HRP960445A2 - New process for the preparation of ropivacaine hydrochloride monohydrate - Google Patents
New process for the preparation of ropivacaine hydrochloride monohydrate Download PDFInfo
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- 238000000034 method Methods 0.000 title claims description 34
- NDNSIBYYUOEUSV-RSAXXLAASA-N (S)-ropivacaine hydrochloride (anhydrous) Chemical compound [Cl-].CCC[NH+]1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C NDNSIBYYUOEUSV-RSAXXLAASA-N 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title claims description 7
- 229960003691 ropivacaine hydrochloride monohydrate Drugs 0.000 title claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- 238000002425 crystallisation Methods 0.000 claims description 15
- 230000008025 crystallization Effects 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical group [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 238000000605 extraction Methods 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 229960001813 ropivacaine hydrochloride Drugs 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 6
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000009518 sodium iodide Nutrition 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 230000029936 alkylation Effects 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 229950000188 halopropane Drugs 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000005119 centrifugation Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 3
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- DXDIHODZARUBLA-DTPOWOMPSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid;hydrate Chemical compound O.O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 DXDIHODZARUBLA-DTPOWOMPSA-N 0.000 description 1
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 description 1
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 1
- SILRCGDPZGQJOQ-UHFFFAOYSA-N 2,6-Pipecoloxylidide Chemical compound CC1=CC=CC(C)=C1NC(=O)C1NCCCC1 SILRCGDPZGQJOQ-UHFFFAOYSA-N 0.000 description 1
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229960003150 bupivacaine Drugs 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 229960002409 mepivacaine Drugs 0.000 description 1
- INWLQCZOYSRPNW-UHFFFAOYSA-N mepivacaine Chemical compound CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C INWLQCZOYSRPNW-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Polje izuma The field of invention
Sadašnji izum se odnosi na novi postupak priprave ropivakain hidroklorid monohidrata. The present invention relates to a new process for the preparation of ropivacaine hydrochloride monohydrate.
Pozadina i prijašnja saznanja Background and previous knowledge
Problem koji prethodi sadašnjem izumu je bio osigurati postupak prilagođen tvorničkoj proizvodnji, koji bi dao ponovljiva visoko enantiomerna iskorištenja i visoku optičku čistoću. The problem preceding the present invention was to provide a process adapted to factory production, which would give reproducible high enantiomeric yields and high optical purity.
Ropivakain hidroklorid monohidrat je trivijalno ime za spoj (S)-(-)-1-propil-2',6'-pipekoloksilidid hidroklorid monohidrat, spoj koji je lokalni anestetik opisan u EP 0 239 710. On se pripravlja dodatkom vode i vrućeg acetona ropivakain hidrokloridu nakon čega željeni produkt kristalizira. Postupak priprave početne tvari, ropivakain hidroklorida, je opisan u EP 0 151 110. Ropivacaine hydrochloride monohydrate is a trivial name for the compound (S)-(-)-1-propyl-2',6'-pipecoloxylidide hydrochloride monohydrate, a compound which is a local anesthetic described in EP 0 239 710. It is prepared by adding water and hot acetone ropivacaine hydrochloride, after which the desired product crystallizes. The procedure for the preparation of the starting substance, ropivacaine hydrochloride, is described in EP 0 151 110.
