WO2017175233A1 - Procédé de synthèse en phase liquide et à grande échelle de la carbétocine et ses nouveaux intermédiaires - Google Patents

Procédé de synthèse en phase liquide et à grande échelle de la carbétocine et ses nouveaux intermédiaires Download PDF

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WO2017175233A1
WO2017175233A1 PCT/IN2016/000177 IN2016000177W WO2017175233A1 WO 2017175233 A1 WO2017175233 A1 WO 2017175233A1 IN 2016000177 W IN2016000177 W IN 2016000177W WO 2017175233 A1 WO2017175233 A1 WO 2017175233A1
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formula
group
solvent
compound
reaction
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PCT/IN2016/000177
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Khalid Anwer Mohammed
Mohosin Layek Mohammed
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Davuluri Ramamohan Rao
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity

Definitions

  • the present invention relates to process for large scale liquid phase synthesis of Carbetocin shown in formula
  • the invention also relates to the process for syntheses of novel intermediates of formula (A) and formula (B) used in the synthesis of Carbetocin (I).
  • Carbetocin is a synthetic cyclic octapeptide containing two unnatural amino acids. Carbetocin is an obstetric drug used to control postpartum hemmorage (Trade names: Duratocin, Pabal, and Lonactene).
  • the drug substance is chemically designated as (2S)-1-[(3S, 6S, 9S, 12S, 15S)-12-[(2S)-butan-2-yl]-9-(2- carbamoylethyl)-6-(carbomoylmethyl)-15-[(4-hydroxyphenyl)methyl]-16-methyl-5, 8, 11, 14, 17- pentaoxo- 1 -thia-4,7, 10, 13, 16-pentazacycloicosane-3-carbonyl]-N-[( IS)- 1 carbamoylmethylcarbamoyl)-3- methyl-butyl] pyrrolidine-2-carboxamide and is represented by the following structural formula ( ⁇ ).
  • Carbetocin can also be represented as: Cyclo[Butyryl-Tyr(Me)-Ile-Gln-Asn-Cys]-Pro-Leu- Gly-NH ; where Tyr(Me) is O-methyltyrosine, He is isoleucine, Gin is glutamine, Asn is asparagine, Cys is cysteine, Pro is proline, Leu is leucine, and Gly-N3 ⁇ 4 is glycinamide.
  • the couplings were mediated by diisopropylcarbodiimide (DIC)/ 1-Hydroxybenzotriazole (HOBt) using a 3-fold excess of reagents.
  • the linear peptide was cleaved using trifluoroacetic acid (TFA)/ triisopropylsilane (TIPS)/ water (H 2 0):: 95/2.5/2.5 (v/v) cocktail, and cyclized with N ( N,N',N'-Tetramethyl- 0-( lH-benzotriazol- 1 -yl)uronium hexafluorophosphate, ⁇ 9-(Benzotriazol- 1 -yl)-NN, N' N- tetramethyluronium hexafluorophosphate (HBTU)/ ⁇ , ⁇ -Diisopropylethylamine (DIEA) in ⁇ , ⁇ - Dimethylformamide (DMF).
  • TFA trifluoroace
  • the peptide was assembled on Rink amide resin. Protecting group was removed and cyclized on resin. The peptide was cleaved from resin, purified and lyophilized.
  • Fmoc-SPPS methodology has been used to produce gram quantities of Carbetocin however, multiple kilos to hundreds of kilos are best produced by using the liquid phase approach.
  • WO 98/46634 and WO 99/26964 patents describe the inherent advantages of liquid phase synthesis. SPPS is best suited for the synthesis of limited quantities (up to 1 Kg), while classical solution synthesis or liquid phase peptide synthesis (LPPS) is preferred for larger scale (up to several hundred kilograms) synthesis of the product.
  • LPPS liquid phase peptide synthesis
  • CN 102477082A described a liquid phase process for the preparation of Carbetocin.
  • Carbetocin was divided in to three segments: Br-(C3 ⁇ 4)3-Tyr (Me)-Ile-OH (Segment 1), H-Gln(Trt)-Asn(Trt)-Cys(Trt)-OMe (Segment 2), and H-Pro-Leu-Gly-NH 2 (Segment 3).
  • Segment- 1 was coupled with Segment-2 to give Br-(CH 2 ) 3 -Tyr (Me)-Ile-Gln(Trt)-Asn(Trt)-Cys(Trt)-OMe, which was purified, saponified, and coupled with Segment-3 to give linear peptide.
