CC1C2(C)C DLKVHFJZTKTFRS-UHFFFAOYSA-N 0.000 abstract 4
- 239000003638 chemical reducing agent Substances 0.000 abstract 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical group [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 abstract 1
- 239000013078 crystal Substances 0.000 abstract 1
- 230000032050 esterification Effects 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006386 neutralization reaction Methods 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 239000011591 potassium Substances 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000008399 tap water Substances 0.000 description 3
- 235000020679 tap water Nutrition 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 238000010189 synthetic method Methods 0.000 description 2
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- 208000037157 Azotemia Diseases 0.000 description 1
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- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000019926 Keshan disease Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- 208000019622 heart disease Diseases 0.000 description 1
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- 239000001257 hydrogen Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a process for synthesizing oxocamphor. The process comprises the steps of dissolving camphor in chloroform, adding bromine for completing bromination, obtaining pi-acetyloxaphor through esterification and reduction, adding potassium hydroxide and ethanol for hydrolysis, extracting through chloroform, adding solvent oil for crystallization, dissolving crystals in water, adding sulfuric acid and the like for oxidation, performing addition after neutralization, adding aether for extraction to obtain oxocamphor addition liquid, adding sodium carbonate for decomposition reaction, using aether for extraction to obtain oxocamphor aether liquid, sequentially performing concentration, alkali washing, water washing, dehydration and decoloration, and obtaining the oxocamphor. The process has the advantages of substituting bromination reaction for chlorine reaction, changing gaseous reaction, realizing liquid reaction, lowering risk, reducing reaction steps, using copper acetate substituted zinc powder as a reducing agent, lowering risk and raising product yield. As an end product is purified through extraction, decomposition and re-extraction after salt formation, the purity of the product is improved and reaches the current injection standard that the purity is higher than 99 percent in China.
Description
Denomination of invention
The present invention discloses a kind of technique for synthesizing vitacampher, is to the improvement of existing synthesis technique, belongs to pharmaceutical chemicals synthesis technology field.
Background technology
The oxycamphor chemical name that the present invention relates to is dextrorotation-п-oxycamphor (d-trans-п-oxocamphor), be called for short п-oxycamphor.
Chemical structure:
This product is to be used for the treatment of acute and cardiac tonic chronic cardiac insufficiency.Cardiac tonic effect and central excitation effect are stronger than camphor, and toxicity is lower, there is no local irritation.Can strengthen heartbeat in the time of in a small amount, the excited respiratory centre of meeting increases depth of respiration and intensity when relatively large, can excitedly breathe vasomotor center during greater amount, makes peripheral blood vessel contraction and increased blood pressure, and subcutaneous absorption is rapid.The clinical cardiac stimulant that is used for, excited respiratory centre and be applicable to acute depletedly at heart, general heart disease cycle penalty, oedema, acute collapse and expiratory dyspnea also are used for Keshan disease and rescue valvular heart disease and uremia etc.
At present, the synthetic method of vitacampher is to adopt the rich explained hereafter of Japanese western light so far, and the method from camphor begins to adopt fully chemosynthesis makes п-vitacampher.Operational path is as follows:
But this synthetic method route is long, and yield is low, only about 3%, and this has just caused the increase of production cost.Secondly, very easily catch fire during the camphor bromination, great danger is arranged, produce dangerous; The three wastes are difficult for handling, and do not meet the environmental requirement of country.Once more, end product purity is about 93% only, is lower than national existing injection standard (version Chinese Pharmacopoeia in 2005).In a word, existing manufacturing technique complexity, time grows, yields poorly, quality instability, cost height, can not satisfy the demand in market, need improve old technology, and the quality of old explained hereafter vitacampher is very unstable, the bulk drug of producing can not meet the standard of national injection bulk drug, and therefore, the improvement of raw material synthesis technique is imperative.
Summary of the invention
The present invention discloses a kind of technique for synthesizing vitacampher, has overcome that existing complex manufacturing, time are grown, yielded poorly, quality instability, shortcoming that cost is high.
