CN104650166A - New preparation method of macrolide - Google Patents
New preparation method of macrolide Download PDFInfo
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- CN104650166A CN104650166A CN201410655730.5A CN201410655730A CN104650166A CN 104650166 A CN104650166 A CN 104650166A CN 201410655730 A CN201410655730 A CN 201410655730A CN 104650166 A CN104650166 A CN 104650166A
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- acid
- diazabicylo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
Abstract
The invention relates to a new preparation method of macrolides, belonging to the field of medicinal chemistry. The invention further relates to a preparation method of Solithromycin. The new preparation method comprises the following step of carrying out 7-th position saccharide ring removal, hydroxyl oxidation and reductive amination with a side chain to obtain an important intermediate (5) having a formula shown in the specification. The preparation method of Solithromycin, disclosed by the invention, has the advantages of few side reactions, operation simpleness and convenience, high yield and high suitability for industrial production. The structure of the intermediate (5) is as shown in the specification.
Description
Technical field
The present invention relates to the preparation method of macrolide, be specifically related to the preparation method of third generation macrolide rope Citropten.
Background technology
Rope Citropten (CEM-101) is third generation macrolide antibiotics, and be also that the first fluorine entering clinical investigation phase replaces ketone lactone medicine, has a broad antifungal spectrum, all has activity to the bacterium of resistance to Macrolide and ketolide antibiotics.Researched and developed by Optimer company, Cempra is authorized to research and develop oral capsule dosage form, be applicable to treatment community acquired pneumonia (CAP), chronic obstructive pulmonary disease (COPD), bacterial pneumonia and N. gonorrhoeae infections, also studying the treatment for bacteriological infection, comprise Mycobacterium leprae, bacterial urethritis, Bacillus anthracis, bird type Mycobacterium tuberculosis and bacterial cutaneous and skin structure infection.
It is from clarithromycin that the preparation method of rope Citropten is described in the method that WO 2009/05557, WO 2009/05557 reports, by the synthesis of different approach, as shown in Scheme 1:
This operational path is long, and form five-ring triazole side chain by azido-and amino-benzene acetylene generation click-reaction after oxidation, amino-benzene ethyne reactive is high, easily causes side reaction.
PCT application WO2014145210 reports the synthetic route be shown below, i.e. route 2:
Route 2 goes up side chain before the oxidation, and side chain will stand desugar ring protection base, be oxidized and the step such as to fluoridize, and easily produces by product, and increases macromolecular polarity, reduces its solubleness at organic solvent, brings inconvenience to aftertreatment.
Summary of the invention
In view of the deficiencies in the prior art, the present invention seeks to exploitation new technology route, to solve the deficiency of existing operational path.
A preparation method for intermediate 5,
It comprises the following steps:
Step 1) 7 sugared rings removing intermediate (2) obtain intermediate (3),
Step 2) hydroxyl oxidize on 7 of intermediate (3) is obtained intermediate (4),
Step 3) intermediate (4) and side chain (A) react and obtain intermediate (5) under organic amine exists,
Step 1) described in remove the reaction of sugared ring in presence of an acid, acid includes but not limited to hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, trifluoroacetic acid, formic acid or hydrofluoric acid or its mixture.In one embodiment, described acid is hydrochloric acid.Common solvent is water, polar organic solvent or its combination such as, and polar organic solvent comprises such as acetone, methyl iso-butyl ketone (MIBK), methyl alcohol, ethanol, Virahol, n-propyl alcohol, the trimethyl carbinol or propyl carbinol or its mixture.In certain embodiments, described solvent is the admixture solvent of acetone and water.The reaction removing sugared ring at all temps, such as, can be carried out in the scope of about 0 degree Celsius to about 70 degrees Celsius, in certain embodiments, carries out under about 20 degrees Celsius to about 60 degrees Celsius, in one embodiment, carries out under about 40 degrees Celsius.