US patent br. 1,180,712 objavljuje postupak priprave levo-1-n-butil-2',6'-pipekoloksilidida. Rečeni postupak uključuje prvi stupanj odijeljivanja dl-2',6'-pipekoloksilidida, gdje dl-2',6'-pipekoloksilidid reagira s 0,0-dibenzoil-d-vinskom kiselinom i nakon toga nastala smjesa diastereoizomera 0,0-dibenzoil-d-tartarata reagira s vrijućim acetonom, u acetonu netopiva desno-2',6'-pipekoloksilidna sol je odijeljena i lijevo-2',6'-pipekoloksilidna sol je izolirana iz acetonske otopine. Međutim, opisani postupak je zamršen i uključuje izolaciju produkta iz vrućeg acetona, to jest to je jednostavan način za laboratorije koji ne mogu primijeniti tvorničku proizvodnju. US patent no. 1,180,712 discloses a process for the preparation of levo-1-n-butyl-2',6'-pipecoloxylidide. Said process includes the first stage of separation of dl-2',6'-pipecoloxylidide, where dl-2',6'-pipecoloxylidide reacts with 0,0-dibenzoyl-d-tartaric acid and then the resulting mixture of diastereoisomers of 0,0-dibenzoyl- d-tartrate reacts with boiling acetone, the acetone-insoluble right-2',6'-pipecoloxylide salt is separated and the left-2',6'-pipecoloxylide salt is isolated from the acetone solution. However, the described procedure is complicated and involves isolation of the product from hot acetone, that is, it is a simple method for laboratories that cannot apply factory production.
Ideja o upotrebi načina razdvajanja radi dobivanja duže djelujućeg jednog enantiomera lokalnog anestetika mepivakaina i bupivakaina je objavljena u J.Med.Chem., 14 (1971) 891-892. Smjesa 2',6'-pipekoloksilidida je tretirana s dibenzoil-L-vinskom kiselinom monohidratom, gdje je izopropanol dodan odjeljujući u izopropanolu netopivi enantiomer, nakon čega je željeni enantiomer izoliran. Upotreba izopropanola ne daje sustav za kristalizaciju koji je stabilan kroz vrijeme potrebno za tvorničku proizvodnju. To je radi prezasićenosti otopine s neželjenim enantiomerom, i stoga kristalizacija u krivom pravcu može lako započeti malim uznemiravanjem, što znači da izopropanol nije pogodan za upotrebu kod produkcije na većoj skali. The idea of using a separation method to obtain a longer-acting single enantiomer of the local anesthetics mepivacaine and bupivacaine was published in J.Med.Chem., 14 (1971) 891-892. The mixture of 2',6'-pipecoloxylidide was treated with dibenzoyl-L-tartaric acid monohydrate, where isopropanol was added separating the isopropanol-insoluble enantiomer, after which the desired enantiomer was isolated. The use of isopropanol does not provide a crystallization system that is stable over the time required for factory production. This is due to the supersaturation of the solution with the undesired enantiomer, and therefore crystallization in the wrong direction can easily start with a small disturbance, which means that isopropanol is not suitable for use in large-scale production.
U Acta Chem. Scand. B, 41 (1987) 757-761, opisana je upotreba izopropanola skupa s različitim sadržajem vode za stupanj odijeljivanja. Ove kombinacije su dale različita iskorištenja i kvalitetu. Također kombinacija izopropanola i vode je dala sustav kristalizacije koji nije dovoljno stabilan za tvorničku proizvodnju. In Acta Chem. Scand. B, 41 (1987) 757-761, the use of isopropanol together with different water contents for the separation step is described. These combinations gave different yields and quality. Also, the combination of isopropanol and water gave a crystallization system that is not stable enough for factory production.
Prikaz izuma Presentation of the invention
Sadašnji izum je usmjeren prema postupku pogodnom za pripravu ropivakain hidroklorid monohidrata na velikoj skali, koji je spoj s formulom (I) The present invention is directed to a process suitable for the large-scale preparation of ropivacaine hydrochloride monohydrate, which is a compound of formula (I)
[image] [image]
Ovaj novi postupak uključuje tri stupnja, od kojih je prvi stupanj odijeljivanje. This new procedure includes three stages, the first stage of which is separation.
Nađeno je da upotrebom sredstva za odijeljivanje koje čini stabilan kristalizacijski sustav s vodom, poželjno kombinacija ketona i vode, je moguće odijeliti neželjeni (R)-pipekoloksilidid i izolirati (S)-pipekoloksilidid u prvom stupnju. Tako je postignut kristalizacijski sustav koji je postojan do 24 sata, stoje dovoljno za tvorničku proizvodnju. It has been found that using a separating agent that forms a stable crystallization system with water, preferably a combination of ketones and water, it is possible to separate the undesired (R)-pipecoloxylidide and isolate the (S)-pipecoloxylidide in the first step. This is how a crystallization system was achieved that is stable for up to 24 hours, enough for factory production.
