CN103172683B - A kind of preparation method of Dalacina - Google Patents
A kind of preparation method of Dalacina Download PDFInfo
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Abstract
The invention provides a kind of preparation method of Dalacina, described preparation method comprises the following steps: (1) makes U 10149a and Vilsmeier reagent carry out chlorination, obtains the reaction solution containing Dalacina crude product; (2) above-mentioned reaction solution is obtained clindamycin free alkali through being hydrolyzed, extracting, concentrate, then by described clindamycin free alkali in 90 ~ 120 DEG C of insulations 20 ~ 120 minutes; (3) at concentration of volume percent be 90% ~ 95% aqueous ethanolic solution in, described clindamycin free alkali, through salt-forming reaction, obtains Dalacina ethylate; (4) by the dealcoholysis of described Dalacina ethylate, obtained described Dalacina.Preparation method of the present invention passes through process optimization, effective control also significantly reduces foreign matter content, obtains the Dalacina of high-quality, finished product purity more than 99.5%, especially 7-table Determination of Clindamycin < 0.1%, 4-chlorine clindamycin does not detect.Method of the present invention is applicable to industrialization and produces.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to a kind of preparation method of bulk drug, particularly a kind of preparation method of Dalacina.
Background technology
Clindamycin is that 7 hydroxyls of lincomycin are replaced the semi-synthetic derivative obtained by chlorine atom, is lincosamides.Its antimicrobial spectrum is identical with lincomycin, and anti-microbial activity comparatively lincomycin is strong 4 ~ 8 times, absorbs soon and completely.Be applicable to anerobe, streptococcus pneumoniae, other streptococcuses (except enterococcus spp) and the lower respiratory infection caused by responsive S. aureus L-forms and skin soft-tissue infection; And normal treatment of combining with other antibacterials for abdominal cavity infection and pelvic infection.Clindamycin determined curative effect, is included by multinational pharmacopeia.The clindamycin of clinical application has its hydrochloride, phosphoric acid ester and cetylate, and wherein Dalacina has oral preparation and injection.
Dalacina, chemistry chloro-6,7, the 8-tri-deoxidation-L-Su Shi-α-D-noside hydrochlorides of (2S-is trans)-6-(1-methyl-4-propyl group-2-tetramethyleneimine carbonic acid amido)-1-sulfo--methyl-7-by name, structural formula is:
Dalacina
The industrialized preparing process of Dalacina adopts usually: take U 10149a as raw material, carries out chlorination with Vilsmeier reagent, obtains Dalacina crude product, then carries out aftertreatment, obtains Dalacina finished product; Common post-treating method comprises: the Dalacina crude product that chlorination obtains obtains clindamycin free alkali through hydrolysis, extraction, concentrated solvent of removing, clindamycin free alkali changes Dalacina alcoholate again into, dealcoholysis, obtained Dalacina finished product.Chemical equation is as follows:
The synthesis step of Dalacina is more, and technique is more complicated, adopts different process to prepare Vilsmeier reagent and adopt different post-treating methods all can have an impact to the yield of Dalacina finished product and quality.
The people such as Hu Shuchen (" China Medicine University's journal ", 1992,23(4), 248-249 page) adopt phosphorus oxychloride and DMF to prepare Vilsmeier reagent, and then for the preparation of Dalacina, after conventional aftertreatment, product yield 86.5%, content 86.32%(vapor-phase chromatography detects), total impurities content is less than 5%, and single contaminant content is all less than 4.5%.The shortcoming of this technique is that total impurities content is high, discharges a large amount of phosphorus-containing wastewater, contaminate environment.
Jiang faithful and upright person waits people's (" science and technology circular ", 6 phases in 2003,491-493 page) improve the technique preparing Dalacina, the preparation process and the chlorination that phosphorus oxychloride and DMF are synthesized Vilsmeier reagent carry out simultaneously, final step is crystallization Dalacina in aqueous acetone solution, total recovery reaches 88.6%, and content is not less than 83%.This technique exists that total impurities content is higher, the problem of environmental pollution equally.
Chinese patent application CN200710112238.3 discloses a kind of method of suitability for industrialized production Dalacina, adopts two trichloromethyl carbonate or superpalite and acid amides to react and prepares Vilsmeier reagent.The application of this reagent makes quality product be greatly improved, HPLC purity > 97.8%, molar yield 78 ~ 87%, but foreign matter content is not quite clear.The present inventor is repeated the embodiment of this patent application, and the content recording impurity 7-table clindamycin is 0.8 ~ 1.0%, still higher, can not meet the demand of high-end customer.
7-shows clindamycin
Chinese patent application CN200710071197.8 discloses a kind of preparation method of Dalacina ethylate, U 10149a, chloroform, DMF, solid phosgene and oxidation inhibitor are mixed, react 15 ~ 40 hours at 50 ~ 80 DEG C, hydrolysis, chloroform extraction, concentrated organic phase removing chloroform at 50 ~ 75 DEG C, obtain clindamycin free alkali, then add dehydrated alcohol and carry out crystallization, obtain Dalacina ethylate, yield 87 ~ 93%, foreign matter content is not quite clear.
Chinese patent application CN200710194916.5 discloses a kind of preparation method of Dalacina, and chlorinating agent is selected from POCl
3, SOCl
2and COCl
2, adopt the staircase response of-5 ~ 120 DEG C, preferably-5 ~ 5 DEG C are reacted 3 hours, then 25 ~ 50 DEG C of reactions 3 ~ 7 hours, then 50 ~ 70 DEG C of reactions 3 hours, in lower alcohol, crystallization went out Dalacina alcoholate, and drying turns crystalline substance and obtains Dalacina.Yield 84%, foreign matter content is not quite clear.
