DK3199523T3 - Ny fremgangsmåde til fremstilling af n-phenyl-n-(4-piperidinyl)-amidderivater, såsom remifentanil og carfentanil - Google Patents
Ny fremgangsmåde til fremstilling af n-phenyl-n-(4-piperidinyl)-amidderivater, såsom remifentanil og carfentanil Download PDFInfo
- Publication number
- DK3199523T3 DK3199523T3 DK16153393.0T DK16153393T DK3199523T3 DK 3199523 T3 DK3199523 T3 DK 3199523T3 DK 16153393 T DK16153393 T DK 16153393T DK 3199523 T3 DK3199523 T3 DK 3199523T3
- Authority
- DK
- Denmark
- Prior art keywords
- process according
- phenylamino
- formula
- sodium
- ethyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Claims (10)
1. Fremgangsmåde til fremstilling af forbindelsen med formel (I):
som omfatter reaktion af en forbindelse med formel (II):
med et acyleringsmiddel med formel (IV) i nærvær af en orthoester med formel (III) i et aprotisk opløsningsmiddel: R-C(OR2)3 (III) R3-COX (IV) hvor R2, R3 uafhængigt er methyl eller ethyl; M er hydrogen, lithium, natrium eller kalium; R er hydrogen, methyl eller ethyl, og X er et halogenatom, såsom chlor, brom og iod; R1 er en substitueret alkyl eller substitueret arylgruppe, såsom benzyl, 2-phenylethyl, 3-methoxy-3-oxopropyl, 2-thiofuran-2-ylethyl, (4-ethyl-5-oxo-4,5-dihydro-1 H-1,2,3,4-tetrazol-1 -yl)ethyl.
2. Fremgangsmåde ifølge krav 1, der er kendetegnet ved, at det aprotiske opløsningsmiddel er toluen, tetrahydrofuran, 1,4-dioxan, dichlormethan, ethylacetat, isopropylacetat, DMS, DMSO og chloroform.
3. Fremgangsmåde ifølge krav 1, der er kendetegnet ved, at acyleringsmidlet er acetylchlorid, acetylbromid, acetyliodid, propionylchlorid, propionylbromid, propionylio did.
4. Fremgangsmåde ifølge krav 1, der er kendetegnet ved, at orthoesteren er trimethylorthoformat, triethylorthoformat, trimethylorthoacetat, triethylorthoacetat, trimethylorthopropionat, triethylorthopropionat.
5. Fremgangsmåde ifølge krav 1, der er kendetegnet ved, at reaktionen udføres ved en temperatur i intervallet 15-120 °C.
6. Fremgangsmåde ifølge krav 1, der er kendetegnet ved, at forbindelsen med formel (I) isoleres i form af et syreadditionssalt deraf
7. Fremgangsmåde til fremstilling af remifentanil (la) ifølge den inkluderede figur, som består af trinene: a) katalytisk debenzylering af et lithium-, natrium- eller kaliumsalt af l-benzyl-4-(phenylamino)piperidin-4-carboxylsyre (V) med palladium på trækul; b) alkylering af lithium-, natrium- eller kaliumsaltet af 4-phenylamino-4-piperidincarboxylsyre (VI) med methylacrylat; c) acylering af lithium-, natrium- eller kaliumsaltet af l-(3-methoxy-3-oxopropyl)-4-phenylamino-4-piperidincarboxylsyre (lix) med propionylchlorid, propionylbromid eller propionyliodid i nærvær af trimethylortho acetat eller trimethylorthopropionat i dichlormethan og til slut isolering af remifentanil i form af et oxalat eller hydrochloridsalt.
8. Fremgangsmåde ifølge krav 7, der er kendetegnet ved, at den benzylbeskyttende gruppe fjernes fra forbindelsen (V) ved reduktion med hydrogen og en palladiumkatalysator ved en temperatur på mellem 25 og 80 °C og et tryk på mellem 1 og 10 bar i en alifatisk alkohol.
9. Fremgangsmåde ifølge krav 7, der er kendetegnet ved, at alkylering af et salt af 4-phenylamino-4-piperidincarboxylsyre (VI) med methylacrylat udføres ved en temperatur i intervallet 25-80 °C i en alifatisk alkohol.
10. Fremgangsmåde ifølge krav 8 og 9, der er kendetegnet ved, at den alifatiske alkohol er methanol, ethanol, 1-propanol og 2-propanol.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP16153393.0A EP3199523B1 (en) | 2016-01-29 | 2016-01-29 | The new process for producing n-phenyl-n-(4-piperidinyl) amide derivatives such as remifentanil and carfentanil |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK3199523T3 true DK3199523T3 (da) | 2018-11-26 |
Family
ID=55272337
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK16153393.0T DK3199523T3 (da) | 2016-01-29 | 2016-01-29 | Ny fremgangsmåde til fremstilling af n-phenyl-n-(4-piperidinyl)-amidderivater, såsom remifentanil og carfentanil |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP3199523B1 (da) |
| DK (1) | DK3199523T3 (da) |
| ES (1) | ES2699636T3 (da) |
| PL (1) | PL3199523T3 (da) |
| PT (1) | PT3199523T (da) |
| SI (1) | SI3199523T1 (da) |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3998834A (en) | 1975-03-14 | 1976-12-21 | Janssen Pharmaceutica N.V. | N-(4-piperidinyl)-n-phenylamides and -carbamates |
| US5019583A (en) | 1989-02-15 | 1991-05-28 | Glaxo Inc. | N-phenyl-N-(4-piperidinyl)amides useful as analgesics |
| US5106983A (en) | 1990-04-30 | 1992-04-21 | The United States Of America As Represented By The Secretary Of The Army | Process of making carfentanil and related analgesics |
| GB9316863D0 (en) | 1993-08-13 | 1993-09-29 | Glaxo Group Ltd | Chemical process |
| EP1246801B1 (en) | 1999-12-06 | 2006-09-20 | Mallinckrodt Inc. | Methods for the syntheses of alfentanil, sufentanil and remifentanil |
| AU2003277552A1 (en) * | 2002-11-06 | 2004-06-07 | Takeda Pharmaceutical Company Limited | Receptor regulator |
| JP2009524659A (ja) * | 2006-01-24 | 2009-07-02 | マリンクロッド・インコーポレイテッド | レミフェンタニルの合成方法 |
-
2016
- 2016-01-29 DK DK16153393.0T patent/DK3199523T3/da active
- 2016-01-29 ES ES16153393T patent/ES2699636T3/es active Active
- 2016-01-29 SI SI201630102T patent/SI3199523T1/sl unknown
- 2016-01-29 PT PT16153393T patent/PT3199523T/pt unknown
- 2016-01-29 EP EP16153393.0A patent/EP3199523B1/en not_active Not-in-force
- 2016-01-29 PL PL16153393T patent/PL3199523T3/pl unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PT3199523T (pt) | 2018-11-14 |
| ES2699636T3 (es) | 2019-02-12 |
| PL3199523T3 (pl) | 2019-03-29 |
| EP3199523B1 (en) | 2018-08-15 |
| SI3199523T1 (sl) | 2018-12-31 |
| EP3199523A1 (en) | 2017-08-02 |
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