  • the linear peptide was deprotected and cyclized in presence of an organic base such as l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine (NMM), ⁇ , ⁇ -Diisopropylethylamine (DIPEA) or collidine.
  • DBU l,8-Diazabicyclo[5.4.0]undec-7-ene
  • NMM N-methylmorpholine
  • DIPEA ⁇ , ⁇ -Diisopropylethylamine
  • collidine collidine
  • the main object of the invention is to develop a large scale liquid phase synthesis process for Carbetocin that furnishes the active pharmaceutical ingredient (API) in high yield and purity.
  • a further object of the invention is to provide a cost effective process for the synthesis of Carbetocin.
  • the present invention provides a process for large scale liquid phase synthesis of Carbetocin of formula (I),
  • the invention provides a novel intermediate of formula (A), which is useful in the preparation of Carbetocin of formula (I)
  • the invention provides a process for the preparation of novel intermediate of formula (A)
  • the invention provides a process for the preparation of novel intermediate of formula (B);
  • Z is benzyloxycarbonyl and R2 is an alkyl group.
  • R2 is an alkyl group.
  • alkyl means straight chain or branched hydrocarbon consisting solely of carbon and hydrogen atoms, containing one to eight carbon atoms. "Alkyl” groups representing methyl, ethyl, n-propyl, and so on.
  • salts include anions of oraganic or inorganic acids.
  • organic acids include benzoic acid, benzenesulfonic acid, p-toluenesulfonic acid and so on.
  • inorganic acids include hydrochloric acid, sulphuric acid, etc. Accordingly, the present invention provides a process for the preparation of formula (I).
  • Scheme-1 Synthetic scheme for preparation of Carbetocin.
  • the coupling agent used in the reaction is selected from the group consisting of Benzotriazole- 1 -yl-oxy-tris- (dimethylamino)-phosphonium hexafluorophosphate (BOP), Benzotriazole- 1-yl-oxy-tris-pyrrolidino- phosphonium hexafluorophosphate (PyBOP), 0-(IH-Benzotriazol-l-yl)-N,N, N, N- tetramethyluronium tetrafluoroborate (TBTU), 0-(7-Azabenzotriazole- 1 -yl)-N,N,N,N-tetramethyluronium tetrafluoroborate (TATU), 0-(lH-Benzotriazole-
  • the additive used in the reaction is selected from the group consisting of 1-Hydroxybenzotriazole (HOBt), Hydroxy-3,4- dihydro-4-oxo-l,2,3-benzotriazine (HOOBt), l-Hydroxy-7-azabenzotriazole (HO At) or Oxyma, preferably using HOBt.
  • the base used in the reaction is selected form the group consisting of N-methylmorpholine (NMM), N, N-diisopropylethylamine (DIPEA), triethylamine or collidine, preferably using NMM.
  • the solvent used in the reaction is selected from the group consisting of ACN (acetonitrile), tetrahydrofuran (THF), ethyl acetate (EtOAc), ⁇ , ⁇ -Dimethylformamide (DMF), N-Methylpyrrolidone (NMP), dichloromethane (DCM) or dimethylacetamide (DMAC), preferably using DMF.
  • the reaction temperature may range from 5 °C to 10 °C and preferably at a temperature in the range from 0 °C to 5 °C.
  • the duration of the reaction may range from 1 hour to 12 hours, preferably for a period of 3 hours.
  • the coupling agent used in the reaction is selected from the group consisting of BOP, PyBOP, TBTU or HBTU, preferably using PyBOP.
  • the base used in the reaction is selected form the group consisting of NMM, DIPEA, TEA or collidine, preferably using NMM.
  • the solvent used in the reaction is selected from the group consisting of THF, DMF, NMP or DMAc, preferably using DMF.
  • the reaction temperature may range from 20 °C to 40 °C and preferably at a temperature in the range from 25 °C to 35 °C.
  • the solvent used in the reaction is selected from the group consisting of DIPE (Diisopropyl ether), MTBE (Methyl tertiary butyl ether), DEE (Diethyl ether), DCM, ACN or EA, preferably using MTBE.
  • the invention provides a novel intermediate of formula (A), which is useful for the preparation of Carbetocin of formula (I).
  • Scheme-2 illustrates the process for the preparation of formula (A);
  • Ri is an alkyl group.
  • the invention provides a novel intermediate of formula (A), which is useful for the preparation of Carbetocin of formula (I).