Step 2) described in oxidation usually adopt conventional oxidant include but not limited to Swern oxidation as DMSO/ oxalyl chloride, DMSO/ Vanadium Pentoxide in FLAKES, Dess-Martin oxygenant (DMP, 1,1,1-triacetoxyl group-1,1-dihydro-1,2-benzo iodine is mixed oxa--3 (1H)-one), PCC oxygenant, Jones reagent and other reagent is as chromium oxygenant, permanganate or dimethyl sulphide etc.In certain embodiments, step 2) described in oxidation adopt oxygenant dimethyl sulphide.Step 2) described in oxidation carry out in the halogenated hydrocarbon solvents such as methylene dichloride, trichloromethane, tetracol phenixin, 1,2-ethylene dichloride.
Step 3) organic amine described in reaction of intermediate (4) and side chain (A) is triethylamine, N, dinethylformamide, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), dicyclohexylcarbodiimide (DCC), N, N-lutidine amine (DMAP), 1, one or more of 4-diazabicylo [2.2.2] octane (DABCO), 1,5-diazabicylo [4.3.0]-5-in ninth of the ten Heavenly Stems alkene (DBN); In certain embodiments, described organic amine is 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), 1,5-diazabicylo [4.3.0]-5-in ninth of the ten Heavenly Stems alkene (DBN) or its combination.
Step 3) reaction of intermediate (4) and side chain (A) carries out in organic solvent is as one or more in DMSO, methylene dichloride, tetrahydrofuran (THF), ethyl acetate, acetone, benzene,toluene,xylene or chlorobenzene, in certain embodiments, described organic solvent is the mixed solvent of DMSO and methylene dichloride.
Protection on hydroxyl on sugared ring is generated intermediate 1 by clarithromycin benzoyl oxide by operational path of the present invention; then under the effect of organic bases as DBU and CDI, intermediate 2 is generated; then under the effect of hydrochloric acid, intermediate 3 is generated; intermediate 4 is generated again through oxidation; intermediate 4 and side chain (A) reaction generate intermediate 5; then through selective fluorination generate intermediate 6, namely obtain rope Citropten after intermediate 6 deprotection, concrete reaction formula as shown in Scheme 3:
The invention provides the preparation method of the short rope Citropten of a kind of operational path, go up after which step and namely go up side chain (A), oxidation impurities is less, and such cost is lower, convenient post-treatment.Adopt route of the present invention, be that raw material obtains rope Citropten through 7 steps with clarithromycin, ultimate production is more than 60%.
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the context of the invention, DMAP:4-Dimethylamino pyridine; DBU:1,8-diazabicylo 11 carbon-7-alkene; CDI:N, N'-carbonyl dimidazoles; MTBE: methyl tertiary butyl ether; The two benzsulfamide of NFSI:N-fluoro, DMSO is dimethyl sulfoxide (DMSO).
The preparation of embodiment 1 intermediate 1
Joined in 500mL ethyl acetate by 100g clarithromycin, add 11.4g DMAP, 53.0g benzoyl oxide, 13.2g triethylamine, be warming up to 70 DEG C, insulated and stirred, sample censorship after reaction 16h, reaction terminates.Be cooled to 30-40 DEG C, add the washing of 300mL4% sodium hydrogen carbonate solution, after separatory, evaporate to dryness ethyl acetate solvent obtains 140g intermediate 1, purity about 96%, yield 97%.
Embodiment 2 prepares intermediate 2
Intermediate 1 (40g) joins in 160mL toluene, after stirring and dissolving, adds 12.19g DBU, adds the CDI of 16.24g again, room temperature (28 DEG C) stirring reaction 24h after stirring 30min; After completion of the reaction, concentrating under reduced pressure, except desolventizing, after adding 200mL water stirring 5h, filters, washes, and gained solid obtains 49g intermediate 2, productive rate 93% at the dry 40 DEG C of dry 12h of vacuum drying oven.
