CN106854163B - A kind of preparation process of Doxycycline Hyclate intermediate hydride - Google Patents
A kind of preparation process of Doxycycline Hyclate intermediate hydride Download PDFInfo
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- CN106854163B CN106854163B CN201611218593.4A CN201611218593A CN106854163B CN 106854163 B CN106854163 B CN 106854163B CN 201611218593 A CN201611218593 A CN 201611218593A CN 106854163 B CN106854163 B CN 106854163B
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- C07—ORGANIC CHEMISTRY
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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Abstract
The invention discloses a kind of preparation processes of Doxycycline Hyclate intermediate hydride.The preparation process includes: that the dewatering pan containing HF is added in dried terramycin chloro thing, and reaction is dehydrated, and after standing, is concentrated by evaporation and removes HF, concentrate is received with methanol；With the methanol solution in calcium hydroxide or lime powder and after reception concentrate；Methanol solution after neutralization is in the presence of Pd/C catalyst and inhibitor, and after hydrogenation reaction, filtering, gained filtrate reacts into salt with sulfosalicylic acid methanol solution, can obtain Doxycycline Hyclate intermediate hydride.Preparation process of the invention is not necessarily to p-methyl benzenesulfonic acid, and process is simple to operation, and production cost substantially reduces.
Description
Technical field
This application involves Doxycycline Hyclate the field of chemical synthesis more particularly to a kind of Doxycycline Hyclate intermediate to hydrogenate
The preparation process of object.
Background technique
The main process of Doxycycline Hyclate preparation at present is using terramycin as starting material, through chloro, dehydration, hydrogen
Change, convert, being made at processes such as salt.Terramycin chloro thing is after being dehydrated with p-methyl benzenesulfonic acid at salt, formation 11 α of dehydrate-chlorine
Generation -4- (dimethylamino) -3,5,10,12 α-tetrahydroxy -1,11,12- trioxy- -1,4,4 α, 5,5 α, 6,11,11 α, 12,12 α -
Decahydro -2- aphthacene formamide tosilate.The dehydrate is in alcohol solvent and after Pd/C and auxiliary material catalytic hydrogenation, with
Sulfosalicylic acid prepares 6 Alpha-Methyl -4- (dimethylamino) -3,5,10,12,12 α-penta hydroxy group -1,11- dioxos -1,4,4 at salt
α, 5,5 α, 6,11,12 α-octahydro -2- aphthacene formamide sulfonate, i.e. Doxycycline Hyclate intermediate hydride.
It can be seen that terramycin chloro thing is through HF in traditional method for preparing Doxycycline Hyclate intermediate hydride
It is needed after dehydration with a large amount of p-methyl benzenesulfonic acid at the raw material that just can be used as hydrogenation after salt, crystallization, filtering, so that production
The recovery difficult of increased costs, paratoluenesulfonic acid sodium salt and sulfosalicylic acid sodium salt also increases.
Summary of the invention
The operational sequence of Doxycycline Hyclate intermediate hydride is prepared for reduction, reduces production cost, and the present invention provides
A kind of preparation process of Doxycycline Hyclate intermediate hydride, includes the following steps:
Terramycin generates chloro thing after chlorination；
The dewatering pan containing HF is added after pneumatic conveying drying removes methanol, by dried chloro thing in chloro thing, is stirred to react 8
After~10 hours, feed liquid is put into hugging and stands 6~8 hours；
The reaction mechanism is as follows for this step:
Feed liquid in hugging is concentrated by evaporation by film evaporator and removes HF, the feed liquid after being concentrated, after the concentration
Feed liquid received while stirring with methanol solution, while controlling and receiving the methanol solution temperature of concentrate at 0~25 DEG C；
Methanol solution calcium hydroxide or lime powder neutralization after receiving concentrate do not evaporate most HF, are neutralized
Methanol solution afterwards；
The reaction mechanism is as follows for this step:
2HF+Ca(OH)2=CaF2+2H2O
2HF+CaO=CaF2+H2O
The methyl alcohol mixed liquor that catalyst containing Pd/C and inhibitor are prepared in hydrogenation reaction cauldron, by the methanol after the neutralization
Solution vacuum is transferred in the hydrogenation reaction cauldron for being loaded with the methyl alcohol mixed liquor, is added pure water, is made methanol body in whole system
Fraction is 30~80%, replaces the air in the hydrogenation reaction cauldron with nitrogen, reaction temperature and hydrogen at 45~65 DEG C
Under conditions of pressure is 0.35~0.6Mpa, after hydrogenation reaction 4~5 hours, reaction solution is obtained；The reaction solution is passed through into filtering
Device removes Pd/C, crosses cleaner liquid and adds sulfosalicylic acid methanol solution at salt, obtains Doxycycline Hyclate intermediate hydrogen after crystallization, filtering
Compound.