Technical solution of the present invention is as follows:
1. the preparation of a-bromocamphor
Camphor is dissolved in the chloroform, adds bromine and finish bromination reaction, get crude product
-bromocamphor;
2. the preparation of a-п dibromocamphor
Under cooling,, obtain a-п dibromocamphor with carrying out bromination reaction in a-bromocamphor adding oleum and the bromine;
3. the preparation of п-oxycamphor
In Potassium ethanoate, glacial acetic acid solution, add a-п dibromocamphor and carry out esterification reaction, get X-bromo-π-acetyl oxycamphor; The adding neutralized verdigris carries out reduction reaction and gets π-acetyl oxycamphor; Add potassium hydroxide, ethanol be hydrolyzed react п-oxycamphor solution; Add chloroform and extract, the crystallization of solubilizing agent oil gets п-oxycamphor;
4. the preparation of п-vitacampher
п-oxycamphor is soluble in water, adding sulfuric acid, sodium dichromate 99, methionine(Met) carry out oxidizing reaction, get vitacampher solution, add yellow soda ash and obtain the vitacampher neutralizer, add sodium bisulfite and carry out addition reaction, extract with ether and to obtain vitacampher addition liquid, add yellow soda ash once more and carry out decomposition reaction, get the vitacampher ether solution with extracted with diethyl ether, add yellow soda ash after concentrating and carry out alkali cleaning, the adding distil water washing adds Calcium Chloride Powder Anhydrous, carbon element, and dehydration and decolorization obtains vitacampher.
Operational path is as follows:
Process flow sheet: see Fig. 3.
Concrete synthesis technique may further comprise the steps:
(1) in 6kg camphor, add chloroform 1000～2000ml, heat 60～80 ℃, agitation and dropping 6～7kg bromine in 3～8 hours, heat temperature raising to 100～110 ℃ kept temperature 2 hours～3 hours then, promptly reached reaction end, after the discharging cooling crude product
-bromocamphor; Press 1:(1～2) weight ratio will
-bromocamphor product is dissolved in and carries out recrystallization in the ethanol, the lucifuge seasoning,
-bromocamphor product;
(2) contain SO in preparation
3Among oleum 20～24kg of 3～6%, below 20 ℃, agitation condition drops into down 3.6～4.4kg bromine, stir, with step (1) gained
-bromocamphor input, temperature of reaction is controlled below 40 ℃, and heated up 2～4 hours naturally in the back that feeds intake, and heating is raised to 18～25 ℃, reacts and reaches reaction end in 7～10 days;
Pouring reactant into frozen water mixed solution 60～80kg that 1:1 is housed decomposes in the bottle, add 10～20L chloroform extraction again, isolate acid solution water,, divide disacidify water to get trichloromethane liquid again with the clear water methyl chloride liquid of giving a baby a bath on the third day after its birth, change in the crystallization bottle, after reclaiming trichloromethane, 60～70 ℃ of leftover materials coolings under agitation add methyl alcohol 5～10L crystallisation by cooling and filter, xln soaks after-filtration with 2～5L methyl alcohol again and gets dibromocamphor, seasoning;
(3) in the dibromocamphor of step (2) gained, add Glacial acetic acid 1.3～2.7kg successively, Potassium ethanoate 4～6kg heated 170～200 ℃ of beginning back flow reaction 20～24 hours, added neutralized verdigris 0.4～0.6kg, reacted and promptly reached reaction end in 4～6 hours; After adding boiling water, add ethanol 0.8～1L of 95% again, be cooled to 40 ℃, the ratio that adds 2～3kg potassium hydroxide in 2L water adds potassium hydroxide solution, and temperature keeps below 7 ℃, reflux 2 hours, add water 10～15L, adding trichloromethane 20～30L extraction oxycamphor below 40 ℃; Reclaim trichloromethane, residual solution is under agitation put into 3～6L solvent oil, and is static more than 8 hours, and suction filtration is drying to obtain the oxycamphor crystallization;
(4) get the oxycamphor of step (3) gained, add the boiling water dissolving, add sodium dichromate 99 440～520g, methionine(Met) 10～16g, 60% sulfuric acid, 400～600ml heats 58～64 ℃ of reactions 1 hour, add sodium dichromate 99 200～280g and 60% sulfuric acid, 360～400ml again, stir, reacted 30 minutes, reach reaction end, cooling is below 25 ℃, under agitation add yellow soda ash 600～640g, in and PH reach between 5～6,3.6kg sodium bisulfite and 5.2L ether are added stir again, after 1 hour, add 3.6kg yellow soda ash and decompose, decomposed solution does not have alcohol ether with 440L again and extracts vitacampher in decomposing, and the redistillation of gained vitacampher ether solution is reclaimed ether and concentrated, wash with 5% aqueous sodium carbonate 40ml, separating reaction liquid washes with water again, branch vibration layer, alkali lye; Water liquid is again with ether solution extraction, adds Calcium Chloride Powder Anhydrous 80～120g after medicine ether is merged branch vibration layer, activated carbon 20g fully vibrates, and places, and filters filtrate and reclaims ether when closely dried, drain with vacuum tightness again, vitacampher (seeing Fig. 1, Fig. 2).