Nije moguće povećati enantiomerno iskorištenje ni u jednom od dva uzastopna postupka, što znači da je prvi stupanj od velike važnosti. Stoga je slijedeći vid sadašnjeg izuma bio dobiti ponovljivo visoko enantiomerno iskorištenje i visoku optičku čistoću u prvom stupnju. To je postignuto upotrebom kombinacije ketona, koji skupa s vodom čini postojan kristalizacijski sustav, i vode. It is not possible to increase the enantiomeric yield in either of the two consecutive processes, which means that the first step is of great importance. Therefore, a further aspect of the present invention was to obtain reproducible high enantiomeric recovery and high optical purity in the first step. This was achieved by using a combination of ketones, which together with water form a stable crystallization system, and water.
Novi postupak prema sadašnjem izumu za pripravu spoja (I) uključuje slijedeće stupnjeve: The new process according to the present invention for the preparation of compound (I) includes the following steps:
Stupanj l Degree l
(i) Racemična početna tvar pipekoloksilidid hidroklorid formule (II) (i) Racemic starting substance pipecoloxylidide hydrochloride of formula (II)
[image] [image]
je oslobođena svoje HCl soli ekstrakcijom u neko organsko otapalo s razrijeđenom lužinom; was freed from its HCl salt by extraction into an organic solvent with dilute alkali;
(ii) pipekoloksilidid je odijeljen kristalizacijom sa sredstvom za odijeljivanje koje čini postojan kristalizacijski sustav s vodom, i kristaliničan produkt je oslobođen svoje soli ekstrakcijom u neko organsko otapalo koje otapa minimalno oko 1% (volumno) vode s razrijeđenom lužinom, dajući spoj (S)-pipekoloksilidid formule (III) (ii) the pipecoloxylidide is separated by crystallization with a separating agent that forms a stable crystallization system with water, and the crystalline product is freed from its salt by extraction into some organic solvent that dissolves a minimum of about 1% (by volume) of water with dilute alkali, giving compound (S) - pipecoloxylidide of formula (III)
[image] [image]
Stupanj 2: Stage 2:
(i) (S)-pipekoloksilidid formule (III) je alkiliran s 1-halopropanom, poželjno s 1-brompropanom ili 1-jodpropanom, u nazočnosti lužine i po izboru uz katalizator, reakcija je okončana grijanjem, poželjno na temperaturi refluksa, ili po izboru kod niže temperature što međutim znači da je reakcija okončana sporije, nakon čega su anorganske soli odijeljene ekstrakcijom s vodom; (i) (S)-pipecoloxylidide of formula (III) is alkylated with 1-halopropane, preferably with 1-bromopropane or 1-iodopropane, in the presence of alkali and optionally with a catalyst, the reaction is terminated by heating, preferably at reflux temperature, or by selection at a lower temperature, which, however, means that the reaction ended more slowly, after which the inorganic salts were separated by extraction with water;
(ii) Dobivena otopina u stupnju 2(i) je po izboru razrijeđena i produkt je taložen kao ropivakain hidroklorid formule (IV) (ii) The solution obtained in step 2(i) is optionally diluted and the product is precipitated as ropivacaine hydrochloride of formula (IV)
[image] [image]
koji je nakon toga izoliran; which was subsequently isolated;
Stupanj 3: Dobiveni produkt (IV) u stupnju 2(ii) je otopljen u vodenom acetonu, poželjno kod temperature refluksa, produkt (I) je taložen dodatkom acetona, i konačno je produkt izoliran i sušen. Step 3: The product (IV) obtained in step 2(ii) is dissolved in aqueous acetone, preferably at reflux temperature, the product (I) is precipitated by the addition of acetone, and finally the product is isolated and dried.