The reaction mechanism is as follows for this step:
In above-mentioned steps provided by the present invention, known side can be adopted by known method or be similar to chloro thing
It is prepared by method.For example, chloro thing can be prepared with terramycin and acetochloroanilide.
In above-mentioned steps provided by the present invention, the weight ratio of the chloro thing and HF is 1:1.5~2, preferably 1:
2.Controlling dewatering pan to add the temperature of chloro thing by chilled brine collet is 0~10 DEG C, after being stirred to react 8~10h, stands 6
~8h, preferably 5~10 DEG C, be stirred to react 8h, stand 6h.
In above-mentioned steps provided by the present invention, the feed liquid in hugging, which is preferably concentrated by falling film evaporator, removes HF.
Receive the preferred methanol of organic solvent of concentrated liquid.It should be noted that in real reaction, if using 100 kilograms of chloros
Object, the methanol volume for receiving concentrated liquid is preferably 200L-300L, and the amount of methanol volume used herein is by reaction kettle size
Limitation.In addition, it is necessary to control and receive the temperature of the methanol solution of concentrate at 0~25 DEG C, preferably 5~15 DEG C.
In above-mentioned steps provided by the present invention, since the pH of the methanol solution after reception concentrate is less than 1, in solution
Containing not evaporating most HF, the calcium hydroxide or lime powder that powder particle size can be used less than 300 mesh neutralize HF.Example
Such as, 100 kilograms of calcium hydroxides or lime powder can be dispersed in the methanol of 300~500L, is uniformly mixing to obtain hydrogen-oxygen
Change calcium or calcium oxide methanol slurry；It is cold while stirring in methanol solution after the slurries to be slowly added dropwise to reception concentrate
But, the methanol solution temperature after controlling and receiving concentrate is 5~25 DEG C, preferably 5~15 DEG C.Methanol after receiving concentrate
When pH value of solution is 3~5, stop that the slurries are added dropwise.The calcirm-fluoride solid generated is removed with filter, washs fluorine with a small amount of methanol
Change calcium solid, filtered fluid is merged with cleaning solution, the methanol solution after being neutralized.
In above-mentioned steps provided by the present invention, the weight ratio of the chloro thing and Pd/C catalyst be 1:0.1~
0.15, preferably 1:0.1.The inhibitor is quinoline, methylthiouracil, pyridine or lead acetate, preferably quinoline.It is described
The weight ratio of Pd/C catalyst and the inhibitor is 10~15:1, preferably 10:1.In step of hydrogenation, need according to aforementioned step
The volume of methanol used in rapid adds pure water into the hydrogenation reaction cauldron, contains the volume of methanol in the hydrogenation reaction cauldron
Amount is 30~80%, preferably 40~60%, most preferably 50%.Hydrogenation temperature can control at 45~65 DEG C, preferably
It is 60~65 DEG C, most preferably 60 DEG C.Hydrogen Vapor Pressure can control in 0.35~0.6Mpa in the hydrogenation reaction cauldron.
