BG61652B1 - Method for the preparation of clindamycin falmitate hydrochloride - Google Patents
Method for the preparation of clindamycin falmitate hydrochloride Download PDFInfo
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- BG61652B1 BG61652B1 BG97839A BG9783993A BG61652B1 BG 61652 B1 BG61652 B1 BG 61652B1 BG 97839 A BG97839 A BG 97839A BG 9783993 A BG9783993 A BG 9783993A BG 61652 B1 BG61652 B1 BG 61652B1
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- Prior art keywords
- clindamycin
- hydrochloride
- isopropylidene
- acetone
- palmitate hydrochloride
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- 238000000034 method Methods 0.000 title claims abstract description 17
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 title claims description 11
- 229960002227 clindamycin Drugs 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 6
- GTNDZRUWKHDICY-DJHAJVGHSA-N Clindamycin palmitate hydrochloride Chemical compound Cl.O1[C@H](SC)[C@H](OC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@@H](O)[C@H]1[C@@H]([C@H](C)Cl)NC(=O)[C@H]1N(C)C[C@H](CCC)C1 GTNDZRUWKHDICY-DJHAJVGHSA-N 0.000 claims description 13
- 229960001200 clindamycin hydrochloride Drugs 0.000 claims description 11
- 229960000792 clindamycin palmitate hydrochloride Drugs 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 4
- FGQLGYBGTRHODR-UHFFFAOYSA-N 2,2-diethoxypropane Chemical compound CCOC(C)(C)OCC FGQLGYBGTRHODR-UHFFFAOYSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 3
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 3
- 238000002955 isolation Methods 0.000 abstract 2
- 229960004714 clindamycin palmitate Drugs 0.000 abstract 1
- OYSKUZDIHNKWLV-PRUAPSLNSA-N clindamycin palmitate Chemical compound O1[C@H](SC)[C@H](OC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@@H](O)[C@H]1[C@@H]([C@H](C)Cl)NC(=O)[C@H]1N(C)C[C@H](CCC)C1 OYSKUZDIHNKWLV-PRUAPSLNSA-N 0.000 abstract 1
- 239000013078 crystal Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 9
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- GVGJMVMACNERRI-UHFFFAOYSA-N Cl.[CH2-]C(=O)C Chemical compound Cl.[CH2-]C(=O)C GVGJMVMACNERRI-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229920002717 polyvinylpyridine Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Изобретението се отнася до метод за получаване на клиндамицин палмитат хидрохлорид от клиндамицин хидрохлорид изопропанолсолват.The invention relates to a method for the preparation of clindamycin palmitate hydrochloride from clindamycin hydrochloride isopropanol solvate.
Известен е метод за получаване на клиндамицин палмитат хидрохлорид от клиндамицин хидрохлорид хидрат (US 3 580 904). Основни недостатъци на метода са следните:A method is known for the preparation of clindamycin palmitate hydrochloride from clindamycin hydrochloride hydrate (US Pat. No. 3,580,904). The main disadvantages of the method are the following:
- Защитата на трета и четвърта позиция се извършва с анизалдехид чрез азеотропно отстраняване на водата с бензол, който е токсичен, канцерогенен и създава опасност за работещите и за качеството на крайния продукт;- The protection of the third and fourth positions is carried out with anisaldehyde by azeotropically removing the water with benzene, which is toxic, carcinogenic and creates a risk for workers and for the quality of the final product;
- Ацилирането се извършва в чист пиридин, което създава проблеми при получаването на суха реакционна среда, опасност от замърсяване на субстанцията и затруднения при регенерацията на разтворителя;- The acylation is carried out in pure pyridine, which creates problems in obtaining a dry reaction medium, danger of contamination of the substance and difficulties in the regeneration of the solvent;
- Полученият при депротекцията анизалдехид и склонността на субстанцията към осмоляване създава проблеми при кристализацията и налага утаяването на субстанцията да се извършва в големи обеми от токсичния ацетонитрил. Анизалдехидът може да придаде на продукта страничен мирис;- The anisaldehyde obtained by deprotection and the tendency of the substance to resin creates crystallization problems and necessitates the precipitation of the substance to be carried out in large volumes of toxic acetonitrile. Anisaldehyde can give the product a side odor;
- Добивът на процеса е сравнително нисък. Като се има предвид, че най-добрият добив от солват до хидрат (US 4 568 741) е 96,9%, а също, че в разглеждания патент, добивът при защитаването е 83%, от анизилиден клиндамицин хидрохлорид до целевия продукт е 84% и общият добив се получава 67,5%.- The yield of the process is relatively low. Given that the best yield from solvate to hydrate (US 4 568 741) is 96.9%, and also that in the present patent, the yield on protection is 83%, from anisilide clindamycin hydrochloride to the target product is 84 % and the total yield is 67.5%.