The present invention and existing synthesis technique now compare its positively effect and are: substitute chlorine reaction with bromo-reaction, change vapor reaction, realize liquid reaction.Reduce danger, reduce reactions steps.Make reductive agent with neutralized verdigris for zinc powder, reduce danger, improve the yield of product.End product adopts the purification process that extracts, decomposes, extracts behind the salify, improves the purity of product, makes it reach the quality standard of GMP regulation.Synthetic route of the present invention is shorter, and yield is about 12.0%; Danger when having avoided the camphor bromination; The quality of product also improves greatly, has reached national existing purity greater than 99% injection standard.
Description of drawings
Fig. 1 is a vitacampher hydrogen spectrogram;
Fig. 2 is a vitacampher carbon spectrogram;
Fig. 3 is a process flow sheet of the present invention.
Embodiment
By following examples the present invention is described for example further, and do not limit the present invention in any way, under the prerequisite that does not deviate from technical solution of the present invention, any change or change that those of ordinary skills that the present invention did are realized easily all will fall within the claim scope of the present invention.
Embodiment 1
(1) with camphor 6kg, place in the 20L reaction flask, add chloroform 1500ml chloroform, the row's of opening bromize hydrogen gas outlet under agitation drips bromine.60～80 ℃ of heat tracings added the 6.6kg bromine in 5 hours, heat temperature raising is to 100 ℃ then, kept 100～105 ℃ of temperature 2 hours 40 minutes, promptly reached reaction end, after the discharging cooling crude product
-bromocamphor.
-bromocamphor product is dissolved in that (1:1) carries out recrystallization in the ethanol.The lucifuge seasoning.Gained
-bromocamphor product 8kg.
(2) at first with a bromine reaction gained
-bromocamphor is divided into two parts, reacts at twice, in each 20L reaction flask, prepares oleum and (contains SO
35%), 10.7kg, temperature under agitation drops into the 2.2kg bromine below 10 ℃ in the bottle, stirs after 20 minutes, will again
The gradation of-bromocamphor drops in the bottle, and in the process of feeding intake, temperature of reaction is controlled below 15 ℃, and intensification is after 3 hours naturally to have thrown the back, and heating is raised to 21～23 ℃, reacts and reaches reaction end in 8 days.
Pour reactant into the 20L bottle, in in the decomposition bottle of dress 5kg ice and 5kg water, add the 10L chloroform extraction again, tell acid solution water again with the 20L clear water methyl chloride liquid of giving a baby a bath on the third day after its birth, divide disacidify water, repeatable operation four times changes trichloromethane liquid in the 20L crystallization bottle over to, behind the recovery trichloromethane, 60～70 ℃ of material coolings, under agitation add methyl alcohol 3L crystallisation by cooling and filter, xln again with 2L methyl alcohol soak twice of 2 hours after-filtration altogether dibromocamphor 2.1kg, change next procedure after the seasoning over to.Filtrate is returned down lot number crystallization usefulness for the second time.