  • Scheme-2 illustrates the process for the preparation of formula (A), Step (i): esterification of Z-Asn(Trt)-OH in the presence of coupling agent, alkyl alcohol and solvent to obtain compound of formula (A 1 ),
  • the coupling agent used in the reaction is selected from the group consisting of BOP, PyBOP, TBTU, TATU, HBTU, HATU, DCC, DIC or EDC.HC1, preferably using TBTU.
  • the alkyl alcohol used in the reaction is selected from the group consisting of methanol, ethanol or propanol.
  • the solvent used in the reaction is selected from the group consisting of NMP, DMF, THF, DCM or EtOAc, preferably using DMF.
  • the reaction is maintained at ambient temperature. The duration of the reaction may range from 1 hour to 12 hours, preferably for a period of 2 hours.
  • the solvent used in the reaction is selected from the group consisting of methanol, ethanol, isopropanol or combination of protic solvent with NMP, DMF, THF or EtOAc, preferably using methanol.
  • the hydrogenation catalyst used in the reaction is Pd/C.
  • the organic or inorganic acid used in the reaction is PTSA, HC1 or sulphuric acid (H2SO 4 ), preferably using PTSA.
  • the reaction temperature may range from 20 °C to 40 °C and preferably at a temperature in the range from 25 °C to 30 °C.
  • the duration of the reaction may range from 1 hour to 12 hours, preferably for a period of 2 hours.
  • the coupling agent used in the reaction is selected from the group consisting of BOP, PyBOP, TBTU, TATU, HBTU, HATU, DCC, DIC or EDC.HC1, preferably using TBTU.
  • the additive used in the reaction is selected from the group consisting of HOBt, HOOBt, HO At, Oxyma or potassium salt of Oxyma, preferably using HOBt.
  • the base used in the reaction is NMM, TEA, DIPEA or collidine, preferably using NMM.
  • the solvent used in the reaction is selected from the group consisting of ACN, NMP, DMF, THF, DCM or EtOAc, preferably using DMF.
  • the reaction temperature may range from -5 °C to 10 °C and preferably at a temperature in the range from 0 °C to 5 °C.
  • the duration of the reaction may range from 1 hour to 12 hours, preferably for a period of 4 to 5 hours.
  • the hydrogenation catalyst used in the reaction is Pd/ C.
  • the organic or inorganic acid used in the reaction is PTSA, HC1 or H2SO4, preferably PTSA.
  • the solvent used in the reaction is selected from the group consisting of methanol, ethanol, isopropanol, or combination of protic solvent with NMP, DMF, THF or EtOAc, preferably methanol.
  • the reaction temperature may range from 20 °C to 35 °C and preferably at a temperature in the range from 25 °C to 30 °C.
  • the duration of the reaction may range from 1 hour to 12 hours, preferably for a period of 2 hours.
  • the coupling agent used in the reaction is selected from the group consisting of BOP, PyBOP, TBTU, TATU, HBTU, HATU, DCC, DIC or EDC.HC1, preferably using TBTU.
  • the additive used in the reaction is selected from the group consisting of HOBt, HOOBt, HO At or Oxyma, preferably using HOBt.
  • the base used in the reaction is selected from the group consisting of NMM, TEA, DIPEA, or collidine, preferably using NMM.
  • the solvent used in the reaction is selected from the group consisting of ACN, NMP, DMF, THF, DCM or EtOAc, preferably using DMF.
  • the reaction temperature may range from -5 °C to 10 °C and preferably at a temperature in the range from 0 °C to 5 °C.
  • the duration of the reaction may range from 1 hour to 12 hours, preferably for a period of 2 hours.
  • the hydrogenation catalyst used in the reaction is Pd/C.
  • the organic or inorganic acid used in the reaction is PTSA, HC1 or H2SO4, preferably using PTSA.
  • the solvent used in the reaction is selected from the group consisting of methanol, ethanol, isopropanol, or combination of protic solvent with NMP, DMF or EtOAc, preferably using combination of methanol and DMF.
  • the coupling agent used in the reaction is selected from the group consisting of BOP, PyBOP, TBTU, TATU, HBTU, HATU, DCC, DIC or EDC.HC1, preferably using TBTU.
  • the additive used in the reaction is selected from the group consisting of HOBt, HOOBt, HO At or Oxyma, preferably using HOBt.
  • the base used in the reaction is NMM, TEA, DIPEA, or collidine, preferably using NMM.