В US 4 849 515 е посочен метод за получаване на клиндамицин-3,4 - ацетонид чрез използване на диметоксипропан. Полученият в резултат на реакцията метанол повишава разтворимостта на целевия продукт, което води до снижаване на добива.U.S. Pat. No. 4,849,515 discloses a method for the preparation of clindamycin-3,4-acetonide using dimethoxypropane. The methanol resulting from the reaction increases the solubility of the target product, leading to a decrease in yield.
Задачата на изобретението е да се създаде метод за получаване на клиндамицин палмитат хидрохлорид с използване на малки количества вредни за здравето реактиви, гарантиращ висок добив и чистота.It is an object of the invention to provide a process for the preparation of clindamycin palmitate hydrochloride using small amounts of health-damaging reagents, ensuring high yield and purity.
Методът съгласно изобретението се състои в получаване от клиндамицин хидрохлорид изопропанолсолват на клиндамицин ацетонид хидрохлорид чрез използване като защитаващ агент - 1,8-3,5 mol диетоксипропан, получен in situ от триетилортоформиат и ацетон в присъствие на каталитични количества силна киселина при 30 до 50°С за 4 до 20 h. Полученият ацетонид хидрохлорид се изолира в кристален вид и се превръща в толуолен разтвор на база. Ацилира се с 1,1-1,5 moi палмитоилхлорид в строго безводни условия специфично на втора позиция при 20 до 30°С за 2-4 h, след което се снема защитата чрез хидролиза в слабо кисела среда при 65 до 80°С за 8 до 20 h. Продуктът се промива като толуолен разтвор и след отстраняване на разтворителя се кристализира в ацетон. Разтворената във вода утайка е филтрира и лиофилизира след кристализация при 0 до 5°С за 2-4 h до прахообразна субстанция.The method according to the invention consists in the preparation of clindamycin hydrochloride isopropanol solvate of clindamycin acetonide hydrochloride by using as a protecting agent - 1.8-3.5 mol of diethoxypropane obtained in situ from triethylorthoformate and acetone in the presence of catalytic amounts of strong acid at 30 to 50 ° From 4 to 20 h. The resulting acetonide hydrochloride was isolated in crystalline form and converted into a toluene solution based on. Acylates with 1.1-1.5 moi palmitoyl chloride under strictly anhydrous conditions, specifically at the second position at 20 to 30 ° C for 2-4 hours, after which the protection is removed by hydrolysis in a slightly acidic medium at 65 to 80 ° C. 8 to 20 h. The product was washed as a toluene solution and, after removal of the solvent, crystallized in acetone. The water-soluble precipitate was filtered off and lyophilized after crystallization at 0 to 5 ° C for 2-4 h to a powder.
Предимствата на метода съгласно изобретението са:The advantages of the method according to the invention are:
- използват се достъпни суровини;- accessible raw materials are used;
- използват се минимални количества вредни за здравето реактиви;- Minimal quantities of health-damaging reagents are used;
- добивът при процеса на защитаване на трета и четвърта позиция е близък до теоретичния;- the yield in the process of protecting the third and fourth positions is close to theoretical;
- при ацилирането с палмитоилхлорид като акцептор на хлороводорода до голяма степен се използва базичната група на самия клиндамицин и количеството на необходимия пиридин е много малко;- Acidylation with palmitoyl chloride as a hydrogen chloride acceptor largely utilizes the basic group of clindamycin itself and the amount of pyridine required is very small;
- при депротекцията се получава като страничен продукт практически безвредния ацетон;- in the deprotection, the virtually harmless acetone is obtained as a by-product;
- относително по-високата стабилност на изопропилиденовата защита пред анизилиденовата изключва образуването на 3- и 4-палмитоилирани продукти;- the relatively higher stability of isopropylidene protection against anisilidene precludes the formation of 3- and 4-palmitoylated products;
- промиването на толуолния разтвор с вода отстранява следите от пиридин и евентуално наличния свободен клиндамицин;- washing the toluene solution with water removes traces of pyridine and any available free clindamycin;
- провеждането на лиофилизация позволява получаването на чиста от механични примеси и дори стерилна субстанция.- carrying out lyophilization permits the production of a pure mechanical impurity and even a sterile substance.
Изобретението се илюстрира със следните примери:The invention is illustrated by the following examples:
Пример 1. 3,4-0-изопропилиденклиндамицин хидрохлоридExample 1. 3,4-0-Isopropylidene clindamycin hydrochloride
Към охладена смес от ацетон, диметилформамид и триетилортоформиат се прибавят 84 g (161 mmol) клиндамицин хидрохлорид изопропанолсолват.To a cooled mixture of acetone, dimethylformamide and triethylorthoformate, 84 g (161 mmol) of clindamycin hydrochloride isopropanol solvate were added.