(3) in exsiccant 20L there-necked flask, add Glacial acetic acid 2kg successively, dibromocamphor with the top generation, Glacial acetic acid potassium 4.67kg, reflux picked up counting (about 170～200 ℃) back flow reaction after 20 hours, stopped heating, refluxed when stopping, add Glacial acetic acid copper 0.467kg, react again and promptly reached reaction end in 6 hours.After retort adds boiling water 0.2L, add 0.8L ethanol again, cool off 40 ℃, potassium hydroxide solution is added in the jar (2L water adds 2.67kg potassium hydroxide), this moment, temperature kept below 7 ℃, reflux 2 hours.Hydrolysis reaction finishes back measured reaction liquid PH, if less than 10, and hydro-oxidation potassium then, reaction again is hydrolyzed.Greater than 10, then reclaim ethanol, till flowing to end.With tap water 15L, add below 40 ℃ trichloromethane 30L divide three times the extraction oxycamphor.Reclaim trichloromethane, raffinate is under agitation put into the beaker that fills the 5L solvent oil, and light yellow oxycamphor crystallization is separated out, and static more than 8 hours, suction filtration is drying to obtain.In crystallisation process, if produce black precipitate, precipitate available dissolve with ethanol, add activated carbon decolorizing again, after carry out recrystallization, can get the about 0.62kg of light yellow oxycamphor crystallization.
(4) get the 300g oxycamphor, after adding the dissolving of 9000ml boiling water, clear and bright liquid places oxidation tank, add sodium dichromate 99 240g then, methionine(Met) 7.5g, 60% sulfuric acid 240ml, in half an hour, divide and add for four times, timing when heating 58 ℃, be incubated 58～64 ℃ of reactions 1 hour, add sodium dichromate 99 120g and 60% sulfuric acid 180ml again, stir, in 58～62% reactions 30 minutes, reach reaction end, cooling is below 25 ℃, change in the addition jar, under agitation add yellow soda ash 320g, in and PH reach between 5～6, in again 1.8kg sodium bisulfite and the 2.6kg aqueous solution being added jar, stirred once in per 10 minutes, after 1 hour, use responseless oxycamphor in the 32L extracted with diethyl ether addition liquid again, return and change in the jar again into liquid, adding 1.8kg yellow soda ash decomposes, decomposed solution does not have the vitacampher of alcohol ether in extract decomposing with 220L again, and gained oxygen divides the redistillation of camphor ether solution to reclaim ether to concentrate 600ml, wash with 5% aqueous sodium carbonate 20ml respectively, separating reaction liquid, use twice washing of 20ml moisture again, branch vibration layer, alkali lye, water liquid are again with 600ml ether solution extraction three times, medicine ether is merged branch vibration layer, place 1 decolouring, respectively add Calcium Chloride Powder Anhydrous 50g in the dehydration bottle, carbo medicinalis 10g fully vibrates, and places 1 hour, when filtration filtrate recovery ether is closely dried, be more than the 600mmHg post with vacuum tightness again, place in 70 ℃ of waters bath with thermostatic control and took out 8 minutes, drain, the vitacampher taking-up carefully is ground into powder, reinstall in the bottle, the similarity condition vacuum takes out 8 exceptionally, takes out cold again, be ground into fine powder, pack in the brown wide-necked bottle, vacuum is drained sealing again, and Liang Chu preserves.Altogether vitacampher 0.31kg
Embodiment 2
(1) with camphor 6kg, place in the 20L reaction flask, add chloroform 1300ml chloroform, the row's of opening bromize hydrogen gas outlet under agitation drips bromine.60～80 ℃ of heat tracings added the 6.0kg bromine in 5 hours, heat temperature raising is to 100 ℃ then, kept 100～110 ℃ of temperature 2 hours 40 minutes, promptly reached reaction end, after the discharging cooling crude product
-bromocamphor.
