CN108794550A - A method of preparing clindamycin phosphate - Google Patents
A method of preparing clindamycin phosphate Download PDFInfo
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- CN108794550A CN108794550A CN201710292253.4A CN201710292253A CN108794550A CN 108794550 A CN108794550 A CN 108794550A CN 201710292253 A CN201710292253 A CN 201710292253A CN 108794550 A CN108794550 A CN 108794550A
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- China
- Prior art keywords
- clindamycin
- propylidene
- phosphorylated
- clindamycin phosphate
- method preparing
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
- C07H15/16—Lincomycin; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The invention discloses a kind of method preparing clindamycin phosphate, this method in turn includes the following steps：Use propylidene clindamycin for raw material; it is reacted with two benzyloxycarbonyl group phosphoryl chloride phosphorus oxychlorides; benzyl protecting group is sloughed by hydrogenation again; finally hydrolysis obtains product clindamycin phosphate in acid condition; the raw materials used in the present invention derives from a wealth of sources abundance, cheap, reaction condition is mild, concise in technology, and each step reaction is routine operation; the purification difficult brought using the lower phosphorus oxychloride of selectivity is avoided, there is preferable application range.
Description
Technical field
The present invention relates to the technical fields of Antibiotics process for preparing medicine, and in particular to a kind of to prepare clindamycin phosphoric acid
The method of ester.
Background technology
Antibiotics drug has undertaken important role since appearing on the market, always in medical procedure, with resistance
Continuous enhancing, the improvement of the new varieties of such drug and original kind advances side by side always.Clindamycin has and woods
Can mycin antibacterial mechanisms having the same, but its antibacterial effect can reach 4-8 times of lincomycin, at the same its before not
It needs to carry out sensitivity test, also has more apparent effect to penicillin, erythromycin and the drug resistant bacterium of lincomycin.
But the preservation condition of clindamycin is more harsh, therefore being prepared into corresponding carboxylate can be more effective
Storage and transport, and carboxylate administration after will soon be hydrolyzed into clindamycin, antibacterial activity is unaffected.As at
The market demand of ripe drug, clindamycin increases year by year, therefore improves its technique, and reducing cost becomes the work of medical personal
Make emphasis.
Clindamycin phosphate main preparation process at present（CN101298463 etc.）In, generally obtaining propylidene compound
After, using phosphorus oxychloride as phosphorus esterification reagent, since there are three chlorine atoms for substitution, selecting response for phosphorus oxychloride
Property is poor, needs to use a large amount of phosphorus oxychloride, and excessive phosphorus oxychloride can bring a large amount of acid waste water, to environment
It is affected.
Invention content
In order to solve the above-mentioned problems in the prior art, the present invention provides a kind of clindamycin phosphates of preparing
Method.
To achieve the above object, the technical solution adopted by the present invention is that：
A method of clindamycin phosphate being prepared, with formula（I）The clindamycin phosphate of expression is by with formula（Ⅲ）It indicates
Propylidene clindamycin obtains in accordance with the following steps：
Preferably, described with formula（Ⅱ）The phosphorylated propylidene clindamycin of expression is by with formula（Ⅲ）The propylidene crin of expression is mould
Element obtains according to the following steps：
A, in the reactor by weight addition propylidene clindamycin（Ⅲ）1 times, 10-15 times of dichloromethane and triethylamine 0.05-
0.2 times, postcooling is stirred evenly to 5-10 DEG C；
B, it by weight the mixed solution that 0.5-0.8 times of dibenzyloxy-phosphoryl chlorine and 2 times of dichloromethane is added is added dropwise, is added dropwise
After warm naturally to 20-25 DEG C；
C, it is reacted after stirring 6-8 hours, after reaction, is filtered to remove insoluble matter, organic phase is used after saturated common salt water washing
Anhydrous sodium sulfate is dried, and is filtered to remove concentration removing solvent after drier, is obtained phosphorylated propylidene clindamycin（Ⅱ）Crude product.
Preferably, described with formula（I）The clindamycin phosphate of expression is by with formula（Ⅱ）The phosphorylated propylidene of expression
Clindamycin is obtained by following steps：
E, by weight addition phosphorylated propylidene clindamycin in pressure reactor（Ⅱ）1 times, 5-10 times of methanol and 10% palladium carbon
0.1 times of catalyst stirs evenly and is passed through hydrogen and is reacted；
F, catalyst is recovered by filtration after completion of the reaction, filtrate concentration removes solvent, and it is molten to add the 2N hydrochloric acid that weight ratio is 1 times
Liquid is warming up to 60-70 DEG C, continues to be stirred to react 18-24 hours, is cooled to 20-25 DEG C after reaction；
G, the ethyl alcohol that weight ratio is 1 times is added, is cooled to 0 DEG C, stands 8-10 hours, the solid of precipitation is collected by filtration, solid is used
It is dried in vacuo after a small amount of cold ethyl alcohol washing, obtains clindamycin phosphate（Ⅰ）.