След разбъркване при 0°С - 30 min, при 25°С - 60 min и при 43°С - 6 h, сместа се охлажда и се прибавят 5 g сух поливинилпиридин. Разбърква се при 0°С 1 h, суспензията се филтрира и продуктът се суши във вакуум приAfter stirring at 0 ° C for 30 min, at 25 ° C for 60 min and at 43 ° C for 6 h, the mixture was cooled and 5 g of dry polyvinylpyridine was added. Stir at 0 ° C for 1 h, filter the suspension and dry the product in vacuo at
90°С. Получават се 84,7 g, от които целевият продукт е 79,7g (159 mmol, 98,7%) 3,4-0-изопропилиденклиндамицин хидрохлорид.90 ° C. 84.7 g are obtained, of which the target product is 79.7 g (159 mmol, 98.7%) of 3,4-0-isopropylidene clindamycin hydrochloride.
Пример 2. Клиндамицин-2-палмитат хидрохлоридExample 2. Clindamycin-2-palmitate hydrochloride
В 500 ml толуол се разтварят 74,6 g 3,4О-изопропилиденклиндамицин хидрохлорид (пример 1) (140 mmol) и сместа се алкализира с триетиламин. Утайката се отстранява чрез филтриране и разтворът се концентрира във вакуум до 250 ml. Прибавят се 10 ml пиридин и при бъркане на ледена баня се прибавят 55 ml палмитоилхлорид в 55 ml толуол. След бъркане при 0°С 30 min и при стайна температура 3 h разтворът се изпарва във вакуум до масло. Прибавят се 250 ml 85% оцетна киселина и разтворът престоява при 75°С за 10 h. Отстранява се оцетната киселина във вакуум й продуктът се разтваря в толуол и се промива двукратно с по 100 ml вода. След отстраняване на толуола във вакуум продуктът се преципитира в ацетон. Преципитатът се филтрира и се продухва със сух въздух 1 h. Влажният клиндамицин палмитат хидрохлорид се разтваря в 500 ml вода и разтворът се лиофилизира. Получават се 83,2 g клиндамицин палмитат хидрохлорид с активност 580 pg/mg (HPLC) (119 mmol, 85%). Общият добив на синтеза е 83,9%.74.6 g of 3,4O-isopropylidene clindamycin hydrochloride (Example 1) (140 mmol) were dissolved in 500 ml of toluene and the mixture was basified with triethylamine. The precipitate was removed by filtration and the solution was concentrated in vacuo to 250 ml. 10 ml of pyridine are added and 55 ml of palmitoyl chloride in 55 ml of toluene are added while stirring in an ice bath. After stirring at 0 ° C for 30 min and at room temperature for 3 h, the solution was evaporated in vacuo to an oil. 250 ml of 85% acetic acid were added and the solution was left at 75 ° C for 10 h. Acetic acid was removed in vacuo and the product was dissolved in toluene and washed twice with 100 ml of water each. After removal of the toluene in vacuo, the product was precipitated in acetone. The precipitate was filtered off and purged with dry air for 1 hour. The wet clindamycin palmitate hydrochloride was dissolved in 500 ml of water and the solution lyophilized. 83.2 g of clindamycin palmitate hydrochloride were obtained with an activity of 580 pg / mg (HPLC) (119 mmol, 85%). The total synthesis yield was 83.9%.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BG97839A BG61652B1 (en) | 1993-05-31 | 1993-05-31 | Method for the preparation of clindamycin falmitate hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BG97839A BG61652B1 (en) | 1993-05-31 | 1993-05-31 | Method for the preparation of clindamycin falmitate hydrochloride |
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| Publication Number | Publication Date |
|---|---|
| BG97839A BG97839A (en) | 1995-04-28 |
| BG61652B1 true BG61652B1 (en) | 1998-02-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BG97839A BG61652B1 (en) | 1993-05-31 | 1993-05-31 | Method for the preparation of clindamycin falmitate hydrochloride |
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| Country | Link |
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| BG (1) | BG61652B1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100368419C (en) * | 2006-03-01 | 2008-02-13 | 重庆凯林制药有限公司 | Industrial production process of palmitate of clindamycin hydrochloride |
-
1993
- 1993-05-31 BG BG97839A patent/BG61652B1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100368419C (en) * | 2006-03-01 | 2008-02-13 | 重庆凯林制药有限公司 | Industrial production process of palmitate of clindamycin hydrochloride |
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| Publication number | Publication date |
|---|---|
| BG97839A (en) | 1995-04-28 |
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