CN107056641B - A kind of preparation method of fortimicin - Google Patents
A kind of preparation method of fortimicin Download PDFInfo
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- CN107056641B CN107056641B CN201710227183.4A CN201710227183A CN107056641B CN 107056641 B CN107056641 B CN 107056641B CN 201710227183 A CN201710227183 A CN 201710227183A CN 107056641 B CN107056641 B CN 107056641B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention discloses a kind of preparation methods of fortimicin, belong to technical field of medicine synthesis.A kind of technical solution of the present invention main points are as follows: preparation method of fortimicin, specifically include preparation, the synthesis of 11 α-bromo- 6,12- hemiketal terramycin, the synthesis of 11 α-bromo- 6- methine terramycin p-methyl benzenesulfonic acid, the synthesis of α -6- debrominate terramycin tosilate and the synthesis of doxycycline hydrochloride finished product of chiral catalyst.The present invention selects homemade chiral catalyst to add hydrogen, debrominate, improves the production technology of fortimicin, improves yield, reduces industrial production cost, and chiral catalyst used can regenerate repetitive cycling use.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of preparation method of fortimicin.
Background technique
Antibiotic is a kind of drug at most most wide in antimicrobial.In the early 1940s, benzyl penicillin is promoted for clinical
The improvement of antibacterials and the development for accelerating antibacterials.Antibiotic is previously referred to as antibiotic, is the secondary of microorganism
Metabolite or the analog of synthesis, can inhibit the growth and survival of microorganism in vitro, and not generate to host cell serious
Toxic side effect.In clinical treatment, most antibiotic are able to suppress the infection of bacterium, for bacterial infection disease
It prevents and treats.Actually it can not only kill virus and bacteria, and can cause machine to mould, mycoplasma, Chlamydia etc. are other
The microorganism of body-sensing dye also has good inhibition and deactivation, and original name antibiotic is renamed as to present antibiosis in recent years
Element.Antibiotic medicine is the active metabolite extracted from the culture solution of microorganism, and some in fermentation liquid after extracting
Preparation, which is made, to be applied to clinic after modifying for chemical structure and improvement using clinically, having plenty of.It is briefly summarized
It says, antibiotic is exactly that can eliminate and inhibit the various microbial bacterial antimicrobial DP finish that can cause organism infection or morbidity.
Fortimicin is a kind of semi-synthetic tetracycline antibiotics for the long-acting, broad-spectrum being processed by terramycin, antibacterial
Wide spectrum and antibacterial action is strong may also suppress Richettsia, pneumonia branch original except there is effect outer to gram-positive bacteria and negative bacterium
Body, sand holes mycoplasma and Amoeba etc..It is especially more sensitive to the respiratory tract common bacteria of chronic bronchitis patient.Simultaneously
With certain antibechic, eliminating the phlegm and antiasthmatic effect.In addition, the medicine is also widely used in veterinary drug, a variety of germ infection are treated.
The market demand of fortimicin is very big, reaches 5000-6000 tons every year, and only China is producing now, is mainly breaking a seal, is raising
The ground such as state, Hebei and Yancheng.However original production technology is primarily present that environmental pollution is serious, atom is uneconomical and production cost
The disadvantages of high, this also exactly in the world it is other country not the reproduction product the main reason for.Although China is still producing now,
Considerable economic benefit is also obtained, but brought using sacrificialing environment and resource as cost.Therefore, it is necessary in original base
New fortimicin green synthesis process is developed on plinth, to reduce environmental pollution and reduce cost.
The production technology of fortimicin is to obtain the chloro- 6- first of 11 α-through chloro and dehydration using terramycin as raw material at present
Then base terramycin tosilate obtains 6- methyl terramycin salt through a step hydrogenization method or two step hydrogenization methods, finally turns salt
Be refining to obtain fortimicin, wherein chloro, be dehydrated and to turn salt refining technics comparing mature, and hydrogenating is that stereoselectivity is anti-
It answers, that there are stereoselectivities is poor, yield is low in this step reaction, the cost of manufacture of catalyst height and the disadvantages of environmental pollution, technique
It need to be further improved.