In above-mentioned steps provided by the present invention, the weight ratio of chloro thing and sulfosalicylic acid is 1:0.7~0.8, excellent
It is selected as 1:0.75.
The method for preparing Doxycycline Hyclate intermediate hydride of the invention is used after terramycin chloro thing is reacted with HF
Methanol receives, without with p-methyl benzenesulfonic acid, at salt, crystallization, filtering, hydrogenation can directly being carried out after neutralization, adds sulfosalicylic acid
After salt, crystallization, filtering, Doxycycline Hyclate intermediate hydride is obtained.Of the invention prepares Doxycycline Hyclate intermediate
The method of hydride reduces operational sequence, reduces production cost；The recovery difficult for reducing sulfosalicylic acid sodium salt, improves
The rate of recovery and product purity of sulfosalicylic acid sodium salt；Energy consumption is reduced, reduces disposal of three wastes cost, improves enterprise product
Competitiveness.
Specific embodiment
Below by embodiment to further illustrate the technical scheme of the present invention.The following examples are not constituted to the present invention
The limitation of technical solution, to those skilled in the art, technical characteristic can modify under the teachings of the present invention.
Embodiment 1
Terramycin generates chloro thing after chlorination, and chloro thing removes methanol through pneumatic conveying drying.It is public by dried 100
In jin chloro thing sucking dehydration pot, by HF in dehydration pot: the weight ratio of chloro thing is that 1.5:1 prepares 150 kilograms
HF, and it is cooled to -20 DEG C or less in advance with chilled brine collet.It is stirred when sucking chloro thing, control sucks the reaction temperature of chloro thing
Degree is 5~10 DEG C, continues to be stirred to react 8 hours, stops stirring, stands 6 hours.By the dehydration feed liquid of end of reaction, pass through drop
Film evaporator concentration removes HF.Liquid after concentration can be with the 200L methanol received in kettle to receive, and is pressed from both sides with chilled brine
Set by 200L methanol be cooled in advance 0 DEG C hereinafter, then while open stir while receive, control and receive the temperature of the methanol solution of concentrate
At 0~25 DEG C.
Due to not evaporating most HF containing part in the methanol solution after reception concentrate, pH is less than 1.Hydrogen-oxygen can be used
Change calcium powder (powder particle size is less than 300 mesh) Lai Zhonghe HF, concrete operations are as follows: 100 kilograms of calcium hydroxide powder are dispersed
In the methanol of 300L, stir evenly to form calcium hydroxide methanol slurry.First after slurries to be slowly added dropwise to reception concentrate
It in alcoholic solution, cools down while stirring, the methanol solution temperature after controlling and receiving concentrate is 5~25 DEG C, is added dropwise to reception concentration
When methanol solution pH after liquid is 3, stop being added dropwise.Methanol solution after reception concentrate is passed through into filter and removes the fluorine generated
Change calcium solid, and washs calcirm-fluoride solid with a small amount of methanol.Merge filtered fluid and cleaning solution, it is molten to obtain the methanol that neutralization finishes
Liquid, it is spare.
The scattered Pd/C of methanol and inhibitor quinoline will be used (by weight chloro thing: Pd/C: quinoline=100:10:1)
It is added in hydrogenation reaction cauldron.The methanol solution that neutralization is finished again, is transferred to the hydrogenation reaction cauldron with vacuum.It adds a certain amount of
Pure water, make methanol volume content 40% in whole system.The air in the hydrogenation reaction cauldron is replaced with nitrogen, unlatching is stirred
It mixes, heating is to slowly warm up to 45~65 DEG C, adds hydrogen, control Hydrogen Vapor Pressure in 0.35~0.45Mpa.Hydrogenation reaction 4~5 hours
Afterwards, stop stirring, the hydrogen being vented in the hydrogenation reaction cauldron is replaced 3 times with nitrogen, by reaction material liquid by filter, is gone
Except Pd/C.75kg sulfosalicylic acid is dissolved with the methanol aqueous solution of 100L volume fraction 30%.By filtered fluid and sulfosalicylic acid
Methanol solution mixing, stirring crystallize into salt in 2 hours.Filtering for crystallizing object removes mother liquor, with the methanol aqueous solution of volume fraction 50%
Filter cake is washed, obtained solid is Doxycycline Hyclate intermediate hydride.Wherein, relative to chloro thing, the receipts of hydride
Rate is up to 75~80%, and the content of beta isomer is less than 5%.