Chinese patent application CN201010200802.9 discloses a kind of preparation method of Dalacina, U 10149a, DMF, oxidation inhibitor and solid phosgene carry out chlorination in low haloalkane, react 20 ~ 50 hours at 30 ~ 50 DEG C, final step directly by clindamycin free alkali and hydrochloric acid salify, obtains Dalacina.The 7-of this technique shows Determination of Clindamycin≤0.2%, but long reaction time, solid phosgene consumption is large, and the present inventor repeats to test the HPLC purity <97% recording Dalacina finished product, the reaction of raw material U 10149a is incomplete, content >2%.
In general, the existing preparation method of Dalacina still Shortcomings, product purity needs to be improved further, and related substances content is higher, can not meet the requirement of high-end customer.And Dalacina is the raw material of synthesis Clindamycin Phosphate, clindamycin palmitate, improves its quality to guaranteeing that drug safety is extremely important.Therefore the preparation technology improving Dalacina is necessary.
Summary of the invention
The technical problem to be solved in the present invention overcomes the deficiencies in the prior art, provides a kind of preparation method of high-quality Dalacina.
The preparation method of Dalacina provided by the invention, comprises the following steps:
(1) make U 10149a and Vilsmeier reagent carry out chlorination, obtain the reaction solution containing Dalacina crude product;
(2) above-mentioned reaction solution is obtained clindamycin free alkali through being hydrolyzed, extracting, concentrate, then by described clindamycin free alkali in 90 ~ 120 DEG C of insulations 20 ~ 120 minutes;
(3) at concentration of volume percent be 90% ~ 95% aqueous ethanolic solution in, described clindamycin free alkali, through salt-forming reaction, obtains Dalacina ethylate;
(4) by the dealcoholysis of described Dalacina ethylate, obtained described Dalacina.
Preferably, in described step (2), described clindamycin free alkali was 90 ~ 100 DEG C of insulations 40 ~ 80 minutes.
Preferably, in described step (1), described chlorination carries out 8 ~ 15 hours at 40 ~ 50 DEG C, carries out 1 ~ 5 hour afterwards at 55 ~ 65 DEG C.
More preferably, in described step (1), described chlorination carries out 10 ~ 12 hours at 45 ~ 50 DEG C, carries out 2 ~ 4 hours afterwards at 60 ~ 65 DEG C.
Preferably, in described step (1), described Vilsmeier reagent is formed in chlorination solvent chloroform by solid phosgene and DMF.
More preferably, in described step (1), the mass ratio of described U 10149a, solid phosgene, DMF and chloroform is 1:1.0 ~ 1.3:1.5 ~ 2:7 ~ 12.
Further preferably, in described step (1), the mass ratio of described U 10149a, solid phosgene, DMF and chloroform is 1:1.0 ~ 1.1:1.6 ~ 1.8:8 ~ 10.
Preferably, in described step (1), described chlorination is joined by described solid phosgene in the reaction system containing chloroform, DMF and U 10149a to complete.
More preferably, in described step (1), described in add be added by described solid phosgene in batches or be mixed with chloroformic solution to add, the temperature adding fashionable maintenance reaction system is 0 ~ 15 DEG C.
The generative process of Vilsmeier reagent and chlorination are carried out by the present invention simultaneously, simplify operation, avoid the problems such as the easy moisture absorption, the not easily preservation that previously prepared good Vilsmeier reagent brings.
When content of lincomycin hydrochloride is less than 1.0% in the reaction system of HPLC detecting step (1), react complete.
Preferably, described step (2) is specially: at 10 ~ 30 DEG C, described reaction solution is joined in aqueous sodium hydroxide solution, adjust pH is 9 ~ 12, be hydrolyzed 2 ~ 4 hours, then use chloroform extraction, organic phase (not needing drying) is not occurring to dripless higher than 80 DEG C of vacuum concentration, obtain clindamycin free alkali, then by described clindamycin free alkali 90 ~ 100 DEG C of insulations 40 ~ 80 minutes.
Preferably, described step (3) is specially: it is in the aqueous ethanolic solution of 90 ~ 95% that the clindamycin free alkali that step (2) obtains is dissolved in concentration of volume percent, passes into hydrogen chloride gas, and adjust pH is 1 ~ 2; Or be dissolved in ethanol by clindamycin free alkali, adding concentrated hydrochloric acid adjust pH is 1 ~ 2, and the concentration of volume percent then adding water to aqueous ethanolic solution is 90 ~ 95%; After crystallization, be incubated 1 ~ 2 hour at 10 ~ 20 DEG C complete with crystallization, filter, be the aqueous ethanolic solution washing of 90 ~ 95% with concentration of volume percent, obtain Dalacina ethylate.
Preferably, described step (4) is specially: be dissolved in the water by described Dalacina ethylate, vacuum concentration, remove ethanol, resistates adds acetone solution, then joins in acetone by aqueous acetone solution, separate out solid, filtration, vacuum-drying, obtain described Dalacina.
Preferably, the HPLC purity of described U 10149a is not less than 99.5%.
It will be understood by those skilled in the art that each step of the present invention, all carry out under abundant agitation condition.
Preparation method of the present invention can obtain high-quality Dalacina, its HPLC purity >99.5%, total impurities content <0.5%, the equal <0.1% of single contaminant content.
In the application, " DMF " represents DMF.
The present inventor completes of the present invention by following process.
The known impurities of the Dalacina that " Chinese Pharmacopoeia " includes has lincomycin, clindamycin B and 7-to show clindamycin.The present inventor has also found a kind of new impurity 4-chlorine clindamycin under study for action, and this impurity has no open report, and its structural formula is as follows:
4-chlorine clindamycin
In order to obtain the product of high-quality, present inventors studied the common industrialized preparing process of Dalacina, its reactions steps comprises: (1) makes U 10149a and Vilsmeier reagent carry out chlorination, obtains the reaction solution containing Dalacina crude product; (2) above-mentioned reaction solution is hydrolyzed, extracts, concentrates, obtain clindamycin free alkali; (3) described clindamycin free alkali is through salt-forming reaction, obtains Dalacina ethylate; (4) by the dealcoholysis of described Dalacina ethylate, obtained Dalacina finished product.