-bromocamphor product is dissolved in that (1:1) carries out recrystallization in the ethanol.The lucifuge seasoning.Gained
-bromocamphor product 7.8kg
(2) at first with a bromine reaction gained
-bromocamphor is divided into two parts, reacts at twice, in each 20L reaction flask, prepares oleum and (contains SO
34%), 10.7kg, temperature under agitation drops into the 2.0kg bromine below 10 ℃ in the bottle, stirs after 20 minutes, will again
The gradation of-bromocamphor drops in the bottle, and in the process of feeding intake, temperature of reaction is controlled below 15 ℃, and intensification is after 3 hours naturally to have thrown the back, and heating is raised to 21～23 ℃, reacts and reaches reaction end in 8 days.
Pour reactant into the 20L bottle, in in the decomposition bottle of dress 4kg ice and 4kg water, add the 8L chloroform extraction again, tell acid solution water again with the 20L clear water methyl chloride liquid of giving a baby a bath on the third day after its birth, divide disacidify water, repeatable operation four times changes trichloromethane liquid in the 20L crystallization bottle over to, behind the recovery trichloromethane, 60～70 ℃ of material coolings, under agitation add methyl alcohol 2L crystallisation by cooling and filter, xln again with 1.5L methyl alcohol soak twice of 2 hours after-filtration altogether dibromocamphor 1.85kg, change next procedure after the seasoning over to.Filtrate is returned down lot number crystallization usefulness for the second time.
(3) in exsiccant 20L there-necked flask, add Glacial acetic acid 1.85kg successively, dibromocamphor with the top generation, Glacial acetic acid potassium 4.35kg, reflux picked up counting (about 170～200 ℃) back flow reaction after 20 hours, stopped heating, refluxed when stopping, add Glacial acetic acid copper 0.435kg, react again and promptly reached reaction end in 5 hours.After retort adds boiling water 0.2L, add 0.8L ethanol again, cool off 40 ℃, potassium hydroxide solution is added in the jar (2L water adds 2.4kg potassium hydroxide), this moment, temperature kept below 7 ℃, reflux 2 hours.Hydrolysis reaction finishes back measured reaction liquid PH, if less than 10, and hydro-oxidation potassium then, reaction again is hydrolyzed.Greater than 10, then reclaim ethanol, till flowing to end.With tap water 15L, add below 40 ℃ trichloromethane 30L divide three times the extraction oxycamphor.Reclaim trichloromethane, raffinate is under agitation put into the beaker that fills the 5L solvent oil, and light yellow oxycamphor crystallization is separated out, and static more than 8 hours, suction filtration is drying to obtain.In crystallisation process, if produce black precipitate, precipitate available dissolve with ethanol, add activated carbon decolorizing again, after carry out recrystallization, can get the about 0.55kg of light yellow oxycamphor crystallization.
(4) get the 300g oxycamphor, after adding the dissolving of 9000ml boiling water, clear and bright liquid places oxidation tank, add sodium dichromate 99 230g then, methionine(Met) 7g, 60% sulfuric acid 240ml, in half an hour, divide and add for four times, timing when heating 60 ℃, be incubated 58～64 ℃ of reactions 1 hour, add sodium dichromate 99 110g and 60% sulfuric acid 170ml again, stir, in 58～62% reactions 30 minutes, reach reaction end, cooling is below 25 ℃, change in the addition jar, under agitation add yellow soda ash 300g, in and PH reach between 5～6, in again 1.8kg sodium bisulfite and the 2.6kg aqueous solution being added jar, stirred once in per 10 minutes, after 1 hour, use responseless oxycamphor in the 30L extracted with diethyl ether addition liquid again, return and change in the jar again into liquid, adding 1.8kg yellow soda ash decomposes, decomposed solution does not have the vitacampher of alcohol ether in extract decomposing with 200L again, and gained oxygen divides the redistillation of camphor ether solution to reclaim ether to concentrate 550ml, wash with 5% aqueous sodium carbonate 20ml respectively, separating reaction liquid, use twice washing of 20ml moisture again, branch vibration layer, alkali lye, water liquid are again with 600ml ether solution extraction three times, medicine ether is merged branch vibration layer, place 1 decolouring, respectively add Calcium Chloride Powder Anhydrous 40g in the dehydration bottle, carbo medicinalis 10g fully vibrates, and places 1 hour, when filtration filtrate recovery ether is closely dried, be more than the 600mmHg post with vacuum tightness again, place in 70 ℃ of waters bath with thermostatic control and took out 8 minutes, drain, the vitacampher taking-up carefully is ground into powder, reinstall in the bottle, the similarity condition vacuum takes out 8 exceptionally, takes out cold again, be ground into fine powder, pack in the brown wide-necked bottle, vacuum is drained sealing again, and Liang Chu preserves.Altogether vitacampher 0.25kg.