  • the solvent used in the reaction is selected from the group consisting of ACN, NMP, DMF, THF, DCM or EtOAc, preferably using DMF.
  • the reaction temperature may range from 20 °C to 35 °C and preferably at a temperature in the range from 25 °C to 30 °C.
  • the duration of the reaction may range from 1 hour to 12 hours, preferably for a period of 3 hours.
  • the solvent used in the reaction is selected from the group consisting of acetone, methanol, ethanol, NMP, DMF or THF, preferably using THF.
  • the base used in the reaction is selected from the group consisting of alkali base, sodium hydroxide (NaOH), sodium carbonate (Na2C03), cesium carbonate (CS2CO3), lithium hydroxide ( LiOH), preferably using LiOH or L1OH.H2O.
  • the reaction temperature may range from -5°C to 10°C and preferably at a temperature in the range from 0 °C to 5 °C.
  • the duration of the reaction may range from 1 hour to 12 hours, preferably for a period of 2 hours.
  • the invention provides a novel intermediate of formula (B), which is useful for the preparation of Carbetocin of formula (I).
  • Scheme-3 illustrates the process for the preparation of formula (B);
  • the coupling agent used in the reaction is selected from the group consisting of BOP, PyBOP, TBTU, TATU, HBTU, HATU, DCC, DIC or EDC.HC1, preferably using TBTU.
  • the additive used in the reaction is selected from the group consisting of HOBt, HOOBt, HO At or Oxyma, preferably using HOBt.
  • the base used in the reaction is NMM, DIPEA, TEA or collidine, preferably using NMM.
  • the solvent used in the reaction is selected from the group consisting of ACN, DMF, NMP, THF, DCM, EtOAc or DMAc, preferably using EtOAc.
  • the reaction temperature may range from 5 °C to 20 °C and preferably at a temperature in the range from 10 °C to 15 °C.
  • the duration of the reaction may range from 10 minutes to 12 hours, preferably for a period of 15 minutes.
  • the solvent used in the reaction is selected from the group consisting of methanol, ethanol, isopropanol or combination of protic solvent with DMF, NMP, THF or EtOAc, preferably using methanol.
  • the hydrogenation catalyst used in the reaction is Pd/C.
  • the organic or inorganic acid used in the reaction is PTSA, HC1 or H2SO4), preferably using PTSA.
  • the reaction temperature may range from 35 °C to 45 °C and preferably at 40 °C.
  • the coupling agent used in the reaction is selected from the group consisting of BOP, PyBOP, TBTU, TATU, HBTU, HATU, DCC, DIC or EDC.HC1, preferably using TBTU.
  • the additive used in the reaction is selected from the group consisting of HOBt, HOOBt, HO At or Oxyma, preferably using HOBt.
  • the base used in the reaction is selected from the group consisting of NMM, DDPEA, TEA or collidine, preferably using NMM.
  • the solvent used in the reaction is selected from the group consisting of ACN, DMF, NMP, THF, DCM, EtOAc, methanol, ethanol or DMAc, preferably using EtOAc.
  • the reaction temperature may range from 5°C to 20°C and preferably at a temperature in the range from 10 °C to 15 °C.
  • the duration of the reaction may range from 1 hour to 12 hours, preferably for a period of 6 hours.
  • the solvent used in the reaction is selected from the group consisting of ACN, DMF, NMP, THF, DCM, EtOAc, methanol, ethanol or DMAc, preferably using methanol.
  • Ammonia gas is used for ammonolysis.
  • the reaction temperature may range from 20 °C to 35 °G and preferably at a temperature in the range from 25 °C to 30 °C. The reaction is maintained for overnight.
  • the hydrogenation catalyst used in the reaction is Pd/C.
  • the solvent used in the reaction is selected from the group consisting of methanol, ethanol, isopropanol, or combination of alcoholic solvent with ACN, DMF, NMP, EtOAc or DMAc, preferably using methanol.
  • the coupling agent used in the reaction is selected from the group consisting of BOP, PyBOP, TBTU, TATU, HBTU, HATU, DCC, DIC or EDC.HC1, preferably using EDC.HC1.
  • the additive used in the reaction is selected from the group consisting of HOBt, HOOBt, HO At or Oxyma, preferably using HOBt.
  • the solvent used in the reaction is selected from the group consisting of acetonitrile, DMF, NMP, TFfF, DCM, EtOAc or DMAc, preferably using DMF.
  • the reaction is performed with or without using base.