The present inventor finds through large quantifier elimination, and the main source of impurity comprises: raw material U 10149a is brought into, and chlorination is incomplete or side reaction occurs, and the change of chlorination processing condition.
In order to control the raw band excess of imports target impurity, particularly Lincomycin B, application claims uses HPLC purity to be not less than the U 10149a of 99.5%, thus the content of the impurity clindamycin B controlling impurity woods Mycosporin B reaction and obtain.
React completely to make raw material U 10149a, the present invention needs to use excessive Vilsmeier reagent to participate in reaction, and strengthens the consumption of Vilsmeier reagent further, does not have a significant effect to speed of response, but reaction preference can be caused to be deteriorated, to increase foreign matter content.Consider that solid phosgene has certain hazardness simultaneously, need to use excessive DMF to ensure that itself and solid phosgene complete reaction generate Vilsmeier reagent.Therefore, finally determine, the mass ratio that feeds intake of U 10149a, solid phosgene, DMF and chloroform is 1:1.0 ~ 1.3:1.5 ~ 2:7 ~ 12, is preferably 1:1.0 ~ 1.1:1.6 ~ 1.8:8 ~ 10.
Impurity 7-shows the epimer that clindamycin is clindamycin.Producing cause is: in chlorination, when Vilsmeier reagent, from during the 7-position hydroxyl der Frontalangriff of U 10149a, side reaction occurs, forms 7-and shows clindamycin.
The producing cause of impurity 4-chlorine clindamycin may be: Dalacina and excessive Vilsmeier reagent react further.Reaction equation is as follows:
Present inventors studied the impact of temperature and time on product of chlorination, the clindamycin free alkali that the reaction solution containing Dalacina crude product adopting HPLC chlorine detection generation to be obtained by reacting obtains through hydrolysis, extraction, the results are shown in Table 1:
The temperature and time of table 1 chlorination is on the impact of clindamycin free alkali purity
Table 1 result shows: chlorination temperature is lower than 50 DEG C, and speed of response is slow, the time is long, and the content that 7-shows clindamycin is lower, and the reaction of raw material lincomycin not exclusively.Chlorination temperature is higher than 50 DEG C, and speed of response significantly increases, but reaction preference decreases, and the content that 7-shows clindamycin also increases thereupon.Chlorination temperature is higher than 55 DEG C of reactions for a long time, and the content that 7-shows clindamycin and 4-chlorine clindamycin is higher, and product purity is lower.Chlorination temperature more than 60 DEG C ~ 65 DEG C of backflows time, within usual 15 hours, react completely, but 7-to show the content of clindamycin higher.Adopt ladder-elevating temperature, be conducive to chlorination completely and improve yield, foreign matter content is corresponding lower simultaneously.Therefore, preferred described chlorination first 40 ~ 50 DEG C of reactions 8 ~ 15 hours, then is warmed up to 55 ~ 65 DEG C of reactions 1 ~ 5 hour; More preferably described chlorination carries out 10 ~ 12 hours at 45 ~ 50 DEG C, and 60 ~ 65 DEG C are carried out 2 ~ 4 hours afterwards.
What chlorination obtained is hydrolyzed containing the reaction solution of Dalacina crude product, extract, in clindamycin free alkali that concentrated dry solvent obtains containing have an appointment 0.9% impurity 7-show clindamycin, further research finds, this impurity at high temperature can be degraded, for some time is incubated at 90 ~ 120 DEG C, this foreign matter content obviously declines, and the content of clindamycin free alkali does not decline substantially; More than 120 DEG C insulation or soaking time long, then the content of clindamycin free alkali can decline.Testing data is in table 2.
Table 2 heat-retaining condition is on the impact of clindamycin free alkali purity
Table 2 result shows: what chlorination obtained is hydrolyzed containing the reaction solution of Dalacina crude product, extract, clindamycin free alkali that concentrated dry solvent obtains is conducive to improving the quality of products 90 ~ 120 DEG C of insulations for 20 ~ 120 minutes, particularly the content of 7-table clindamycin significantly reduces, and preferably 90 ~ 100 DEG C are incubated 40 ~ 80 minutes.
Research also finds, impurity 4-chlorine clindamycin is that in the aqueous ethanolic solution of 90 ~ 95%, solubleness is good at concentration of volume percent, can remove in the last handling process of step (3).
Compared to existing technology, the preparation method of Dalacina of the present invention has remarkable advantage, pass through process optimization, effective control also significantly reduces foreign matter content, obtains high-quality product, the HPLC high purity more than 99.5% of Dalacina finished product, total impurities content <0.5%, the equal <0.1% of single contaminant content, especially 7-show Determination of Clindamycin <0.1%, and 4-chlorine clindamycin does not detect.Method of the present invention is applicable to industrialization and produces.
Embodiment
To contribute to explaining the present invention further by following examples, but be not used in restriction content of the present invention.
Raw materials and reagent are commercially available prod.
Detecting instrument has:
High performance liquid chromatography (HPLC) instrument, model: Shimadzu LC-20A, Shimadzu Corporation.
HPLC testing conditions was with reference to version " Chinese Pharmacopoeia " in 2010.
400MHz FT-NMR nuclear magnetic resonance spectrometer, model: Bruker Avance400, Bruker company.