Embodiment 3
(1) with camphor 6kg, place in the 20L reaction flask, add chloroform 1700ml chloroform, the row's of opening bromize hydrogen gas outlet under agitation drips bromine.60～80 ℃ of heat tracings added the 7.0kg bromine in 5 hours, heat temperature raising is to 100 ℃ then, kept 100～105 ℃ of temperature 3 hours, promptly reached reaction end, after the discharging cooling crude product
-bromocamphor.
-bromocamphor product is dissolved in that (1:1) carries out recrystallization in the ethanol.The lucifuge seasoning.Gained
-bromocamphor product 8.0kg
(2) at first with a bromine reaction gained
-bromocamphor is divided into two parts, reacts at twice, in each 20L reaction flask, prepares oleum and (contains SO
36%), 10.7kg, temperature under agitation drops into the 2.4kg bromine below 10 ℃ in the bottle, stirs after 20 minutes, will again
The gradation of-bromocamphor drops in the bottle, and in the process of feeding intake, temperature of reaction is controlled below 15 ℃, and intensification is after 3 hours naturally to have thrown the back, and heating is raised to 21～23 ℃, reacts and reaches reaction end in 9 days.
Pour reactant into the 20L bottle, in in the decomposition bottle of dress 6kg ice and 6kg water, add the 10L chloroform extraction again, tell acid solution water again with the 20L clear water methyl chloride liquid of giving a baby a bath on the third day after its birth, divide disacidify water, repeatable operation four times changes trichloromethane liquid in the 20L crystallization bottle over to, behind the recovery trichloromethane, 60～70 ℃ of material coolings, under agitation add methyl alcohol 4L crystallisation by cooling and filter, xln again with 2L methyl alcohol soak twice of 2 hours after-filtration altogether dibromocamphor 2.1kg, change next procedure after the seasoning over to.Filtrate is returned down lot number crystallization usefulness for the second time.
(3) in exsiccant 20L there-necked flask, add Glacial acetic acid 2.1kg successively, dibromocamphor with the top generation, Glacial acetic acid potassium 4.87kg, reflux picked up counting (about 170～200 ℃) back flow reaction after 20 hours, stopped heating, refluxed when stopping, add Glacial acetic acid copper 0.487kg, react again and promptly reached reaction end in 8 hours.After retort adds boiling water 0.4L, add 1.0L ethanol again, cool off 40 ℃, potassium hydroxide solution is added in the jar (2L water adds 2.8kg potassium hydroxide), this moment, temperature kept below 7 ℃, reflux 2 hours.Hydrolysis reaction finishes back measured reaction liquid PH, if less than 10, and hydro-oxidation potassium then, reaction again is hydrolyzed.Greater than 10, then reclaim ethanol, till flowing to end.With tap water 20L, add below 40 ℃ trichloromethane 32L divide three times the extraction oxycamphor.Reclaim trichloromethane, raffinate is under agitation put into the beaker that fills the 5L solvent oil, and light yellow oxycamphor crystallization is separated out, and static more than 8 hours, suction filtration is drying to obtain.In crystallisation process, if produce black precipitate, precipitate available dissolve with ethanol, add activated carbon decolorizing again, after carry out recrystallization, can get the about 0.56kg of light yellow oxycamphor crystallization.