Embodiment 3 prepares intermediate 3
Intermediate 2 (40g) is joined in 120mL acetone and 120mL water, after stirring 10min, solid all dissolves, and adds the hydrochloric acid of 40mL 5%, is warming up to 40 DEG C of reaction 12h, after completion of the reaction, be cooled to 20-25 DEG C, regulate pH to 10-11, product is separated out, filtration, washing, gained solid obtain 23g intermediate 3, productive rate 95% at the dry 40 DEG C of dry 12h of vacuum drying oven.
Embodiment 4 prepares intermediate 4
After intermediate 3 (2.45g) is dissolved with 10mL methylene dichloride, be cooled to-20 DEG C, then add 1.52g dimethyl sulphide, after stirring 1h, add the dichloromethane solution (10g intermediate 3 is dissolved in 30mL methylene dichloride) of intermediate 3, after-20 degree stir 3h, slowly add Et
3n (1.2g),-20 DEG C of insulation 1.5h, slowly return to 20-25 DEG C of stirring, after completion of the reaction in 1.5h, after reaction terminates, the S-WAT adding 20g 1% washes 2 organic layers, and evaporate to dryness organic layer adds 10% aqueous sodium carbonate of MTBE and 20g of 20g, and MTBE merges organic layer after washing 1 time, 10g 10% aqueous sodium carbonate and saturated sodium-chloride respectively wash 3 times, solvent is removed in saturated common salt water washing 35 DEG C decompression, obtains the intermediate 4 of 9.3g, productive rate 91%.
Embodiment 5 prepares intermediate 5
Intermediate 4 (10g) adds 30mL DMSO and 30mL methylene dichloride, after stirring and dissolving, adds 9.04g side chain (A) (according to method preparation disclosed in WO2014145210), add 0.74gDBU, 25 DEG C are stirred 24h, and sampling detects, and reaction terminates.When 40 DEG C of underpressure distillation are extremely flowed out without obvious liquid, be cooled to 20-25 DEG C, add 60mL water, stir 2h, filtration, washing, drying, obtain 10.3g intermediate 5, productive rate 93%.
Embodiment 6 prepares intermediate 6
10g intermediate 5 is joined in 80mL THF, after stirring, be cooled to-35 DEG C, add 1.65g potassium tert.-butoxide, after stirring 10min, drip NFSI solution (4.3g NFSI is dissolved in 20mL THF), about 15-20min dropwises, after dropwising, rise to 25 DEG C, sample after insulation 2h, 5% sodium bicarbonate of 50g washes organic layer, and then wash with 25g salt, solvent evaporated obtains foaming solid, add 30mL Virahol again, be warming up to 40 DEG C, solid all dissolves, drip 30mL water, be cooled to 20-25 DEG C, filter, washing, dry, obtain 7.0g intermediate 06, productive rate 96%.
Embodiment 7 prepares rope Citropten
10g intermediate 06 is joined in 50mL methyl alcohol, is warming up to 40 DEG C, insulation reaction 24h, is cooled to 20-25 DEG C, drip 50mL water, be cooled to 0-5 DEG C, stir 2h, filter, rope Citropten that washing, drying can arrive 8.1g, productive rate: 98%.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (10)
1. a preparation method for intermediate 5,
It comprises the following steps:
Step 1) 7 sugared rings removing intermediate (2) obtain intermediate (3),
Step 2) hydroxyl oxidize on 7 of intermediate (3) is obtained intermediate (4),
Step 3) intermediate (4) and side chain (A) react and obtain intermediate (5) under organic amine exists,
2. the method for claim 1, step 1) described in remove the reaction of sugared ring in presence of an acid, described acid is hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, trifluoroacetic acid, formic acid or hydrofluoric acid or its mixture.
3. the method for claim 1, step 1) described in remove sugared ring reaction carry out in the admixture solvent of acetone and water.
4. the method for claim 1, step 1) described in remove sugared ring reaction carry out at about 20 degrees Celsius to about 60 degrees Celsius.
5. the method for claim 1, step 2) described in oxidation adopt oxygenant dimethyl sulphide.