Preferably, the phosphorylated propylidene clindamycin obtained in the step c（Ⅱ）If crude product detects phosphorus through HPLC
Acylated propylidene clindamycin（Ⅱ）Content is 95% or more, then can be directly used for reacting in next step, if phosphorylated propylidene crin is mould
Element（Ⅱ）Content is less than 95%, then needs to can be used for reacting in next step by purifying rear.
Preferably, the weight ratio of dichloromethane is 10-12 times in the step a, the weight ratio of triethylamine is 0.1-
0.15 times.
Preferably, 0.64-0.71 times of dibenzyloxy-phosphoryl chlorine and 2 times is added by weight dropwise addition in the step b
The mixed solution of dichloromethane.
Preferably, keeping reaction solution to be reacted under 20-30 DEG C, 50psi pressure after being passed through hydrogen in the step e
10-15 hours.
The present invention, as phosphorus esterification reagent, can largely improve reaction selectivity using dibenzyloxy-phosphoryl chlorine,
And dosage is less, and almost without acid waste water, the influence to environment is also smaller, meanwhile, each step reaction is routine operation,
Equipment operation is succinct, and various raw materials are all commercially available, and price is suitable and in liberal supply, there is preferable application prospect.
Specific implementation mode
With reference to embodiment, the present invention will be further described.
Embodiment 1
A. phosphorylated propylidene clindamycin（Ⅱ）Preparation
Propylidene clindamycin is added in the reactor（Ⅲ）（463g, 1.0mol）, dichloromethane（5550g）With triethylamine (69g),
Postcooling is stirred evenly to 5-10 DEG C, then is added dropwise and dibenzyloxy-phosphoryl chlorine (326g, 1.1mol) and dichloromethane (926g) is added
Mixed solution, warm naturally to room temperature after being added dropwise, continue to be stirred to react 8 hours, after reaction, be filtered to remove insoluble
Object, organic phase are dried after saturated common salt water washing with anhydrous sodium sulfate, are filtered to remove concentration removing solvent after drier, are obtained
Big residue is phosphorylated propylidene clindamycin（Ⅱ）Crude product, is 614.5g, and yield about 85.0% is more than through HPLC detection levels
95%, product needs not move through to be further purified and can be directly used for reacting in next step.
B. clindamycin phosphate（Ⅰ）Preparation
Phosphorylated propylidene clindamycin is added in pressure reactor（Ⅱ）（723g, 1.0mol）, methanol（7200g）With 10% palladium
C catalyst（72.3g）, stirred evenly after finishing and be passed through hydrogen, reaction solution is kept to react 15 under 20-30 DEG C, 50psi pressure
Hour, catalyst is recovered by filtration after completion of the reaction, filtrate concentration removes most of solvent, adds 2N hydrochloric acid solutions（723g）,
It is warming up to 60-70 DEG C, continues to be stirred to react 24 hours, is cooled to room temperature after reaction, adds ethyl alcohol（723g）, it is cooled to
It 0 DEG C, stands overnight, the solid of precipitation is collected by filtration, solid is dried in vacuo after being washed with a small amount of cold ethyl alcohol, obtains clindamycin
Phosphate（Ⅰ）, it is 423.6g, yield about 84.2%.
1H NMR (D2O, 400MHz) δ：5.54(d,1H,J/Hz= 6),4. 50-4.55 ( m, 1H),
3.82-3.85(m,1H),4.31-4.36(m,1H),3.90-3.93(m,1H),4.41-4.44(m,1H), 4.55-
4.65(m,1H),1.44(d,3H,J/Hz=6),2.19(s,3H),4.36-4.41(m,1H), 2.33-2.39(m,3H),
2.90-2.98(m,2H),1.31-1.47(m,4H),0.93(t,3H,J/Hz=4), 2.95(s,3H).FAB-MS(m/z)：504
(M+H)。
Embodiment 2
Other steps are same as Example 1, only the phosphorylated propylidene clindamycin of step A（Ⅱ）Preparation method it is as follows：
Propylidene clindamycin is added in the reactor（Ⅲ）（463g, 1.0mol）, dichloromethane（4650g）And triethylamine
(46.3g) stirs evenly postcooling to 5-10 DEG C, then is added dropwise and dibenzyloxy-phosphoryl chlorine (296.5g, 1.0mol) and dichloro is added
The mixed solution of methane (926g), room temperature is warmed naturally to after being added dropwise, and continues to be stirred to react 6 hours, after reaction, mistake
Insoluble matter is filtered out, organic phase is dried after saturated common salt water washing with anhydrous sodium sulfate, is filtered to remove after drier to concentrate and be removed
Solvent is removed, it is phosphorylated propylidene clindamycin to obtain big residue（Ⅱ）Crude product, is 504.3g, and yield about 59.8% is examined through HPLC
It surveys content and is more than 95%, product needs not move through to be further purified and can be directly used for reacting in next step.