In addition, when producing Doxycycline Hyclate using the technique for preparing Doxycycline Hyclate intermediate hydride, sulfo group
The rate of recovery of sodium salicylate is up to 90~93%.
Embodiment 2
Terramycin generates chloro thing after chlorination, and chloro thing removes methanol through pneumatic conveying drying.It is public by dried 100
In jin chloro thing sucking dehydration pot, by HF in dehydration pot: chloro thing weight ratio prepares 200 kilograms of HF for 2:1, and
It is cooled to -20 DEG C or less in advance with chilled brine collet.It is stirred when sucking chloro thing, the reaction temperature that control sucks chloro thing is 0
~5 DEG C, continue to be stirred to react 10 hours, stop stirring, stands 8 hours.By the dehydration feed liquid of end of reaction, pass through falling film evaporation
Device concentration removes HF.Liquid after concentration is received with the 300L methanol received in kettle, and with chilled brine collet by 300L methanol
In advance be cooled to 0 DEG C hereinafter, then while open stirring while receive, control and receive the temperature of the methanol solution of concentrate at 0~15 DEG C.
Due to not evaporating most HF containing part in the methanol solution after reception concentrate, pH is less than 1.Oxidation can be used
Calcium powder (powder particle size is less than 300 mesh) Lai Zhonghe does not evaporate most HF, and concrete operations are as follows: by 100 kilograms of calcium oxide powders
End is dispersed in the methanol of 500L, stirs evenly to form calcium oxide methanol slurry.After reception concentrate is slowly added dropwise in slurries
Methanol solution in, cool down while stirring, the methanol solution temperature after controlling and receiving concentrate be 5~15 DEG C, be added dropwise to reception
When methanol solution pH after concentrate is 5, stop being added dropwise.Methanol solution after reception concentrate is passed through into filter and removes generation
Calcirm-fluoride solid, and wash calcirm-fluoride solid with a small amount of methanol.Merge filtered fluid and cleaning solution, obtains neutralizing the methanol finished
Solution, it is spare.
The scattered Pd/C of methanol and inhibitor quinoline will be used (by weight chloro thing: Pd/C: quinoline=100:15:1)
It is added in the hydrogenation reaction cauldron.The methanol solution that neutralization is finished again, is transferred to the hydrogenation reaction cauldron with vacuum.Addition one
Quantitative pure water makes methanol volume content 60% in whole system.The air in the hydrogenation reaction cauldron is replaced with nitrogen, is opened
Stirring is opened, heating is to slowly warm up to 45~65 DEG C, adds hydrogen, controls Hydrogen Vapor Pressure in 0.45~0.6Mpa.Hydrogenation reaction 4~5 is small
Shi Hou stops stirring, and the hydrogen being vented in the hydrogenation reaction cauldron is replaced 3 times with nitrogen, and reaction material liquid is passed through filter,
Remove Pd/C.75kg sulfosalicylic acid is dissolved with the methanol aqueous solution that 100L volume fraction is 50%.By filtered fluid and sulfo group water
The mixing of poplar acid methanol solution, stirring crystallize into salt in 2 hours.Filtering for crystallizing object removes mother liquor, washs filter cake with pure methanol, obtain
Solid be Doxycycline Hyclate intermediate hydride.Wherein, relative to chloro thing, the yield of hydride up to 73~
79%, the content of beta isomer is less than 2%.
In addition, when producing Doxycycline Hyclate using the technique for preparing Doxycycline Hyclate intermediate hydride, sulfo group
The rate of recovery of sodium salicylate is up to 90~95%.