In step of hydrogenation, the hydrogenation route industrially used at present has: catalyst used in a step hydrogenization method is poison
Change palladium carbon or silica gel bonded triphenylphosphine radium chloride, since 6 of product 6- methyl terramycin tosilate are chirality
Carbon atom, there are α and two kinds of isomers of β, and wherein the bioactivity of biological activity ratio's beta isomer of αisomer is big, are that target produces
Object, beta isomer, which needs to refine, to be removed.The palladium carbon poisoned is heterogeneous catalysis, and stereoselectivity is poor, and the content of beta isomer can
Up to 10%, the yield of αisomer is only 60%, and advantage is the renewable recycling of catalyst.Silica gel bonded triphenylphosphine chlorination
Rhodium, stereoselectivity is good, and yield is up to 90%, and the content of beta isomer is then lower than 2%, and catalyst secondary less can be reused, but it is made
Make to need special silica gel first and bridging agent bonding, then again with Rh (PPh3)3Cl bonding, it is cumbersome, but also one can be lost
Expensive Rh (the PPh in part3)3Cl, therefore the higher cost of catalyst.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of preparation method of fortimicin, selected certainly in the preparation method
The chiral catalyst of system adds hydrogen, debrominate, improves the production technology of fortimicin, improves yield, reduce industrial production at
This, and chiral catalyst used being capable of regeneration cycle use.
The present invention adopts the following technical scheme that a kind of preparation method of fortimicin is special to solve above-mentioned technical problem
Sign is specific steps are as follows:
A, inorganic supported compound calcium carbonate or hydroxyl phosphorus is added in equipped with thermometer and churned mechanically reaction vessel
Lime stone adds saturation ammonium acetate solution, and reaction solution is warming up to 100 DEG C of holding 2h, is down to room temperature suction filtration, filter cake deionization
Water washing adds the hydrogen peroxide that molar concentration is 1mol/L, is warming up to 40 DEG C of holding 1h, be down to room temperature suction filtration, dry to neutrality
It is dry to obtain pretreated inorganic supported compound；
B, metal chloride palladium chloride or platinous chloride and methanol are added in the reaction vessel, adds carboxymethyl cellulose
Plain sodium is 4.5 with the pH of sodium carbonate regulation system, pretreated inorganic supported compound is then added, 2h is stirred at room temperature
After be put into autoclave, under conditions of 100KPa, 100 DEG C stir hydrogenation reduction 2h, decompression filter, rushed with deionized water
It is washed till neutrality and through silver nitrate solution detection without chloride ion, dry 3h obtains chiral catalyst under the conditions of 60 DEG C of normal pressure, the hand
Property catalyst be palladium/calcium carbonate, platinum/calcium carbonate, palladium/hydroxyapatite or platinum/hydroxyapatite；
C, successively methanol, Oxytetracycline Base and methanol ammonia are placed in reaction vessel, it is cooling after 20 ~ 30 DEG C of stirring 30min
To -10 ~ -15 DEG C, the primary NBS that drying and crushing is added simultaneously stirs 15min, and TLC monitors raw material fully reacting, has in reaction solution big
It measures solid to be precipitated, rejection filter is washed with cold methanol up to 11 α-bromo- 6,12- hemiketal terramycin；
D, the benzene for crossing Non-aqueous processing is added in the reaction kettle with dehydration device, and nitrogen is passed through into reaction kettle,
11 α-bromo- 6,12- hemiketal terramycin is added under stirring condition, adds hydroxyls dehydrate agent T-Al2O3, first at room temperature
2h is stirred, then is warming up to the water of back flow reaction and the generation of discharge reaction in time, is cooled to 50 after TLC monitoring raw material fully reacting
DEG C, reaction solution is filtered while hot, filters out the hydroxyls dehydrate agent T-Al of solid2O3, reaction dissolvent benzene is evaporated off in filtrate, and raffinate doubles
The ethyl alcohol of amount dilutes, and it is 1 ~ 2 that the ethanol solution for adding ammonia, which is neutralized to pH, is cooled to 0 DEG C of rejection filter, with cold ethanol washing, is filtering