Sredstva za odijeljivanje koja se mogu upotrijebiti u stupnju l(i) su L-(-)-dibenzoil vinska kiselina ili (L)-(-)-ditoluil vinska kiselina, L-(-)-dibenzoil vinska kiselina je najpoželjnije sredstvo za odijeljivanje. Separating agents that can be used in step 1(i) are L-(-)-dibenzoyl tartaric acid or (L)-(-)-ditoluyl tartaric acid, L-(-)-dibenzoyl tartaric acid being the most preferred separating agent .
Razrijeđena lužina u stupnju l(i) je poželjno odabrana između natrij-hidroksida, kalij-hidroksida, natrij-karbonata ili kalij-karbonata. The dilute alkali in step 1(i) is preferably selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
Poželjna sredstva za odijeljivanje kod kristalizacije u stupnju l(ii) su ketoni koji čine postojani kristalizacijski sustav skupa s vodom. Poželjna otapala za ovu kristalizaciju su aceton ili etilmetil-keton, najpoželjniji je aceton. The preferred separating agents for crystallization in step 1(ii) are ketones, which form a stable crystallization system together with water. The preferred solvents for this crystallization are acetone or ethyl methyl ketone, the most preferred being acetone.
Poželjan sadržaj vode u organskom otapalu upotrijebljenom u stupnju l(ii) je 15-25%, najpoželjnije 20%. The preferred water content in the organic solvent used in step 1(ii) is 15-25%, most preferably 20%.
Organsko otapalo upotrijebljeno kod ekstrakcije u stupnju l(ii) treba otopiti minimalno oko 1% (volumno) vode. Ukoliko ne, reakcija se odvija u dvofaznom sustavu. Štoviše, dodatna količina vode, oko 5%, bi poželjno trebala biti nazočna za vrijeme reakcije. Izbor organskog otapala upotrijebljenog u ekstrakciji stupnja l(ii) će se ocijeniti kod sposobne osobe. Međutim, organsko otapalo se poželjno odabire između izobutilmetil-ketona, acetonitrila, etanola, butanola ili toluena, ali se i ostala otapala mogu upotrijebiti. Izobutilmetil-keton je posebno poželjan. The organic solvent used in the extraction in step 1(ii) should dissolve a minimum of about 1% (by volume) of water. If not, the reaction takes place in a two-phase system. Moreover, an additional amount of water, about 5%, should preferably be present during the reaction. The choice of organic solvent used in the extraction of step l(ii) will be evaluated by a skilled person. However, the organic solvent is preferably selected from isobutylmethyl ketone, acetonitrile, ethanol, butanol or toluene, but other solvents can also be used. Isobutylmethyl ketone is particularly preferred.
Reakcija alkilacije stupnja 2(i) je provedena u nazočnosti lužine i poželjno uz katalizator. Ukoliko je upotrijebljen 1-jodpropan kao sredstvo za alkilaciju, upotreba katalizatora nije neophodna u cilju provedbe reakcije. Međutim, reakcija može biti vrlo duga bez upotrebe katalizatora. The alkylation reaction of step 2(i) is carried out in the presence of alkali and preferably with a catalyst. If 1-iodopropane is used as an alkylating agent, the use of a catalyst is not necessary in order to carry out the reaction. However, the reaction can be very long without the use of a catalyst.
Lužine koje se mogu upotrijebiti u stupnju 2(i) će se ocijeniti kod sposobne osobe u području. Međutim, karbonati, osobito kalij-karbonat ili natrij-karbonat, ili amini, osobito trietilamin, su poželjni. Najpoželjniji izbor lužine je kalij-karbonat. Alkalis that may be used in step 2(i) shall be evaluated by a person skilled in the art. However, carbonates, especially potassium carbonate or sodium carbonate, or amines, especially triethylamine, are preferred. The most preferred choice of alkali is potassium carbonate.
Katalizator upotrijebljen u stupnju 2(i) je jodni katalizator, poželjno natrij-jodid. The catalyst used in step 2(i) is an iodine catalyst, preferably sodium iodide.