ABI3200Q TRAP series connection quadrupole linear ion trap mass spectrometer, model: 3200QTRAP, American AB I company.
embodiment 1the preparation of Dalacina
Successively 90kg chloroform, 16kgDMF and 10kg U 10149a (HPLC purity 99.6%) are joined in reactor, be cooled to 0 DEG C, add 10kg solid phosgene in batches, control temperature in the kettle when adding and be no more than 15 DEG C, then 40 DEG C of reactions 15 hours are warmed up to, then 65 DEG C of reactions 3 hours.In HPLC detection reaction system, the content of U 10149a is less than 1.0%, reacts complete.
Above-mentioned reaction solution is cooled to 20 DEG C, drip the aqueous sodium hydroxide solution of 10%, adjust pH to be 9, system temperature control is no more than 30 DEG C, is incubated 2 hours, stratification, aqueous phase with 70kg chloroform extraction once, merge organic phase, with 20L washing once, organic phase vacuum concentration below 80 DEG C occurs to dripless, obtains clindamycin free alkali.Then this clindamycin free alkali is warmed up to 120 DEG C of insulations 20 minutes, resistates is cooled to 60 DEG C, joining 40L concentration of volume percent is in the aqueous ethanolic solution of 90%, logical hydrogen chloride gas, to pH=2, cools to 10 DEG C, is incubated 1 hour, filter, with the aqueous ethanolic solution washing that concentration of volume percent is 90%, vacuum-drying, obtains Dalacina ethylate 10.5kg.
The Dalacina ethylate of gained is dissolved in 21L water, vacuum concentration below 60 DEG C, removes ethanol, stops concentrated when steaming solvent 19kg, add 20L acetone solution, press filtration while hot, filtrate joins in 80L acetone, separates out Dalacina, filter, filter cake, 70 DEG C of vacuum-dryings 10 hours, obtains Dalacina 8.9kg, molar yield: 85.7%.
HPLC purity: Dalacina finished product: 99.6%; 7-shows clindamycin: 0.05%, 4-chlorine clindamycin: do not detect.
1h-NMR data: (500MHz, DMSO-d6) δ: 0.86 (t, 3H), 1.28 (m, 2H), 1.33 (d, 3H), 1.40 (m, 2H), 2.02 (s, 3H), 2.02,2.18 (m, 2H), 2.20 (m, 1H), 2.89,3.63 (d, 2H), 2.88 (s, 3H), 3.38 (m, 1H), 3.78 (d, 1H), 3.90 (m, 1H), 4.10 (d, 1H), 4.22 (d, 1H), 4.43 (d, 1H), 4.49 (d, 1H), 5.19 (d, 1H), 8.17 (d, 1H), 9.81 (s, 1H).
embodiment 2the preparation of Dalacina
Successively 120kg chloroform, 20kgDMF and 10kg U 10149a (HPLC purity 99.6%) are joined in reactor, be cooled to 0 DEG C, add 13kg solid phosgene in batches, control temperature in the kettle when adding and be no more than 15 DEG C, then 50 DEG C of reactions 15 hours are warmed up to, then 55 DEG C of reactions 5 hours.In HPLC detection reaction system, the content of U 10149a is less than 1.0%, reacts complete.
Above-mentioned reaction solution is cooled to 20 DEG C, drip the aqueous sodium hydroxide solution of 10%, adjust pH to be 12, system temperature control is no more than 30 DEG C, is incubated 2 hours, stratification, aqueous phase with 70kg chloroform extraction once, merge organic phase, with 20L washing once, organic phase vacuum concentration below 80 DEG C occurs to dripless, obtains clindamycin free alkali.Then this clindamycin free alkali is warmed up to 90 DEG C of insulations 100 minutes.Resistates is cooled to 60 DEG C, joining 40L concentration of volume percent is in the aqueous ethanolic solution of 94%, add 2L concentrated hydrochloric acid again, to pH=2, cool to 10 DEG C, be incubated 1 hour, filter, with the aqueous ethanolic solution washing that concentration of volume percent is 94%, vacuum-drying, obtains Dalacina ethylate 10.5kg.
The Dalacina ethylate of gained is dissolved in 21L water, vacuum concentration below 60 DEG C, removes ethanol, stops concentrated when steaming solvent 19kg, add 20L acetone solution, press filtration while hot, filtrate joins in 80L acetone, separates out Dalacina, filter, filter cake, 70 DEG C of vacuum-dryings 10 hours, obtains Dalacina 8.9kg, molar yield: 85.7%.
HPLC purity: Dalacina finished product: 99.6%; 7-shows clindamycin: 0.08%; 4-chlorine clindamycin: do not detect.
1h-NMR data: (500MHz, DMSO-d6) δ: 0.86 (t, 3H), 1.28 (m, 2H), 1.33 (d, 3H), 1.40 (m, 2H), 2.02 (s, 3H), 2.02,2.18 (m, 2H), 2.20 (m, 1H), 2.89,3.63 (d, 2H), 2.88 (s, 3H), 3.38 (m, 1H), 3.78 (d, 1H), 3.90 (m, 1H), 4.10 (d, 1H), 4.22 (d, 1H), 4.43 (d, 1H), 4.49 (d, 1H), 5.19 (d, 1H), 8.17 (d, 1H), 9.81 (s, 1H).
embodiment 3the preparation of Dalacina
Successively 55kg chloroform, 16kgDMF and 10kg U 10149a (HPLC purity 99.5%) are joined in reactor, be cooled to 0 DEG C, drip the solution that 11kg solid phosgene is dissolved in 25kg chloroform, within 3 hours, add, add fashionable temperature in the kettle and be no more than 10 DEG C, then 45 DEG C of reactions 10 hours are warmed up to, then 60 DEG C of reactions 4 hours.When the content of U 10149a is less than 1.0% in HPLC detection reaction system, react complete.