  • the base used in the reaction is selected from the group consisting of NMM, DIPEA, TEA or collidine.
  • the reaction temperature may range from 20 °C to 35 °C and preferably at a temperature in the range from 25 °C to 30 °C.
  • the duration of the reaction may range from 15 minutes to. 12 hours, preferably for a period of
  • the base used in the reaction is selected from the group consisting of sodium carbonate, sodium hydroxide, cyclohexylamine, ethanolamine, piperdine, N-methylpiperzine or tertiary butylamine, preferably tertiary butylamine.
  • the solvent used in the reaction is selected from the group consisting of acetonitrile, DMF, NMP, TFfF, DCM, EtOAc or combination of bi-phasic solvents selected from mixture of ACN-hexane, DMF-hexane, ACN-heptane, DMF- heptane, preferably in the mixture of ACN-heptane or ACN-heptane -toluene.
  • the mixture was stirred for 15 minutes and methanol (63 grams, 1966.2 mM) was added.
  • methanol 63 grams, 1966.2 mM
  • the reaction mass was maintained for 2 hours at an ambient temperature and the progress of reaction was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the reaction was quenched with 2.5% aqueous NaHCCb solution and maintained for 1 hour.
  • the precipitated solid was filtered and washed with water and heptane. It was further purified by precipitation from acetone and water.
  • the reaction was quenched with 2.5% aqueous NaHCCb solution at 10-15 °C and stirred for 1 to 2 hours at 25-30 °C.
  • the precipitated solid was filtered and washed with water and heptane.
  • Acetone was added to the wet compound and stirred for 1 hour.
  • the solid was filtered and washed with 50% acetone in water.
  • mixture of acetone and hexane were added to the wet compound and stirred for 1 hour at 25-30 °C.
  • Boc-Tyr(Me)-OH 29.2 grams, 98.9 mM was dissolved in DMF (360 mL), and the solution was cooled to 0-5 °C.
  • TBTU 31.8 grams, 98.9 mM
  • HOBt 16.7 grams, 109.1 mM
  • NMM 16.7 mL, 151.8 mM
  • the reactants were stirred for 15 minutes.
  • H-Ile-Gln(Trt)-Asn(Trt)-OMe 72.0 grams, 82.6 mM was dissolved in DMF (360 mL) at 25-30 °C, and the solution was cooled to 0-5 °C.
  • Boc-Tyr(Me)-Ile-Gln(Trt)-Asn(Trt)-OMe 75.0 grams; 65.3 mM was dissolved in tetrahydrofuran (1 125 mL) at 25-30 °C, and cooled to 0-5 °C.
  • IN aqueous lithium hydroxide solution (236 mL, 236 mM) was added to the above reaction mass at 0-5 °C over a period of 40 minutes. The reaction was stirred for 3 hours at 0-5 °C and the progress of reaction was monitored by analytical RP-HPLC.
  • Purified water 750 mL was added to the above reaction mass at 0-5 °C over a period of 30 minutes and the pH was adjusted to 3-4 with 10% KHSO4 solution at 0-5 °C.
  • EtOAc 500 mL was added at 25-30 °C and separated the two layers. The aqueous layer was extracted with EtOAc (500 mL). The combined organic extracts were washed with 5% KHSO 4 solution, purified water, and 20% brine solution. The organic layer was treated with anhydrous Na2 SO 4 , and the solvent was removed under reduced pressure.
  • the reaction mixture was stirred for about 30 minutes while allowing the reaction mixture to warm to 25 to 30 °C.
  • the progress of the reaction was monitored by RP-HPLC.
  • the aqueous layer again extracted with the EtOAc.
  • the combined organic layer was washed with 5% aqueous NaHC03, 1 % aqueous HS04, water, and 20% brine solution.
  • the organic layer was dried with anhydrous Na2S04 and the solvents were removed under reduced pressure below 40 °C.
  • the residue was suspended in a mixture of DIPE and EtOAc, and stirred for 3 h.
  • Fmoc-Cys ⁇ (CH2)3COO'Bu ⁇ -Pro-Leu-Gly-NH 2 (40 grams; 53.2 mM) was dissolved in acetonitnle (600 mL) and treated with tertiary butyl amine (33.4 mL, 317.8 mM) at 25 to 30 °C.
  • a mixture of toluene (40 mL) and heptane (200 mL) was added to the reaction mixture. The progress of reaction was monitored by HPLC. The undissolved material was filtered, and the heptane layer was separated from acetonitrile.