Otopina dobivena u stupnju 2(i) je poželjno razrijeđena s acetonom u stupnju 2(ii). The solution obtained in step 2(i) is preferably diluted with acetone in step 2(ii).
Detaljan opis izuma Detailed description of the invention
Izum će sada biti opisan s više detalja u slijedećim primjerima. The invention will now be described in more detail in the following examples.
Primjer 1: Stupanj l, razdvajanje Example 1: Stage l, separation
Pipekoloksilidid hidroklorid (1,0 kg), aceton (3,75 L) i voda (0,85 L) su pomiješani. NaOH (vodeni) je dodan do pH> 11. Tako nastale faze su odijeljene i organska faza je razrijeđena s vodom (1,4 L). L-(-)-dibenzoil vinska kiselina (0,67 kg), otopljena u acetonu (3,75 L), je dodana. Otopina je cijepljena i ohlađena na 2°C. Kristali su odijeljeni centrifugiranjem i isprani s acetonom, pa izobutilmetil-ketonom. Produkt nije sušen. Vlažan kristaliničan produkt je ekstrahiran s izobutilmetil-ketonom (3,60 L) i razrijeđen s NaOH (2,60 L) kod pH> 11. Faze su odijeljene. Organska faza je isprana s vodom (0,60 L) i neposredno je upotrijebljena u slijedećem stupnju. Pipecoloxylidide hydrochloride (1.0 kg), acetone (3.75 L) and water (0.85 L) were mixed. NaOH (aqueous) was added until pH > 11. The phases thus formed were separated and the organic phase was diluted with water (1.4 L). L-(-)-dibenzoyl tartaric acid (0.67 kg), dissolved in acetone (3.75 L), was added. The solution was inoculated and cooled to 2°C. The crystals were separated by centrifugation and washed with acetone, then with isobutylmethyl ketone. The product is not dried. The wet crystalline product was extracted with isobutylmethyl ketone (3.60 L) and diluted with NaOH (2.60 L) at pH>11. The phases were separated. The organic phase was washed with water (0.60 L) and was used immediately in the next step.
Iskorištenje (računato na temelju suhe tvari): ~ 0,39 kg (S)-pipekoloksilidida (~90%). Yield (calculated on the basis of dry matter): ~ 0.39 kg of (S)-pipecoloxylidide (~90%).
Primjer 2: Stupanj 2. alkiliranje i taloženje soli Example 2: Stage 2 alkylation and salt deposition
Primjer 2A: Example 2A:
K2CO3 (0,32 kg), NaI (katalitička količina) i 1-brompropan (0,28 kg) i oko 5% vode je dodano u organsku fazu iz prošlog stupnja. Smjesa je grijana do refluksa radi okončanja reakcije. Suvišak brompropana je uklonjen destilacijom. Reakcijska smjesa je ekstrahirana s vodom (1,70 L). Aceton (1,70 L) je dodan organskoj fazi, a nakon toga HCl (vodeni) do pH~ 2. Otopina je cijepljena i ohlađena na 9°C. Kristali su odijeljeni centrifugiranjem i isprani su s acetonom. Produkt je neposredno upotrijebljen u slijedećem stupnju i nije sušen. K 2 CO 3 (0.32 kg), NaI (catalytic amount) and 1-bromopropane (0.28 kg) and about 5% water were added to the organic phase from the previous step. The mixture was heated to reflux to terminate the reaction. Excess bromopropane was removed by distillation. The reaction mixture was extracted with water (1.70 L). Acetone (1.70 L) was added to the organic phase followed by HCl (aq) to pH~ 2. The solution was filtered and cooled to 9°C. The crystals were separated by centrifugation and washed with acetone. The product was used directly in the next stage and was not dried.
Iskorištenje (računato na temelju suhe tvari): 0,47 kg ropivakain hidroklorida (~90%). Yield (calculated on dry matter basis): 0.47 kg ropivacaine hydrochloride (~90%).