Above-mentioned reaction solution is cooled to 20 DEG C, drip the aqueous sodium hydroxide solution of 10%, adjust pH to be 10, system temperature control is no more than 30 DEG C, is incubated 2 hours, stratification, aqueous phase with 70kg chloroform extraction once, merge organic phase, with 20L washing once, organic phase vacuum concentration below 80 DEG C occurs to dripless, obtains clindamycin free alkali.Then this clindamycin free alkali is warmed up to 100 DEG C of insulations 60 minutes.Resistates is cooled to 60 DEG C, adding 40L concentration of volume percent is in the aqueous ethanolic solution of 95%, logical hydrogen chloride gas is 2 to pH, cool to 10 DEG C, being incubated 1 hour, filtering, is the aqueous ethanolic solution washing of 94% with concentration of volume percent, vacuum-drying, obtains Dalacina ethylate 10.8kg.
The Dalacina ethylate of gained is dissolved in 21L water, vacuum concentration below 60 DEG C, removes ethanol, stops concentrated when steaming solvent 19kg, add 20L acetone solution, press filtration while hot, filtrate joins in 80L acetone, separates out Dalacina, filter, filter cake, 70 DEG C of vacuum-dryings 10 hours, obtains Dalacina 9.1kg, molar yield: 87.6%.
HPLC purity: Dalacina finished product: 99.7%; 7-shows clindamycin: 0.05%; 4-chlorine clindamycin: do not detect.
1h-NMR data: (500MHz, DMSO-d6) δ: 0.86 (t, 3H), 1.28 (m, 2H), 1.33 (d, 3H), 1.40 (m, 2H), 2.02 (s, 3H), 2.02,2.18 (m, 2H), 2.20 (m, 1H), 2.89,3.63 (d, 2H), 2.88 (s, 3H), 3.38 (m, 1H), 3.78 (d, 1H), 3.90 (m, 1H), 4.10 (d, 1H), 4.22 (d, 1H), 4.43 (d, 1H), 4.49 (d, 1H), 5.19 (d, 1H), 8.17 (d, 1H), 9.81 (s, 1H).
embodiment 4the preparation of Dalacina
Successively 90kg chloroform, 17kgDMF and 10kg U 10149a (HPLC purity 99.5%) are joined in reactor, be cooled to 0 DEG C, add 11kg solid phosgene in batches, add fashionable temperature in the kettle and remain on and be no more than 10 DEG C, then 47 DEG C of reactions 11 hours are warmed up to, then 63 DEG C of reactions 3 hours.When the content of U 10149a is less than 1.0% in HPLC detection reaction system, react complete.
Above-mentioned reaction solution is cooled to 20 DEG C, drip the aqueous sodium hydroxide solution of 10%, adjust pH to be 9, system temperature control is no more than 30 DEG C, is incubated 2 hours, stratification, aqueous phase with 70kg chloroform extraction once, merge organic phase, with 20L washing once, organic phase vacuum concentration below 80 DEG C occurs to dripless, obtains clindamycin free alkali.Then this clindamycin free alkali is warmed up to 90 DEG C of insulations 80 minutes.Resistates is cooled to 60 DEG C, adding 40L concentration of volume percent is in the aqueous ethanolic solution of 90%, logical hydrogen chloride gas is 2 to pH, cool to 20 DEG C, being incubated 2 hours, filtering, is the aqueous ethanolic solution washing of 90% with concentration of volume percent, vacuum-drying, obtains Dalacina ethylate 10.8kg.
The Dalacina ethylate of gained is dissolved in 21L water, vacuum concentration below 60 DEG C, removes ethanol, stops concentrated when steaming solvent 19kg, add 20L acetone solution, press filtration while hot, filtrate joins in 80L acetone, separates out Dalacina, filter, filter cake, 70 DEG C of vacuum-dryings 10 hours, obtains Dalacina 9.06kg, molar yield: 87.2%.
HPLC purity: Dalacina finished product: 99.6%; 7-shows clindamycin: 0.04%; 4-chlorine clindamycin: do not detect.
1h-NMR data: (500MHz, DMSO-d6) δ: 0.86 (t, 3H), 1.28 (m, 2H), 1.33 (d, 3H), 1.40 (m, 2H), 2.02 (s, 3H), 2.02,2.18 (m, 2H), 2.20 (m, 1H), 2.89,3.63 (d, 2H), 2.88 (s, 3H), 3.38 (m, 1H), 3.78 (d, 1H), 3.90 (m, 1H), 4.10 (d, 1H), 4.22 (d, 1H), 4.43 (d, 1H), 4.49 (d, 1H), 5.19 (d, 1H), 8.17 (d, 1H), 9.81 (s, 1H).
embodiment 5the preparation of Dalacina
Successively 100kg chloroform, 18kgDMF and 10kg U 10149a (HPLC purity 99.5%) are joined in reactor, be cooled to 0 DEG C, add 10kg solid phosgene in batches, temperature remains on 15 DEG C, then 45 DEG C of reactions 12 hours are warmed up to, again 65 DEG C of reactions 2 hours, in HPLC detection reaction system, the content of U 10149a is less than 1.0%.React complete.
Above-mentioned reaction solution is cooled to 20 DEG C, drip the aqueous sodium hydroxide solution of 10%, adjust pH to be 9, system temperature control is no more than 30 DEG C, is incubated 2 hours, stratification, aqueous phase with 70kg chloroform extraction once, merge organic phase, with 20L washing once, organic phase vacuum concentration below 80 DEG C occurs to dripless, obtains clindamycin free alkali.Then this clindamycin free alkali is warmed up to 100 DEG C of insulations 40 minutes.Resistates is cooled to 60 DEG C, and adding 40L concentration of volume percent is in the aqueous ethanolic solution of 95%, adds 2L concentrated hydrochloric acid, cool to 15 DEG C, be incubated 1 hour, filter, with the aqueous ethanolic solution washing that concentration of volume percent is 95%, vacuum-drying, obtains Dalacina ethylate 10.5kg.