Comparative example
Terramycin generates chloro thing after chlorination, and chloro thing removes methanol through pneumatic conveying drying.It is public by dried 100
In jin chloro thing sucking dehydration pot, by HF in dehydration pot: the weight ratio of chloro thing is that 2:1 prepares 200 kilograms of HF,
And chilled brine collet is cooled to -20 DEG C or less in advance.It is stirred when sucking chloro thing, the reaction temperature that control sucks chloro thing is 0
~5 DEG C, continue to be stirred to react 10 hours, stop stirring, stands 8 hours.By the dehydration feed liquid of end of reaction, pass through falling film evaporation
Device concentration removes HF.Liquid after concentration is received with the 300L ethyl alcohol received in kettle, and with chilled brine collet by 300L ethyl alcohol
It is cooled to 0 DEG C in advance hereinafter, then receiving when opening stirring, the temperature of the ethanol solution after controlling and receiving concentrate is less than 25 DEG C.
Ethanol solution after receiving concentrate is stirred with being mixed with 100 kilograms of p-methyl benzenesulfonic acid that 200L ethyl alcohol has dissolved
Salt crystallization is mixed, stops stirring, the cooling and standings of collet brine ice 8 hours or more after crystallization, blowing is separated by solid-liquid separation, centrifugation 2
Hour, by filter cake crushing packing, for use.The ethanol water that 300L ethanol content is 40% is added in hydrogenation reaction cauldron, adds
Enter 15 kilograms of Pd/C and 1 kilogram of quinoline (by weight chloro thing: Pd/C: quinoline=100:15:1), the filter cake powder that will be crushed
Material is added in the hydrogenation reaction cauldron.The air in the hydrogenation reaction cauldron is replaced with nitrogen, opens stirring, heats slowly heating
To 45~65 DEG C, add hydrogen, control Hydrogen Vapor Pressure in 0.45~0.6Mpa.After hydrogenation reaction 4~5 hours, stop stirring, is vented institute
The hydrogen in hydrogenation reaction cauldron is stated, is replaced 3 times with nitrogen, by reaction material liquid by filter, removes Pd/C.It is molten with 100L ethyl alcohol
It terminates an agreement 75 kilograms of sulfosalicylic acids.Filtered fluid is mixed with sulfosalicylic acid ethanol solution, stirring crystallizes into salt in 2 hours.Filtering
Crystal removes mother liquor, is Doxycycline Hyclate intermediate hydride with the solid that ethanol washing filter cake obtains, wherein phase
For chloro thing, for the yield of hydride up to 65~70%, the content of beta isomer is 8~10%.
In addition, when producing Doxycycline Hyclate using the technique for preparing Doxycycline Hyclate intermediate hydride, sulfo group
The rate of recovery of sodium salicylate is only 50~60%.
To sum up, the hydrogenation of Doxycycline Hyclate intermediate can be prepared in technique of the invention without using p-methyl benzenesulfonic acid
Object reduces operational sequence, reduces production cost, reduces the recovery difficult of sulfosalicylic acid sodium salt, improves sulfosalisylic
The rate of recovery and product purity of sour sodium.
It is the preferable embodiment of the present invention above, wherein the operation that do not address in detail is those of ordinary skill in the art
Common knowledge.Protection scope of the present invention is based on the contents of the claims, it is any based on technique enlightenment of the invention and into
Capable process modification, also within the protection scope of the present invention.