Embodiment 3
Other steps are same as Example 1, only the phosphorylated propylidene clindamycin of step A（Ⅱ）Preparation method it is as follows：
Propylidene clindamycin is added in the reactor（Ⅲ）（463g, 1.0mol）, dichloromethane（5100g）And triethylamine
(55.6g) stirs evenly postcooling to 5-10 DEG C, then is added dropwise and dibenzyloxy-phosphoryl chlorine (311g, 1.05mol) and dichloromethane is added
The mixed solution of alkane (926g), room temperature is warmed naturally to after being added dropwise, and continues to be stirred to react 7 hours, after reaction, filtering
Insoluble matter is removed, organic phase is dried after saturated common salt water washing with anhydrous sodium sulfate, and removing is concentrated after being filtered to remove drier
Solvent, it is phosphorylated propylidene clindamycin to obtain big residue（Ⅱ）Crude product, is 552.4g, and yield about 76.4% is detected through HPLC
Content is more than 95%, and product needs not move through to be further purified and can be directly used for reacting in next step.
Embodiment 4
Other steps are same as Example 1, only the clindamycin phosphate of step B（Ⅰ）Preparation method it is as follows：
Phosphorylated propylidene clindamycin is added in pressure reactor（Ⅱ）（723g, 1.0mol）, methanol（3650g）With 10% palladium
C catalyst（72.3g）, stirred evenly after finishing and be passed through hydrogen, reaction solution is kept to react 10 under 20-30 DEG C, 50psi pressure
Hour, catalyst is recovered by filtration after completion of the reaction, filtrate concentration removes most of solvent, adds 2N hydrochloric acid solutions（723g）,
It is warming up to 60-70 DEG C, continues to be stirred to react 18 hours, is cooled to room temperature after reaction, adds ethyl alcohol（723g）, it is cooled to
It 0 DEG C, stands overnight, the solid of precipitation is collected by filtration, solid is dried in vacuo after being washed with a small amount of cold ethyl alcohol, obtains clindamycin
Phosphate（Ⅰ）, it is 326.7g, yield about 65.0%.
1H NMR (D2O, 400MHz) δ：5.54(d,1H,J/Hz= 6),4. 50-4.55 ( m, 1H),
3.82-3.85(m,1H),4.31-4.36(m,1H),3.90-3.93(m,1H),4.41-4.44(m,1H), 4.55-
4.65(m,1H),1.44(d,3H,J/Hz=6),2.19(s,3H),4.36-4.41(m,1H), 2.33-2.39(m,3H),
2.90-2.98(m,2H),1.31-1.47(m,4H),0.93(t,3H,J/Hz=4), 2.95(s,3H).FAB-MS(m/z)：504
(M+H)。
Embodiment 5
Other steps are same as Example 1, only the clindamycin phosphate of step B（Ⅰ）Preparation method it is as follows：
Phosphorylated propylidene clindamycin is added in pressure reactor（Ⅱ）（723g, 1.0mol）, methanol（5400g）With 10% palladium
C catalyst（72.3g）, stirred evenly after finishing and be passed through hydrogen, reaction solution is kept to react 12 under 20-30 DEG C, 50psi pressure
Hour, catalyst is recovered by filtration after completion of the reaction, filtrate concentration removes most of solvent, adds 2N hydrochloric acid solutions（723g）,
It is warming up to 60-70 DEG C, continues to be stirred to react 21 hours, is cooled to room temperature after reaction, adds ethyl alcohol（723g）, it is cooled to
It 0 DEG C, stands overnight, the solid of precipitation is collected by filtration, solid is dried in vacuo after being washed with a small amount of cold ethyl alcohol, obtains clindamycin
Phosphate（Ⅰ）, it is 385.4g, yield about 76.6%.
1H NMR (D2O, 400MHz) δ：5.54(d,1H,J/Hz= 6),4. 50-4.55 ( m, 1H),
3.82-3.85(m,1H),4.31-4.36(m,1H),3.90-3.93(m,1H),4.41-4.44(m,1H), 4.55-
4.65(m,1H),1.44(d,3H,J/Hz=6),2.19(s,3H),4.36-4.41(m,1H), 2.33-2.39(m,3H),
2.90-2.98(m,2H),1.31-1.47(m,4H),0.93(t,3H,J/Hz=4), 2.95(s,3H).FAB-MS(m/z)：504
(M+H)。
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all the present invention spirit and
All any modification, equivalent and improvement made by within principle etc., are all included in the scope of protection of the present invention.