The Dalacina ethylate of gained is dissolved in 21L water, vacuum concentration below 60 DEG C, removes ethanol, stops concentrated when steaming solvent 19kg, add 20L acetone solution, press filtration while hot, filtrate joins in 100L acetone, separates out Dalacina, filter, filter cake, 70 DEG C of vacuum-dryings 10 hours, obtains Dalacina 9.0kg, molar yield: 86.6%.
HPLC purity: Dalacina finished product: 99.5%; 7-shows clindamycin: 0.07%; 4-chlorine clindamycin: do not detect.
1h-NMR data: (500MHz, DMSO-d6) δ: 0.86 (t, 3H), 1.28 (m, 2H), 1.33 (d, 3H), 1.40 (m, 2H), 2.02 (s, 3H), 2.02,2.18 (m, 2H), 2.20 (m, 1H), 2.89,3.63 (d, 2H), 2.88 (s, 3H), 3.38 (m, 1H), 3.78 (d, 1H), 3.90 (m, 1H), 4.10 (d, 1H), 4.22 (d, 1H), 4.43 (d, 1H), 4.49 (d, 1H), 5.19 (d, 1H), 8.17 (d, 1H), 9.81 (s, 1H).
embodiment 6the preparation of Dalacina
Successively 70kg chloroform, 15kgDMF and 10kg U 10149a (HPLC purity 99.5%) are joined in reactor, be cooled to 0 DEG C, add 13kg solid phosgene in batches, temperature remains on 15 DEG C, then 40 DEG C of reactions 15 hours are warmed up to, again 65 DEG C of reactions 1 hour, in HPLC detection reaction system, the content of U 10149a is less than 1.0%.React complete.
Above-mentioned reaction solution is cooled to 20 DEG C, drip the aqueous sodium hydroxide solution of 10%, adjust pH to be 9, system temperature control is no more than 30 DEG C, is incubated 2 hours, stratification, aqueous phase with 70kg chloroform extraction once, merge organic phase, with 20L washing once, organic phase vacuum concentration below 80 DEG C occurs to dripless, obtains clindamycin free alkali.Then this clindamycin free alkali is warmed up to 120 DEG C of insulations 20 minutes.Resistates is cooled to 60 DEG C, and adding 40L concentration of volume percent is in the aqueous ethanolic solution of 95%, adds 2L concentrated hydrochloric acid, cool to 15 DEG C, be incubated 1 hour, filter, with concentration of volume percent be 95% aqueous ethanolic solution washing, vacuum-drying, obtains Dalacina ethylate 10.0kg.
The Dalacina ethylate of gained is dissolved in 21L water, vacuum concentration below 60 DEG C, removes ethanol, stops concentrated when steaming solvent 19kg, add 20L acetone solution, press filtration while hot, filtrate joins in 100L acetone, separates out Dalacina, filter, filter cake, 70 DEG C of vacuum-dryings 10 hours, obtains Dalacina 8.72kg, molar yield: 83.9%.
HPLC purity: Dalacina finished product: 99.5%; 7-shows clindamycin: 0.07%; 4-chlorine clindamycin: do not detect.
1h-NMR data: (500MHz, DMSO-d6) δ: 0.86 (t, 3H), 1.28 (m, 2H), 1.33 (d, 3H), 1.40 (m, 2H), 2.02 (s, 3H), 2.02,2.18 (m, 2H), 2.20 (m, 1H), 2.89,3.63 (d, 2H), 2.88 (s, 3H), 3.38 (m, 1H), 3.78 (d, 1H), 3.90 (m, 1H), 4.10 (d, 1H), 4.22 (d, 1H), 4.43 (d, 1H), 4.49 (d, 1H), 5.19 (d, 1H), 8.17 (d, 1H), 9.81 (s, 1H).
embodiment 7the preparation of Dalacina
Successively 120kg chloroform, 20kgDMF and 10kg U 10149a (HPLC purity 99.5%) are joined in reactor, be cooled to 0 DEG C, add 12kg solid phosgene in batches, temperature remains on 15 DEG C, then 50 DEG C of reactions 15 hours are warmed up to, again 55 DEG C of reactions 4 hours, in HPLC detection reaction system, the content of U 10149a is less than 1.0%.React complete.
Above-mentioned reaction solution is cooled to 20 DEG C, drip the aqueous sodium hydroxide solution of 10%, adjust pH to be 9, system temperature control is no more than 30 DEG C, is incubated 2 hours, stratification, aqueous phase with 70kg chloroform extraction once, merge organic phase, with 20L washing once, organic phase vacuum concentration below 80 DEG C occurs to dripless, obtains clindamycin free alkali.Then this clindamycin free alkali is warmed up to 90 DEG C of insulations 120 minutes.Resistates is cooled to 60 DEG C, and adding 40L concentration of volume percent is in the aqueous ethanolic solution of 90%, adds 2L concentrated hydrochloric acid, cool to 15 DEG C, be incubated 1 hour, filter, with the aqueous ethanolic solution washing that concentration of volume percent is 90%, vacuum-drying, obtains Dalacina ethylate 10.0kg.
The Dalacina ethylate of gained is dissolved in 21L water, vacuum concentration below 60 DEG C, removes ethanol, stops concentrated when steaming solvent 19kg, add 20L acetone solution, press filtration while hot, filtrate joins in 100L acetone, separates out Dalacina, filter, filter cake, 70 DEG C of vacuum-dryings 10 hours, obtains Dalacina 8.7kg, molar yield: 83.7%.