(4) get the 300g oxycamphor, after adding the dissolving of 9000ml boiling water, clear and bright liquid places oxidation tank, add sodium dichromate 99 250g then, methionine(Met) 8g, 60% sulfuric acid 250ml, in half an hour, divide and add for four times, timing when heating 60 ℃, be incubated 58～64 ℃ of reactions 1 hour, add sodium dichromate 99 130g and 60% sulfuric acid 190ml again, stir, in 58～62% reactions 30 minutes, reach reaction end, cooling is below 25 ℃, change in the addition jar, under agitation add yellow soda ash 330g, in and PH reach between 5～6, in again 1.8kg sodium bisulfite and the 2.6kg aqueous solution being added jar, stirred once in per 10 minutes, after 1 hour, use responseless oxycamphor in the 30L extracted with diethyl ether addition liquid again, return and change in the jar again into liquid, adding 1.8kg yellow soda ash decomposes, decomposed solution does not have the vitacampher of alcohol ether in extract decomposing with 240L again, and gained oxygen divides the redistillation of camphor ether solution to reclaim ether to concentrate 600ml, wash with 5% aqueous sodium carbonate 20ml respectively, separating reaction liquid, use twice washing of 20ml moisture again, branch vibration layer, alkali lye, water liquid are again with 600ml ether solution extraction three times, medicine ether is merged branch vibration layer, place 1 decolouring, respectively add Calcium Chloride Powder Anhydrous 60g in the dehydration bottle, carbo medicinalis 10g fully vibrates, and places 1 hour, when filtration filtrate recovery ether is closely dried, be more than the 600mmHg post with vacuum tightness again, place in 70 ℃ of waters bath with thermostatic control and took out 8 minutes, drain, the vitacampher taking-up carefully is ground into powder, reinstall in the bottle, the similarity condition vacuum takes out 8 exceptionally, takes out cold again, be ground into fine powder, pack in the brown wide-necked bottle, vacuum is drained sealing again, and Liang Chu preserves.Altogether vitacampher 0.26kg.
Claims (2)
1, a kind of technique for synthesizing vitacampher is characterized in that comprising the steps:
1. the preparation of a-bromocamphor
Camphor is dissolved in the chloroform, adds bromine and finish bromination reaction, get crude product
-bromocamphor;
2. the preparation of a-Π dibromocamphor
Under cooling,, obtain a-Π dibromocamphor with carrying out bromination reaction in a-bromocamphor adding oleum and the bromine;
3. the preparation of Π-oxycamphor
In Potassium ethanoate, glacial acetic acid solution, add a-Π dibromocamphor and carry out esterification reaction, get X-bromo-π-acetyl oxycamphor; The adding neutralized verdigris carries out reduction reaction and gets π-acetyl oxycamphor; Add potassium hydroxide, ethanol be hydrolyzed react Π-oxycamphor solution; Add chloroform and extract, the crystallization of solubilizing agent oil gets Π-oxycamphor;
4. the preparation of Π-vitacampher
Π-oxycamphor is soluble in water, adding sulfuric acid, sodium dichromate 99, methionine(Met) carry out oxidizing reaction, get vitacampher solution, add yellow soda ash and obtain the vitacampher neutralizer, add sodium bisulfite and carry out addition reaction, extract with ether and to obtain vitacampher addition liquid, add yellow soda ash once more and carry out decomposition reaction, get the vitacampher ether solution with extracted with diethyl ether, add yellow soda ash after concentrating and carry out alkali cleaning, the adding distil water washing adds Calcium Chloride Powder Anhydrous, carbon element, and dehydration and decolorization obtains vitacampher.