  • EtOAc 200 mL was added to the reaction mixture, and cooled to 0 to 5 °C.
  • the pH of the reaction mixture was adjusted to 3 to 4 using 10% KHSO4 solution and separated aqueous layer.
  • the aqueous layer washed with EtOAc (3x, 1 16 mL), and the organic extracts were discarded.
  • the pH of aqueous layer was adjusted 7 to 8 using 5% aqueous NaHC0 3 solution and extracted with dichloromethane (2x, 600 mL).
  • the dichloromethane layer was washed with brine, water, and dried with anhydrous Na 2 S04.
  • Boc-Tyr(Me)-Ile-Gln(Trt)-Asn(Trt)-OH (20 grams; 17.6 mM) was dissolved in DMF (140 mL). The solution was cooled to 0 to 5 °C. Next, HO At (2.4 grams, 17.6 mM) was added to the solution and maintained for 5-10 minutes at 0-5 °C. A solution of H-Cys ⁇ (CH 2 ) 3 COO3 ⁇ 4u ⁇ -Pro-Leu-GIy-NH (18.6 grams; 35.1 mM) in DMF (80 mL) was added to the above solution at 0-5 °C.
  • Boc-Tyr(Me)-Ile-Gln(Trt)-Asn(Trt)- Cys ⁇ (CH 2 ) 3 COO t Bu ⁇ -Pro-Leu-Gly-NH 2 (25.0 grams, 15.2 mM) was treated with a mixture of trifluoroacetic acid (125 mL ), triisopropylsilane (TIPS, 12.5 mL), and water (6.25 mL) for 0.5 hours at 0 to 5 °C. The reaction mixture was allowed to warm to 25 to 30 °C, and stirring was continued for 1 to 2 hours at 25-30 °C.
  • reaction product was precipitated by adding methyl tert-butyl ether (MTBE) and the solid was filtered.
  • MTBE methyl tert-butyl ether
  • the solid was suspended in MTBE (160 mL), and stirred for 1 hour, filtered, and washed with MTBE.
  • the resultant solid was dissolved in water (160 mL), and filtered.
  • the filtrate was treated with activated carbon at 40 °C and filtered.

Abstract

La présente invention concerne un procédé de synthèse en phase liquide et à grande échelle de la carbétocine. L'invention concerne également de nouveaux intermédiaires de formule (A) et de formule (B) et leurs procédés de préparation.
PCT/IN2016/000177 2016-04-04 2016-07-04 Procédé de synthèse en phase liquide et à grande échelle de la carbétocine et ses nouveaux intermédiaires WO2017175233A1 (fr)

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CN111662362A (zh) * 2020-07-31 2020-09-15 成都诺和晟泰生物科技有限公司 一种卡贝缩宫素的纯化方法
CN112094324A (zh) * 2020-09-21 2020-12-18 宁波三生生物科技有限公司 一种卡贝缩宫素的合成方法
CN113307847A (zh) * 2021-06-07 2021-08-27 辰欣药业股份有限公司 一种卡贝缩宫素的纯化精制方法
CN117567566A (zh) * 2023-11-28 2024-02-20 山东济肽生物科技有限公司 一种环六肽-9的液相合成工艺

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CN102477082A (zh) * 2010-11-26 2012-05-30 杭州和锦科技有限公司 一种液相合成法合成卡贝缩宫素的方法
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111662362A (zh) * 2020-07-31 2020-09-15 成都诺和晟泰生物科技有限公司 一种卡贝缩宫素的纯化方法
CN111662362B (zh) * 2020-07-31 2021-05-28 成都诺和晟泰生物科技有限公司 一种卡贝缩宫素的纯化方法
CN112094324A (zh) * 2020-09-21 2020-12-18 宁波三生生物科技有限公司 一种卡贝缩宫素的合成方法
CN112094324B (zh) * 2020-09-21 2022-05-03 宁波三生生物科技股份有限公司 一种卡贝缩宫素的合成方法
CN113307847A (zh) * 2021-06-07 2021-08-27 辰欣药业股份有限公司 一种卡贝缩宫素的纯化精制方法
CN117567566A (zh) * 2023-11-28 2024-02-20 山东济肽生物科技有限公司 一种环六肽-9的液相合成工艺
CN117567566B (zh) * 2023-11-28 2024-05-03 山东济肽生物科技有限公司 一种环六肽-9的液相合成工艺

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