Primjer 2B: Example 2B:
Kao alternativa slijedi slijedeći postupak. As an alternative, the following procedure is followed.
K2CO3 (0,32 kg), NaI (katalitička količina) i 1-brompropan (0,28 kg) i voda (1,70 L) je dodano u organsku fazu iz prošlog stupnja. Smjesa je grijana do refluksa radi okončanja reakcije. Suvišak brompropana je uklonjen destilacijom. Reakcijska smjesa je odvojena. Aceton (1,70 L) je dodan organskoj fazi, a nakon toga HC1 (vodeni) do pH~ 2. Otopina je cijepljena i ohlađena na 9°C. Kristali su odijeljeni centrifugiranjem i isprani su s acetonom. Produkt je neposredno upotrijebljen u slijedećem stupnju i nije sušen. K 2 CO 3 (0.32 kg), NaI (catalytic amount) and 1-bromopropane (0.28 kg) and water (1.70 L) were added to the organic phase from the previous step. The mixture was heated to reflux to terminate the reaction. Excess bromopropane was removed by distillation. The reaction mixture was separated. Acetone (1.70 L) was added to the organic phase followed by HCl (aq) to pH ~ 2. The solution was filtered and cooled to 9°C. The crystals were separated by centrifugation and washed with acetone. The product was used directly in the next stage and was not dried.
Iskorištenje (računato na temelju suhe tvari): 0,47 kg ropivakain hidroklorida (~90%). Yield (calculated on dry matter basis): 0.47 kg ropivacaine hydrochloride (~90%).
Primjer 3: Stupanj 3, prekristalizacija Example 3: Stage 3, recrystallization
Ropivakain hidroklorid, iz prethodnog stupnja, je razmuljan u acetonu (1,0 L) kod temperature refluksa. Voda (0,60 L) je dodana. Nastala smjesa je filtrirana i dodan je aceton (7,6 L) kod > 40°C. Otopina je cijepljena i ohlađena na 3°C. Kristali su odijeljeni centrifugiranjem i isprani su a acetonom. Ropivacaine hydrochloride, from the previous step, was slurried in acetone (1.0 L) at reflux temperature. Water (0.60 L) was added. The resulting mixture was filtered and acetone (7.6 L) was added at > 40°C. The solution was inoculated and cooled to 3°C. The crystals were separated by centrifugation and washed with acetone.
Kristali su sušeni kod 30-40°C u vakuumu (< 20 kPa). The crystals were dried at 30-40°C in a vacuum (< 20 kPa).
Iskorištenje: ~ 0,42 kg ropivakain hidroklorid monohidrata (~ 80%). Yield: ~ 0.42 kg of ropivacaine hydrochloride monohydrate (~ 80%).
Kemijska analiza konačnog produkta NMR analizom je navedena niže. The chemical analysis of the final product by NMR analysis is listed below.
NMR spektar je dobiven iz otopine 22 mg u 0,7 mL deuterij-oksida (99,95%) kod The NMR spectrum was obtained from a solution of 22 mg in 0.7 mL of deuterium oxide (99.95%) at
23°C. t-Butanol je upotrijebljen kao unutrašnji standard (u.s.). Instrument je bio Varian Gemini 300. 23°C. t-Butanol was used as an internal standard (u.s.). The instrument was a Varian Gemini 300.
Brojevi kod asignacije odgovaraju strukturi i brojevima danim u formuli niže. Rezultati su dani i za protonski spektar (Tablica 1) i za C13 spektar (Tablica 2). The numbers in the assignment correspond to the structure and numbers given in the formula below. The results are given for both the proton spectrum (Table 1) and the C13 spectrum (Table 2).
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Claims (21)
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| HRP960445 HRP960445B1 (en) | 1996-10-02 | 1996-10-02 | New process for the preparation of ropivacaine hydrochloride monohydrate |
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| HRP960445 HRP960445B1 (en) | 1996-10-02 | 1996-10-02 | New process for the preparation of ropivacaine hydrochloride monohydrate |
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