Claims (7)
1. a kind of method preparing clindamycin phosphate, it is characterised in that：With formula（I）The clindamycin phosphate of expression by with
Formula（Ⅲ）The propylidene clindamycin of expression obtains in accordance with the following steps：
。
2. a kind of method preparing clindamycin phosphate according to claim 1, it is characterised in that described with formula
（Ⅱ）The phosphorylated propylidene clindamycin of expression is by with formula（Ⅲ）The propylidene clindamycin of expression obtains according to the following steps：
A, in the reactor by weight addition propylidene clindamycin（Ⅲ）1 times, 10-15 times of dichloromethane and triethylamine 0.05-
0.2 times, postcooling is stirred evenly to 5-10 DEG C；
B, it by weight the mixed solution that 0.5-0.8 times of dibenzyloxy-phosphoryl chlorine and 2 times of dichloromethane is added is added dropwise, is added dropwise
After warm naturally to 20-25 DEG C；
C, it is reacted after stirring 6-8 hours, after reaction, is filtered to remove insoluble matter, organic phase is used after saturated common salt water washing
Anhydrous sodium sulfate is dried, and is filtered to remove concentration removing solvent after drier, is obtained phosphorylated propylidene clindamycin（Ⅱ）Crude product.
3. a kind of method preparing clindamycin phosphate according to claim 1, it is characterised in that described with formula（I）
The clindamycin phosphate of expression is by with formula（Ⅱ）The phosphorylated propylidene clindamycin of expression is obtained by following steps：
E, by weight addition phosphorylated propylidene clindamycin in pressure reactor（Ⅱ）1 times, 5-10 times of methanol and 10% palladium carbon
0.1 times of catalyst stirs evenly and is passed through hydrogen and is reacted；
F, catalyst is recovered by filtration after completion of the reaction, filtrate concentration removes solvent, and it is molten to add the 2N hydrochloric acid that weight ratio is 1 times
Liquid is warming up to 60-70 DEG C, continues to be stirred to react 18-24 hours, is cooled to 20-25 DEG C after reaction；
G, the ethyl alcohol that weight ratio is 1 times is added, is cooled to 0 DEG C, stands 8-10 hours, the solid of precipitation is collected by filtration, solid is used
It is dried in vacuo after a small amount of cold ethyl alcohol washing, obtains clindamycin phosphate（Ⅰ）.
4. a kind of method preparing clindamycin phosphate according to claim 2, it is characterised in that in the step c
Obtained phosphorylated propylidene clindamycin（Ⅱ）If crude product detects phosphorylated propylidene clindamycin through HPLC（Ⅱ）Content be 95% and
More than, then it can be directly used for reacting in next step, if phosphorylated propylidene clindamycin（Ⅱ）Content is less than 95%, then needs by purification
Rear can be used for reacting in next step.
5. a kind of method preparing clindamycin phosphate according to claim 2, it is characterised in that in the step a
The weight ratio of dichloromethane is 10-12 times, and the weight ratio of triethylamine is 0.1-0.15 times.
6. a kind of method preparing clindamycin phosphate according to claim 2, it is characterised in that in the step b
By weight the mixed solution that 0.64-0.71 times of dibenzyloxy-phosphoryl chlorine and 2 times of dichloromethane of addition is added dropwise.
7. a kind of method preparing clindamycin phosphate according to claim 3, it is characterised in that in the step e
Reaction solution is kept to be reacted 10-15 hours under 20-30 DEG C, 50psi pressure after being passed through hydrogen.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5182374A (en) * | 1990-03-21 | 1993-01-26 | American Cyanamid Company | Clindamycin phosphate synthesis |
| CN101704852A (en) * | 2009-11-17 | 2010-05-12 | 海南美兰史克制药有限公司 | Novel route for clindamycin phosphate compounds |
| CN105037457A (en) * | 2015-07-27 | 2015-11-11 | 天方药业有限公司 | Application of tolyltriazole in clindamycin phosphate synthesis |
-
2017
- 2017-04-28 CN CN201710292253.4A patent/CN108794550A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5182374A (en) * | 1990-03-21 | 1993-01-26 | American Cyanamid Company | Clindamycin phosphate synthesis |
| CN101704852A (en) * | 2009-11-17 | 2010-05-12 | 海南美兰史克制药有限公司 | Novel route for clindamycin phosphate compounds |
| CN105037457A (en) * | 2015-07-27 | 2015-11-11 | 天方药业有限公司 | Application of tolyltriazole in clindamycin phosphate synthesis |
Non-Patent Citations (2)
| Title |
|---|
| 李有桂等: ""克林霉素磷酸酯的合成"", 《广州化工》 * |
| 胡国强等: ""相转移催化法合成克林霉素磷酸酯"", 《中国抗生素杂志》 * |
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Application publication date: 20181113 |