P-methyl benzenesulfonic acid is added in liquid, and crystal seed is added, crystallization is precipitated, then be cooled to 0 DEG C of rejection filter, 11 α-bromo- 6- is obtained with cold ethanol washing
Methine terramycin p-methyl benzenesulfonic acid；
E, first DMF is placed in reaction vessel, 11 α-bromo- 6- methine terramycin p-methyl benzenesulfonic acid and chiral catalysis is added
10min is stirred in agent, is added tosilate and is stirred evenly, and sucking hydrogenation fills, and is closed valve, is evacuated to 40mm mercury with vacuum pump
Column maintains 15min, and hydrogen is passed through at 30 ~ 35 DEG C, keeps 1.5 ~ 2 kilograms/cm of internal pressure2, it is passed through hydrogen 2h under stiring to suction
TLC is in sampling when hydrogen is slow, and methine terramycin continues to be passed through hydrogen reaction 2h when being micro, stops reaction, hydrogen is discharged
When to internal pressure being zero, it is passed through nitrogen and rushes remaining hydrogen, be heated to 50 DEG C and be passed through nitrogen, filtered by filter press, be with content
The abundant pressure filtration washing of DMF solution gradation of 10wt% ~ 50wt%, then it is washed with distilled water repetitive cycling use after chiral catalyst,
Filtrate merges with washing lotion in sucting reaction kettle, and DMF content in solution is made to be cooled to 5 DEG C of centrifugal rejection filters in 40wt% ~ 42wt%, filter
Cake is primary with cold ethanol washing, and drying obtains α -6- debrominate terramycin tosilate；
F, hydrogen chloride-dehydrated alcohol and α -6- debrominate terramycin tosilate are sequentially added into reaction vessel, are added
Heat reflux 1h, is cooled to 40 DEG C, and concentrated hydrochloric acid and active carbon is added, stops stirring after 5min, filtering, crystal seed is added in filtrate,
40 ~ 50 DEG C of stirring 3h, are cooled to 10 DEG C of filterings, are successively washed with hydrogen chloride-dehydrated alcohol and dehydrated alcohol, strength obtained by drying
Mycin hydrochloride finished product.
Compared with the prior art, the invention has the following beneficial effects: the present invention select homemade chiral catalyst add hydrogen,
Debrominate improves the production technology of fortimicin, improves yield, reduces industrial production cost, and chirality used is urged
Agent being capable of repetitive cycling use.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
Calcium carbonate 200g is added in equipped with thermometer and churned mechanically 1000mL reaction flask, saturation acetic acid is then added
Reaction solution is warming up to 100 DEG C of holding 2h by ammonium salt solution 100mL, is down to room temperature suction filtration, and filter cake is washed with deionized to neutrality,
The hydrogen peroxide that a certain amount of molar concentration is 1mol/L is added, 40 DEG C of holding 1h are warming up to, is down to room temperature suction filtration, drying obtains
Pretreated calcium carbonate 190g.
Embodiment 2
Hydroxyapatite 200g is added in equipped with thermometer and churned mechanically 1000mL reaction flask, saturation is then added
Reaction solution is warming up to 100 DEG C of holding 2h by ammonium acetate solution 100mL, is down to room temperature suction filtration, and filter cake is washed with deionized into
Property, the hydrogen peroxide that a certain amount of molar concentration is 1mol/L is added, 40 DEG C of holding 1h are warming up to, is down to room temperature suction filtration, drying
Obtain pretreated hydroxyapatite 191g.
Embodiment 3
Palladium chloride 5g is added in reaction flask, adds methanol 100mL, sodium carboxymethylcellulose 1g is then added, uses
The pH of sodium carbonate regulation system be 4.5, be added calcium carbonate 50g, be put into autoclave after 2h is stirred at room temperature, 100KPa,
Hydrogenation reduction 2h is stirred under the conditions of 100 DEG C, decompression filters, and deionized water is washed till neutrality and detects through silver nitrate solution without chlorine
Ion, dry 3h obtains chiral catalyst palladium/calcium carbonate 46g under the conditions of 60 DEG C of normal pressure.