Claims (8)
1. a kind of preparation process of Doxycycline Hyclate intermediate hydride, which comprises the steps of:
The dewatering pan containing HF is added in dried terramycin chloro thing and carries out 8~10h of dehydration, after completing dehydration,
6~8h is stood, is concentrated by evaporation by falling film evaporator and removes HF, obtain concentrate；
Receive the concentrate with methanol, and control and receive concentrate methanol solution temperature at 0~25 DEG C；
With in calcium hydroxide or lime powder and receiving the methanol solution after concentrate, methanol solution after being neutralized；
The methyl alcohol mixed liquor of catalyst containing Pd/C and inhibitor is prepared in hydrogenation reaction cauldron,
Methanol solution vacuum after the neutralization is transferred in the hydrogenation reaction cauldron for being loaded with the methyl alcohol mixed liquor, Xiang Suoshu
Pure water is added in hydrogenation reaction cauldron, makes methanol volume content 30~80%,
Under conditions of 45~65 DEG C of reaction temperatures and Hydrogen Vapor Pressure are 0.35~0.6Mpa, in the hydrogenation reaction cauldron into
Row hydrogenation reaction 4~5 hours, obtain reaction solution；
The reaction solution is removed into the Pd/C catalyst by filter, obtains filtrate；
Add sulfosalicylic acid methanol solution at salt the filtrate, after crystallization, filtering, obtains the hydrogenation of Doxycycline Hyclate intermediate
Object.
2. preparation process according to claim 1, which is characterized in that the terramycin chloro thing and the weight ratio of HF are 1:
1.5~2.
3. preparation process according to claim 1, which is characterized in that further include:
The terramycin chloro thing is being added to the dewatering pan, is being by the temperature that chilled brine collet controls the dewatering pan
0~10 DEG C.
4. preparation process according to claim 1, which is characterized in that described to be connect with calcium hydroxide or lime powder neutralization
Methanol solution after receiving concentrate, includes the following steps:
Powder particle size is dispersed in methyl alcohol, to stir to get calcium hydroxide less than the calcium hydroxide or lime powder of 300 mesh
Or calcium oxide methanol slurry；
The methanol solution after receiving concentrate is added in the slurries, is cooled down while stirring, and control and receive the first after concentrate
Alcoholic solution temperature is 5~25 DEG C, when receiving the methanol solution pH after concentrate is 3~5, stops that the slurries are added；
The calcirm-fluoride solid generated is removed with filter, obtains filtered fluid；
Filtered out calcirm-fluoride solid is washed with a small amount of methanol, and the filtered fluid is merged with cleaning solution, after obtaining neutralization
Methanol solution.
5. preparation process according to claim 1, which is characterized in that the inhibitor is quinoline, methylthiouracil, pyrrole
Pyridine or lead acetate.
6. preparation process according to claim 1, which is characterized in that the terramycin chloro thing and the Pd/C catalyst
Weight ratio be 1:0.1~0.15.
7. preparation process according to claim 1, which is characterized in that the weight of the Pd/C catalyst and the inhibitor
Than for 10~15:1.
8. preparation process according to claim 1, which is characterized in that the weight of the terramycin chloro thing and sulfosalicylic acid
Amount is than being 1:0.7~0.8.
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| CN108440330B (en) * | 2018-06-27 | 2021-03-02 | 常州制药厂有限公司 | Preparation method of doxycycline hydrochloride |
| CN110668969B (en) * | 2019-10-10 | 2022-06-10 | 山东国邦药业有限公司 | Preparation method of methacycline |
| CN111362826B (en) * | 2020-04-20 | 2022-08-26 | 山东国邦药业有限公司 | Preparation method of doxycycline intermediate 11 alpha-chloromethylmethacycline |
| CN114073993A (en) * | 2020-08-13 | 2022-02-22 | 昆山华苏生物科技有限公司 | Method for cleaning waste catalyst in doxycycline hydrochloride hydrogenation reaction |
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| 季明志 等.盐酸多西环素脱水物合成工艺研究.《海峡药学》.2013,第25卷(第9期),第178-179页. |
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Address after: Suzhou City, Jiangsu province 215337 city of Kunshan City Zhou Zhen Kun Tai Road No. 60 Patentee after: Kunshan HuaSu Biotechnology Co., Ltd Address before: 215337, 242 Kun Kun Road, Zhou Town, Suzhou, Jiangsu, Kunshan Patentee before: KUNSHAN HUASU BULK DRUG CO., LTD. |