HPLC purity: Dalacina finished product: 99.7%; 7-shows clindamycin: 0.06%; 4-chlorine clindamycin: do not detect.
1h-NMR data: (500MHz, DMSO-d6) δ: 0.86 (t, 3H), 1.28 (m, 2H), 1.33 (d, 3H), 1.40 (m, 2H), 2.02 (s, 3H), 2.02,2.18 (m, 2H), 2.20 (m, 1H), 2.89,3.63 (d, 2H), 2.88 (s, 3H), 3.38 (m, 1H), 3.78 (d, 1H), 3.90 (m, 1H), 4.10 (d, 1H), 4.22 (d, 1H), 4.43 (d, 1H), 4.49 (d, 1H), 5.19 (d, 1H), 8.17 (d, 1H), 9.81 (s, 1H).
embodiment 8the preparation of Dalacina
Successively 70kg chloroform, 15kgDMF and 10kg U 10149a (HPLC purity 99.5%) are joined in reactor, be cooled to 0 DEG C, add 10kg solid phosgene in batches, temperature remains on 15 DEG C, then 50 DEG C of reactions 10 hours are warmed up to, again 60 DEG C of reactions 3 hours, in HPLC detection reaction system, the content of U 10149a is less than 1.0%.React complete.
Above-mentioned reaction solution is cooled to 20 DEG C, drip the aqueous sodium hydroxide solution of 10%, adjust pH to be 9, system temperature control is no more than 30 DEG C, is incubated 2 hours, stratification, aqueous phase with 70kg chloroform extraction once, merge organic phase, with 20L washing once, organic phase vacuum concentration below 80 DEG C occurs to dripless, obtains clindamycin free alkali.Then this clindamycin free alkali is warmed up to 90 DEG C of insulations 60 minutes.Resistates is cooled to 60 DEG C, and adding 40L concentration of volume percent is in the aqueous ethanolic solution of 95%, adds 2L concentrated hydrochloric acid, cool to 15 DEG C, be incubated 1 hour, filter, with the aqueous ethanolic solution washing that concentration of volume percent is 95%, vacuum-drying, obtains Dalacina ethylate 10.0kg.
The Dalacina ethylate of gained is dissolved in 21L water, vacuum concentration below 60 DEG C, removes ethanol, stops concentrated when steaming solvent 19kg, add 20L acetone solution, press filtration while hot, filtrate joins in 100L acetone, separates out Dalacina, filter, filter cake, 70 DEG C of vacuum-dryings 10 hours, obtains Dalacina 8.8kg, molar yield: 84.7%.
HPLC purity: Dalacina finished product: 99.5%; 7-shows clindamycin: 0.07%; 4-chlorine clindamycin: do not detect.
1h-NMR data: (500MHz, DMSO-d6) δ: 0.86 (t, 3H), 1.28 (m, 2H), 1.33 (d, 3H), 1.40 (m, 2H), 2.02 (s, 3H), 2.02,2.18 (m, 2H), 2.20 (m, 1H), 2.89,3.63 (d, 2H), 2.88 (s, 3H), 3.38 (m, 1H), 3.78 (d, 1H), 3.90 (m, 1H), 4.10 (d, 1H), 4.22 (d, 1H), 4.43 (d, 1H), 4.49 (d, 1H), 5.19 (d, 1H), 8.17 (d, 1H), 9.81 (s, 1H).
embodiment 9the preparation of 4-chlorine clindamycin
Join in reactor by 70g chloroform, 15g DMF and 10g Dalacina (HPLC purity 99.5%) successively, be cooled to 0 DEG C, add 16g solid phosgene in batches, temperature remains on 15 DEG C, is then warmed up to 65 DEG C of reactions 20 hours, reaction solution cool to room temperature.
Drip the aqueous sodium hydroxide solution of 10%, pH is adjusted to be 10, system temperature control is no more than 30 DEG C, is incubated 2 hours, stratification, aqueous phase uses 70kg chloroform extraction once again, merge organic phase, wash once with 20L, organic phase is vacuum concentration below 70 DEG C, resistates silica gel column chromatography (elutriant: methylene dichloride: methyl alcohol=20:1(volume ratio)), obtain 6g4-chlorine clindamycin.
ESI-MS data: M:M+2:M+4 ≈ 9:6:1; M/Z [M+H]
+443, illustrate that this structure is compound of dichloro, i.e. 4-chlorine clindamycin.
1h-NMR data: (500MHz, DMSO-d6) δ: 0.92 (t, 3H), 1.34 (m, 3H), 1.42 (d, 3H), 2.01,2.18 (m, 2H), 2.15 (s, 3H), 2.25 (m, 1H), 2.36, (t, 1H), 2.59 (s, 3H), 3.40 (m, 2H), 3.58 (d, 1H), 3.70 (m, 1H), 3.74 (m, 1H), 4.32 (d, 1H), 4.43 (d, 1H), 4.63 (m, 1H), 5.29 (d, 1H).
comparative examplethe preparation of Dalacina
270g chloroform and 115g DMF is added in reaction flask; drip the solution that 126.5g solid phosgene is dissolved in 375g chloroform; temperature controls at 10 DEG C; then 1 hour is incubated; be cooled to 0 DEG C; add 100g U 10149a (HPLC purity 99.5%) under nitrogen protection in batches, be then warmed up to 60 DEG C of reactions 18 hours, react completely.
Above-mentioned reaction solution is cooled to less than 5 DEG C, adds frozen water 295g, then drip 20% potassium hydroxide aqueous solution, keep system temperature be hydrolyzed below 5 DEG C, hydrolyzation system pH 8 ~ 9 time, keep 1 hour constant.And then adding 500g water, extraction, aqueous phase uses 450g, 330g and 300g chloroform extraction again, merges organic phase, washes once with 700g.