Embodiment 4
Platinous chloride 5g is added in reaction flask, adds methanol 100mL, sodium carboxymethylcellulose 1g is then added, uses
The pH of sodium carbonate regulation system be 4.5, be added calcium carbonate 50g, be put into autoclave after 2h is stirred at room temperature, 100KPa,
Hydrogenation reduction 2h is stirred under the conditions of 100 DEG C, decompression filters, and deionized water is washed till neutrality and detects through silver nitrate solution without chlorine
Ion, dry 3h obtains chiral catalyst platinum/calcium carbonate 43g under the conditions of 60 DEG C of normal pressure.
Embodiment 5
Palladium chloride 5g is added in reaction flask, adds methanol 100mL, sodium carboxymethylcellulose 1g is then added, uses
The pH of sodium carbonate regulation system is 4.5, and hydroxyapatite 50g is added, is put into autoclave after 2h is stirred at room temperature,
100KPa, hydrogenation reduction 2h is stirred under the conditions of 100 DEG C, decompression filters, and deionized water is washed till neutrality and through silver nitrate solution
Detection is without chloride ion, and dry 3h obtains chiral catalyst palladium/hydroxyapatite 45g under the conditions of 60 DEG C of normal pressure.
Embodiment 6
Platinous chloride 5g is added in reaction flask, adds methanol 100mL, sodium carboxymethylcellulose 1g is then added, uses
The pH of sodium carbonate regulation system is 4.5, and hydroxyapatite 50g is added, is put into autoclave after 2h is stirred at room temperature,
100KPa, hydrogenation reduction 2h is stirred under the conditions of 100 DEG C, decompression filters, and deionized water is washed till neutrality and through silver nitrate solution
Detection is without chloride ion, and dry 3h obtains chiral catalyst platinum/hydroxyapatite 47g under the conditions of 60 DEG C of normal pressure.
Embodiment 7
Successively methanol 100g, Oxytetracycline Base 10g and methanol ammonia 0.1g are placed in a reaction flask, in 20 ~ 30 DEG C of stirring 30min
After begin to cool to -10 ~ -15 DEG C, the primary NBS 5g that drying and crushing is added stirs 15min, and TLC monitors raw material fully reacting,
There are a large amount of solids to be precipitated in reaction flask, by rejection filter machine rejection filter, filter cake is washed with cold methanol up to 11 α-bromo- 6,12- hemiketal
Terramycin 11.6g, yield 97%, after mother liquor is fractionated, gained methanol is applied.
Embodiment 8
The benzene 500mL that Non-aqueous processing is crossed is added in the reaction kettle with dehydration device, nitrogen is passed through in reaction kettle,
It is slowly added into 11 α-bromo- 6,12- hemiketal terramycin 10g under stirring, adds hydroxyls dehydrate agent T-Al2O3 2g, first in room temperature
Under the conditions of stir 2h, then be to slowly warm up to flow back and the water T-Al generated of discharge reaction in time2O3, TLC monitoring raw material reacted
Quan Hou, slow cooling filter reaction solution to 50 DEG C while hot, filter out the hydroxyls dehydrate agent of solid, and reaction dissolvent benzene is evaporated off in filtrate,
The ethyl alcohol of the raffinate amount of doubling dilutes, and it is 1 ~ 2 that the ethanol solution (7wt%) for being slowly added into ammonia, which is neutralized to pH, is cooled to 0 DEG C, gets rid of
Filter, is washed with cold ethyl alcohol 200mL, and p-methyl benzenesulfonic acid 5g is added in filtrate, and a small amount of crystal seed is added, crystallization is precipitated, and is cooled to 0 DEG C
Rejection filter obtains 11 α-bromo- 6- methine terramycin p-methyl benzenesulfonic acid 11g with cold ethanol washing, after mother liquor alkali neutralization to neutrality,
It can be applied through distillation gained benzene and ethyl alcohol.