6. the method for claim 1, step 2) described in oxidation carry out in methylene dichloride, trichloromethane, tetracol phenixin or 1,2-ethylene dichloride.
7. the method for claim 1, step 3) described in organic amine be triethylamine, N, dinethylformamide, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), dicyclohexylcarbodiimide (DCC), N, N-lutidine amine (DMAP), 1, one or more of 4-diazabicylo [2.2.2] octane (DABCO), 1,5-diazabicylo [4.3.0]-5-in ninth of the ten Heavenly Stems alkene (DBN).
8. the method for claim 1, step 3) described in organic amine be 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene.
9. the method for claim 1, step 3) carry out in one or more in DMSO, methylene dichloride, tetrahydrofuran (THF), ethyl acetate, acetone, benzene,toluene,xylene or chlorobenzene of the reaction of intermediate (4) and side chain (A).
10. method as claimed in claim 9, described organic solvent is the mixed solvent of DMSO and methylene dichloride.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105348341A (en) * | 2015-12-04 | 2016-02-24 | 浙江京新药业股份有限公司 | Method for preparing solithromycin |
| CN105503976A (en) * | 2015-12-04 | 2016-04-20 | 浙江京新药业股份有限公司 | Solithromycin intermediate |
| CN106432383A (en) * | 2016-09-14 | 2017-02-22 | 重庆两江药物研发中心有限公司 | Solithromycin and preparation method of intermediate thereof |
| CN106518939A (en) * | 2015-09-14 | 2017-03-22 | 江苏奥赛康药业股份有限公司 | Method for preparing Solithromycin compound |
| CN106554381A (en) * | 2015-09-25 | 2017-04-05 | 苏州鹏旭医药科技有限公司 | Ketolide antibiotics intermediate and its preparation method and application |
| CN107216360A (en) * | 2016-03-22 | 2017-09-29 | 浙江京新药业股份有限公司 | A kind of method for preparing rope Citropten |
| CN108610388A (en) * | 2016-12-12 | 2018-10-02 | 浙江京新药业股份有限公司 | A kind of preparation method of macrolide |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106518939A (en) * | 2015-09-14 | 2017-03-22 | 江苏奥赛康药业股份有限公司 | Method for preparing Solithromycin compound |
| CN106518939B (en) * | 2015-09-14 | 2019-12-31 | 江苏奥赛康药业有限公司 | Method for preparing Solithromycin compound |
| CN106554381A (en) * | 2015-09-25 | 2017-04-05 | 苏州鹏旭医药科技有限公司 | Ketolide antibiotics intermediate and its preparation method and application |
| CN105348341A (en) * | 2015-12-04 | 2016-02-24 | 浙江京新药业股份有限公司 | Method for preparing solithromycin |
| CN105503976A (en) * | 2015-12-04 | 2016-04-20 | 浙江京新药业股份有限公司 | Solithromycin intermediate |
| CN105348341B (en) * | 2015-12-04 | 2018-01-09 | 浙江京新药业股份有限公司 | A kind of method for preparing rope Citropten |
| CN105503976B (en) * | 2015-12-04 | 2018-02-06 | 浙江京新药业股份有限公司 | A kind of rope Citropten intermediate |
| CN107216360A (en) * | 2016-03-22 | 2017-09-29 | 浙江京新药业股份有限公司 | A kind of method for preparing rope Citropten |
| CN107216360B (en) * | 2016-03-22 | 2019-06-21 | 浙江京新药业股份有限公司 | A method of preparing rope Citropten |
| CN106432383A (en) * | 2016-09-14 | 2017-02-22 | 重庆两江药物研发中心有限公司 | Solithromycin and preparation method of intermediate thereof |
| CN108610388A (en) * | 2016-12-12 | 2018-10-02 | 浙江京新药业股份有限公司 | A kind of preparation method of macrolide |
| CN108610388B (en) * | 2016-12-12 | 2020-11-06 | 浙江京新药业股份有限公司 | Preparation method of macrolide |
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