2, the described synthesis technique of claim 1 is characterized in that:
(1) in 6kg camphor, add chloroform 1000～2000ml, heat 60～80 ℃, agitation and dropping 6～7kg bromine in 3～8 hours, heat temperature raising to 100～110 ℃ kept temperature 2 hours～3 hours then, promptly reached reaction end, after the discharging cooling crude product
-bromocamphor; By 1: (1～2) weight ratio will
-bromocamphor product is dissolved in and carries out recrystallization in the ethanol, the lucifuge seasoning,
-bromocamphor product;
(2) contain SO in preparation
3Among oleum 20～24kg of 3～6%, below 20 ℃, agitation condition drops into down 3.6～4.4kg bromine, stir, with step (1) gained
-bromocamphor input, temperature of reaction is controlled below 40 ℃, and heated up 2～4 hours naturally in the back that feeds intake, and heating is raised to 18～25 ℃, reacts and reaches reaction end in 7～10 days;
Pouring reactant into frozen water mixed solution 60～80kg that 1:1 is housed decomposes in the bottle, add 10～20L chloroform extraction again, isolate acid solution water,, divide disacidify water to get trichloromethane liquid again with the clear water methyl chloride liquid of giving a baby a bath on the third day after its birth, change in the crystallization bottle, after reclaiming trichloromethane, 60～70 ℃ of leftover materials coolings under agitation add methyl alcohol 5～10L crystallisation by cooling and filter, xln soaks after-filtration with 2～5L methyl alcohol again and gets dibromocamphor, seasoning;
(3) in the dibromocamphor of step (2) gained, add Glacial acetic acid 1.3～2.7kg successively, Potassium ethanoate 4～6kg heated 170～200 ℃ of beginning back flow reaction 20～24 hours, added neutralized verdigris 0.4～0.6kg, reacted and promptly reached reaction end in 4～6 hours; After adding boiling water, add ethanol 0.8～1L of 95% again, be cooled to 40 ℃, the ratio that adds 2～3kg potassium hydroxide in 2L water adds potassium hydroxide solution, and temperature keeps below 7 ℃, reflux 2 hours, add water 10～15L, adding trichloromethane 20～30L extraction oxycamphor below 40 ℃; Reclaim trichloromethane, residual solution is under agitation put into 3～6L solvent oil, and is static more than 8 hours, and suction filtration is drying to obtain the oxycamphor crystallization;
(4) get the oxycamphor of step (3) gained, add the boiling water dissolving, add sodium dichromate 99 440～520g, methionine(Met) 10～16g, 60% sulfuric acid, 400～600ml heats 58～64 ℃ of reactions 1 hour, add sodium dichromate 99 200～280g and 60% sulfuric acid, 360～400ml again, stir, reacted 30 minutes, reach reaction end, cooling is below 25 ℃, under agitation add yellow soda ash 600～640g, in and PH reach between 5～6,3.6kg sodium bisulfite and 5.2L ether are added stir again, after 1 hour, add 3.6kg yellow soda ash and decompose, decomposed solution does not have alcohol ether with 440L again and extracts vitacampher in decomposing, and the redistillation of gained vitacampher ether solution is reclaimed ether and concentrated, wash with 5% aqueous sodium carbonate 40ml, separating reaction liquid washes with water again, branch vibration layer, alkali lye; Water liquid is again with ether solution extraction, adds Calcium Chloride Powder Anhydrous 80～120g after medicine ether is merged branch vibration layer, activated carbon 20g fully vibrates, and places, and filters filtrate and reclaims ether when closely dried, drain with vacuum tightness again, vitacampher.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2624244C1 (en) * | 2016-02-10 | 2017-07-03 | Открытое акционерное общество "Ирбитский химико-фармацевтический завод" | Method of obtaining bromcumphorus |
| CN110540495A (en) * | 2018-05-28 | 2019-12-06 | 江苏柯菲平医药股份有限公司 | synthetic process of camphor oxide |
| CN110538141A (en) * | 2018-05-28 | 2019-12-06 | 江苏柯菲平医药股份有限公司 | oxycocamphor injection and preparation method thereof |
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| RU2613198C1 (en) * | 2016-02-17 | 2017-03-15 | Открытое акционерное общество "Ирбитский химико-фармацевтический завод" | Method for racemic camphor bromide preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2624244C1 (en) * | 2016-02-10 | 2017-07-03 | Открытое акционерное общество "Ирбитский химико-фармацевтический завод" | Method of obtaining bromcumphorus |
| CN110540495A (en) * | 2018-05-28 | 2019-12-06 | 江苏柯菲平医药股份有限公司 | synthetic process of camphor oxide |
| CN110538141A (en) * | 2018-05-28 | 2019-12-06 | 江苏柯菲平医药股份有限公司 | oxycocamphor injection and preparation method thereof |
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