Embodiment 9
First DMF 400mL and water 200mL are put into reaction kettle, chiral catalyst palladium/calcium carbonate 5g, stirring is added
10min is added 11 α-bromo- 6- methine terramycin p-methyl benzenesulfonic acid 50g, stirs evenly, and sucking hydrogenation fills, and closes valve, with
Vacuum pump is evacuated to 40mm mercury column, maintains 15min, and hydrogen is passed through at 30 ~ 35 DEG C, keeps 1.5 ~ 2 kilograms/cm of internal pressure2, stirring
Under be passed through hydrogen 2h, until inhale hydrogen it is slow when, TLC is in sampling, when 11 α-bromo- 6- methine terramycin is micro, continues to be passed through hydrogen
Solid/liquid/gas reactions 2h stops reaction, when hydrogen is slowly expelled to internal pressure is zero, is passed through nitrogen and rushes remaining hydrogen.50 DEG C are heated to,
Logical nitrogen, is filtered by filter press, with the mixed liquor abundant pressure filtration washing by several times of DMF and water that volume content is 20%, then with fitting
Amount distillation water washing chiral catalyst palladium/calcium carbonate simultaneously repeats to be recycled.Filtrate merges with washing lotion, in sucting reaction kettle, makes
DMF content is cooled to 5 DEG C, centrifugal rejection filter, filter cake is primary with a small amount of cold ethanol washing, and drying is in 40wt% ~ 42wt% in solution
α -6- dechlorination terramycin tosilate (fortimicin tosilate) 27g is obtained, ee value is 99.5%
Embodiment 10
First DMF 400mL and water 200mL are put into reaction kettle, chiral catalyst platinum/calcium carbonate 5g, stirring is added
10min is added 11 α-bromo- 6- methine terramycin p-methyl benzenesulfonic acid 50g, stirs evenly, and sucking hydrogenation fills, and closes valve, with
Vacuum pump is evacuated to 40mm mercury column, maintains 15min, and hydrogen is passed through at 30 ~ 35 DEG C, keeps 1.5 ~ 2 kilograms/cm of internal pressure2, stirring
Under be passed through hydrogen 2h, until inhale hydrogen it is slow when, TLC is in sampling, when 11 α-bromo- 6- methine terramycin is micro, continues to be passed through hydrogen
Solid/liquid/gas reactions 2h stops reaction, when hydrogen is slowly expelled to internal pressure is zero, is passed through nitrogen and rushes remaining hydrogen.50 DEG C are heated to,
Logical nitrogen, is filtered by filter press, is heated to 50 DEG C with the DMF(that volume content is 20%) abundant pressure filtration washing by several times, then with fitting
Amount distillation water washing chiral catalyst platinum/calcium carbonate simultaneously repeats to be recycled.Filtrate merges with washing lotion, in sucting reaction kettle, makes
DMF content is cooled to 5 DEG C, centrifugal rejection filter, filter cake is primary with a small amount of cold ethanol washing, and drying is in 40wt% ~ 42wt% in solution
α -6- dechlorination terramycin tosilate (fortimicin tosilate) 29g is obtained, ee value is 99.5%
Embodiment 11
First DMF 400mL and water 200mL are put into reaction kettle, chiral catalyst platinum/hydroxyapatite 5g, stirring is added
10min is added 11 α-bromo- 6- methine terramycin p-methyl benzenesulfonic acid 50g, stirs evenly, and sucking hydrogenation fills, and closes valve, with
Vacuum pump is evacuated to 40mm mercury column, maintains 15min, and hydrogen is passed through at 30 ~ 35 DEG C, keeps 1.5 ~ 2 kilograms/cm of internal pressure2, stirring
Under be passed through hydrogen 2h, until inhale hydrogen it is slow when, TLC is in sampling, when 11 α-bromo- 6- methine terramycin is micro, continues to be passed through hydrogen
Solid/liquid/gas reactions 2h stops reaction.When hydrogen is slowly expelled to internal pressure is zero, it is passed through nitrogen and rushes remaining hydrogen.50 DEG C are heated to,
Logical nitrogen, is filtered by filter press, is heated to 50 DEG C with the DMF(that volume content is 20%) abundant pressure filtration washing by several times, then with fitting