Organic phase 75 ~ 80 DEG C of air distillations, the then dry solvent of vacuum concentration, with 50g ethanol band steam once, resistates adds 200g dehydrated alcohol, then be cooled to 20 DEG C, dripping acidic alcohol is 2 ~ 3 to pH, crystallisation by cooling 3 hours, filter, dry, obtain Dalacina ethylate 100g.
The Dalacina ethylate of gained is dissolved in 200g water, adds activated carbon decolorizing, heat filtering, the filtrate obtained is when 70-75 DEG C of vacuum concentration to resistates is 100g, add 200g acetone, resistates is clearly molten, keeps reflux state, add 650g acetone, crystallisation by cooling, filters, vacuum-drying 10 hours, obtain Dalacina 83g, molar yield 80.0%.
HPLC purity: Dalacina finished product: 98.3%; 7-shows clindamycin: 0.85%; 4-chlorine clindamycin: 0.2%.
1h-NMR data: (500MHz, DMSO-d6) δ: 0.86 (t, 3H), 1.28 (m, 2H), 1.33 (d, 3H), 1.40 (m, 2H), 2.02 (s, 3H), 2.02,2.18 (m, 2H), 2.20 (m, 1H), 2.89,3.63 (d, 2H), 2.88 (s, 3H), 3.38 (m, 1H), 3.78 (d, 1H), 3.90 (m, 1H), 4.10 (d, 1H), 4.22 (d, 1H), 4.43 (d, 1H), 4.49 (d, 1H), 5.19 (d, 1H), 8.17 (d, 1H), 9.81 (s, 1H).
Claims (11)
1. a preparation method for Dalacina, is characterized in that, described preparation method comprises the following steps:
(1) make U 10149a and Vilsmeier reagent carry out chlorination, obtain the reaction solution containing Dalacina crude product;
(2) above-mentioned reaction solution is obtained clindamycin free alkali through being hydrolyzed, extracting, concentrate, then by described clindamycin free alkali in 90 ~ 120 DEG C of insulations 20 ~ 120 minutes;
(3) at concentration of volume percent be 90% ~ 95% aqueous ethanolic solution in, described clindamycin free alkali, through salt-forming reaction, obtains Dalacina ethylate;
(4) by the dealcoholysis of described Dalacina ethylate, obtained described Dalacina.
2. the preparation method of Dalacina according to claim 1, is characterized in that, in described step (2), described clindamycin free alkali was 90 ~ 100 DEG C of insulations 40 ~ 80 minutes.
3. the preparation method of Dalacina according to claim 1 and 2, is characterized in that, in described step (1), described chlorination carries out 8 ~ 15 hours at 40 ~ 50 DEG C, carries out 1 ~ 5 hour afterwards at 55 ~ 65 DEG C.
4. the preparation method of Dalacina according to claim 3, is characterized in that, in described step (1), described chlorination carries out 10 ~ 12 hours at 45 ~ 50 DEG C, carries out 2 ~ 4 hours afterwards at 60 ~ 65 DEG C.
5. the preparation method of the Dalacina according to claim 1 or 4, is characterized in that, in described step (1), described Vilsmeier reagent is formed in chlorination solvent chloroform by solid phosgene and DMF.
6. the preparation method of Dalacina according to claim 5, it is characterized in that, in described step (1), the mass ratio of described U 10149a, solid phosgene, DMF and chloroform is 1:1.0 ~ 1.3:1.5 ~ 2:7 ~ 12.
7. the preparation method of Dalacina according to claim 6, is characterized in that, the mass ratio of described U 10149a, solid phosgene, DMF and chloroform is 1:1.0 ~ 1.1:1.6 ~ 1.8:8 ~ 10.
8. the preparation method of Dalacina according to claim 5, it is characterized in that, in described step (1), described chlorination is joined by described solid phosgene in the reaction system containing chloroform, DMF and U 10149a to complete.
9. the preparation method of Dalacina according to claim 8, it is characterized in that, in described step (1), described in add be added by described solid phosgene in batches or be mixed with chloroformic solution to add, the temperature adding fashionable maintenance reaction system is 0 ~ 15 DEG C.
10. the preparation method of the Dalacina according to claim 1 or 9, it is characterized in that, described step (2) is specially: at 10 ~ 30 DEG C, join in aqueous sodium hydroxide solution by described reaction solution, adjust pH is 9 ~ 12, is hydrolyzed 2 ~ 4 hours, then chloroform extraction is used, organic phase, not occurring to dripless higher than 80 DEG C of vacuum concentration, obtains clindamycin free alkali, then by described clindamycin free alkali 90 ~ 100 DEG C of insulations 40 ~ 80 minutes;
Described step (3) is specially: it is in the aqueous ethanolic solution of 90 ~ 95% that the clindamycin free alkali that step (2) obtains is dissolved in concentration of volume percent, passes into hydrogen chloride gas, and adjust pH is 1 ~ 2; Or be dissolved in ethanol by clindamycin free alkali, adding concentrated hydrochloric acid adjust pH is 1 ~ 2, and the concentration of volume percent then adding water to aqueous ethanolic solution is 90 ~ 95%; After crystallization, be incubated 1 ~ 2 hour at 10 ~ 20 DEG C complete with crystallization, filter, be the aqueous ethanolic solution washing of 90 ~ 95% with concentration of volume percent, obtain Dalacina ethylate;
Described step (4) is specially: be dissolved in the water by described Dalacina ethylate, vacuum concentration, removes ethanol, resistates adds acetone solution, then joins in acetone by aqueous acetone solution, separates out solid, filtration, vacuum-drying, obtain described Dalacina.
The preparation method of 11. Dalacinas according to claim 1, is characterized in that, the HPLC purity of described U 10149a is not less than 99.5%.
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