Amount distillation water washing chiral catalyst platinum/hydroxyapatite simultaneously repeats to be recycled.Filtrate merges with washing lotion, sucting reaction kettle
In, so that DMF content in solution is cooled to 5 DEG C in 40wt% ~ 42wt%, centrifugal rejection filter, filter cake is primary with a small amount of cold ethanol washing,
It dries up to α -6- dechlorination terramycin tosilate (fortimicin tosilate) 36g, ee value is 99.5%
Embodiment 12
First DMF 400mL and water 200mL are put into reaction kettle, chiral catalyst platinum/hydroxyapatite 5g, stirring is added
10min is added 11 α-bromo- 6- methine terramycin p-methyl benzenesulfonic acid 50g, stirs evenly, and sucking hydrogenation fills, and closes valve, with
Vacuum pump is evacuated to 40mm mercury column, maintains 15min, and hydrogen is passed through at 30 ~ 35 DEG C, keeps 1.5 ~ 2 kilograms/cm of internal pressure2, stirring
Under be passed through hydrogen 2h, until inhale hydrogen it is slow when, TLC is in sampling, when 11 α-bromo- 6- methine terramycin is micro, continues to be passed through hydrogen
Solid/liquid/gas reactions 2h stops reaction.When hydrogen is slowly expelled to internal pressure is zero, it is passed through nitrogen and rushes remaining hydrogen.It is added to 50 DEG C,
Logical nitrogen, is filtered by filter press, is heated to 50 DEG C with the DMF(that volume content is 20%) abundant pressure filtration washing by several times, then with fitting
Amount distillation water washing chiral catalyst platinum/hydroxyapatite simultaneously repeats to be recycled.Filtrate merges with washing lotion, sucting reaction kettle
In, so that DMF content in solution is cooled to 5 DEG C in 40wt% ~ 42wt%, centrifugal rejection filter, filter cake is primary with a small amount of cold ethanol washing,
It dries up to α -6- dechlorination terramycin tosilate (fortimicin tosilate) 36g, ee value is 99.5%.
Embodiment 13
Hydrogen chloride-dehydrated alcohol (hydrogen chloride content 10wt%) 200mL and fortimicin are sequentially added in a kettle to first
Benzene sulfonate 50g, is heated to reflux 1h, is cooled to 40 DEG C, stops stirring after concentrated hydrochloric acid 100mL and active carbon 5g, 5min is added, fast
Speed filters, and a small amount of crystal seed is added in filtrate, in 40 ~ 50 DEG C of stirring 3h, 10 DEG C of filterings are cooled to, successively with the anhydrous second of hydrogen chloride-
Pure and mild dehydrated alcohol washing, doxycycline hydrochloride finished product 29g obtained by drying.Refinement mother liquor plus water are made into 50wt% aqueous solution,
Appropriate p-methyl benzenesulfonic acid is added, stirs 2h at 30 ~ 40 DEG C, is cooled to 15 DEG C of filterings, with a small amount of ethanol washing, dries strongly mould
Plain tosilate can be inserted in the resulting fortimicin tosilate of hydrogenation and feed intake.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (1)
1. a kind of preparation method of fortimicin, it is characterised in that specific steps are as follows:
A, inorganic supported compound calcium carbonate or hydroxyapatite is added in equipped with thermometer and churned mechanically reaction vessel,
Saturation ammonium acetate solution is added, reaction solution is warming up to 100 DEG C of holding 2h, is down to room temperature suction filtration, filter cake is washed with deionized water
It washs to neutrality, adds the hydrogen peroxide that molar concentration is 1mol/L, be warming up to 40 DEG C of holding 1h, be down to room temperature suction filtration, dry
To pretreated inorganic supported compound；
B, metal chloride palladium chloride or platinous chloride and methanol are added in the reaction vessel, adds carboxymethyl cellulose
Sodium is 4.5 with the pH of sodium carbonate regulation system, pretreated inorganic supported compound is then added, after 2h is stirred at room temperature
It is put into autoclave, hydrogenation reduction 2h is stirred under conditions of 100KPa, 100 DEG C, decompression is filtered, rinsed with deionized water
To neutrality and through silver nitrate solution detection without chloride ion, dry 3h obtains chiral catalyst under the conditions of 60 DEG C of normal pressure, the chirality
Catalyst is palladium/calcium carbonate, platinum/calcium carbonate, palladium/hydroxyapatite or platinum/hydroxyapatite；
C, successively methanol, Oxytetracycline Base and methanol ammonia are placed in reaction vessel, are cooled to -10 after 20 ~ 30 DEG C of stirring 30min
~ -15 DEG C, the primary NBS that drying and crushing is added simultaneously stirs 15min, and TLC monitors raw material fully reacting, has in reaction solution a large amount of solid
Body is precipitated, rejection filter, is washed with cold methanol up to 11 α-bromo- 6,12- hemiketal terramycin；
D, the benzene for crossing Non-aqueous processing is added in the reaction kettle with dehydration device, and nitrogen is passed through into reaction kettle, is being stirred
Under the conditions of 11 α-bromo- 6,12- hemiketal terramycin is added, add hydroxyls dehydrate agent T-Al2O3, first stir at room temperature
2h, then it is warming up to the water of back flow reaction and the generation of discharge reaction in time, 50 DEG C are cooled to after TLC monitoring raw material fully reacting, is taken advantage of
Heat filters reaction solution, filters out the hydroxyls dehydrate agent T-Al of solid2O3, reaction dissolvent benzene, the second of the raffinate amount of doubling is evaporated off in filtrate
Alcohol dilution, it is 1 ~ 2 that the ethanol solution for adding ammonia, which is neutralized to pH, is cooled to 0 DEG C of rejection filter, with cold ethanol washing, adds in filtrate
Enter p-methyl benzenesulfonic acid, and crystal seed is added, crystallization is precipitated, then be cooled to 0 DEG C of rejection filter, 11 α-bromo- 6- methine is obtained with cold ethanol washing
Terramycin p-methyl benzenesulfonic acid；
E, first DMF 400mL and water 200mL are put into reaction kettle, chiral catalyst platinum/hydroxyapatite 5g, stirring is added
10min is added 11 α-bromo- 6- methine terramycin p-methyl benzenesulfonic acid 50g, stirs evenly, and sucking hydrogenation fills, and closes valve, with
Vacuum pump is evacuated to 40mm mercury column, maintains 15min, and hydrogen is passed through at 30 ~ 35 DEG C, keeps 1.5 ~ 2 kilograms/cm of internal pressure2, stirring
Under be passed through hydrogen 2h, until inhale hydrogen it is slow when, TLC is in sampling, when 11 α-bromo- 6- methine terramycin is micro, continues to be passed through hydrogen
Solid/liquid/gas reactions 2h stops reaction, when hydrogen is slowly expelled to internal pressure is zero, is passed through nitrogen and rushes remaining hydrogen, be heated to 50 DEG C,
Logical nitrogen, is filtered by filter press, abundant pressure filtration washing by several times after being heated to 50 DEG C with the DMF that volume content is 20%, then with fitting
Amount distillation water washing chiral catalyst platinum/hydroxyapatite simultaneously repeats to be recycled, and filtrate merges with washing lotion, sucting reaction kettle
In, so that DMF content in solution is cooled to 5 DEG C in 40wt% ~ 42wt%, centrifugal rejection filter, filter cake is primary with a small amount of cold ethanol washing,
It dries up to α -6- dechlorination terramycin tosilate, ee value is 99.5%；
F, hydrogen chloride-dehydrated alcohol and α -6- debrominate terramycin tosilate are sequentially added into reaction vessel, are heated back
1h is flowed, is cooled to 40 DEG C, concentrated hydrochloric acid and active carbon is added, stops stirring after 5min, filters, crystal seed is added in filtrate, 40 ~ 50
DEG C stirring 3h, be cooled to 10 DEG C of filterings, successively with hydrogen chloride-dehydrated alcohol and dehydrated alcohol washing, fortimicin obtained by drying
Hydrochloride finished product.
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| CN102086165A (en) * | 2010-12-29 | 2011-06-08 | 开封制药(集团)有限公司 | Application of Pd catalyst in hydrogenation process for producing doxycycline |
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