CN116457359A - Synthesis of hydromorphone base - Google Patents

Synthesis of hydromorphone base Download PDF

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CN116457359A
CN116457359A CN202180076350.4A CN202180076350A CN116457359A CN 116457359 A CN116457359 A CN 116457359A CN 202180076350 A CN202180076350 A CN 202180076350A CN 116457359 A CN116457359 A CN 116457359A
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hydromorphone
monohydrate
organic solvent
water
base
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F·D·A·马奎拉斯奥隆德里兹
J·贝萨贝尔穆特
A·A·德里昂马腾
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Ferrer Internacional SA
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Ferrer Internacional SA
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Priority claimed from PCT/EP2021/081515 external-priority patent/WO2022101408A1/en
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Abstract

Via hydromorphone monohydrate (I.H 2 O) conversion of hydromorphone hydrochloride (I.HCl) to hydromorphone base (I).

Description

Synthesis of hydromorphone base
Technical Field
This patent belongs to the field of the preparation and purification of hydromorphone base (I).
Background
Hydromorphone is a powerful opioid used to treat severe pain. Hydromorphone and some related substances have the following chemical structures:
hydromorphone is also known as dihydromorphone. Hydromorphone hydrochloride (i.hcl) is available under several trademarks such asOr->And the like.
The most common form of hydromorphone is the hydrochloride (L-HCl). 1 part of hydromorphone hydrochloride (I.HCl) is dissolved in 3 parts of water. Hydromorphone, such as hydromorphone base (I), in a form that is low in water solubility may be used in some applications.
The inventors have found that the acid/base balance of hydromorphone is complex and that obtaining hydromorphone base (I) from hydromorphone hydrochloride (i·hcl) is not straightforward. According to MERK INDEX,2006, hydromorphone has one acidic and one basic point, pka=8.92 and pKb 7.0:
use of hydromorphone monohydrate (I.H 2 O) as an intermediate, hydromorphone base (I) can be easily obtained from hydromorphone hydrochloride (i·hcl) and has good yield and purity.
In the prior art, solid hydromorphone base (I) has been prepared from the following hydromorphone (i·hcl) solution:
by water (GOMEZ et al 2014,WO15011474 A1, US2015252052AA (pH 7.5), WO 06005112A 1 (pH 9.1, KOH-adjusted), WO 11137086A 1 (pH 9.0), WANG et al 2020 (with NH) 4 OH-adjusted pH), US 2628962A (NH) 4 OH regulated), US 2654756A (NH 4 OH-regulated, m.p.262.5-263 ℃ C.) or WO0134608A1 (pH 8.8, NH) 4 OH regulated),
from a water/ethanol solution (WO 05100361A 1 (pH 10-10.5)),
from a water/1-butanol mixture (WO 06005112A 1 (4:1, pH 9.1 (NaOH-conditioned)),
from a water/2-propanol solution (WO 10118271A 1 (pH 8.7-9.1, NH) 4 OH regulated),
from a methanol solution (CSUK et al 2012 (m.p.264-266 ℃), WO05047291A1, WO 05113557A 1, WO 06104656A 1, US7399859 BA, US2015252052AA or WO 18009856A 1),
recrystallisation in ethanol (WO 06005112A 1 (m.p.264-266 ℃, FTIR (KBr): 1729 (C=O) cm) -1 ) RAPOPORT et al, 1950 (m.p. 266-267 ℃ (removal of solvent from ethyl acetate solution or recrystallisation from ethanol), WO9805667 A1, WO15134003A1 or US2015252052 AA),
from an acetone/2-propanol mixture (ERBING et al, 2016),
from CH 2 Cl 2 MeOH mixture (MURPHY et al, 2014 (m.p).>230 ℃) or US2015225419 AA (6:1)),
-from CH 2 Cl 2 Recrystallisation from heptane (MURPHY et al, 2014 (m.p).>230℃)),
From ethyl acetate/MeOH solution (WO 9805667A 1),
from ethyl acetate (US 2649454 a),
from acetonitrile/ethanol/water solution (WO 11137086A 1 (pH 8.7-9.2, NH) 4 OH regulated),
from THF/acetone solutions (MAZUREK et al 2016, m.p.276.7 ℃ (548.8K, referred to as form I)), or
From ethanol/toluene (MAZUREK et al 2016, m.p.277.0 ℃ (550.2K, referred to as form II)).
According to FISCHER et al, 1949, hydromorphone base (I) is melt decomposed at 257 ℃.
In WO 06091885A 2, D1-hydromorphone, D2-hydromorphone and D3-hydromorphone monohydrate are derived from CHCl 3 /NH 4 Precipitation from the aqueous OH mixture.
In CN108164540 a, a recrystallization method is mentioned, but the solvent is not specifically described.
Summary of The Invention
One aspect of the present invention is a process for preparing hydromorphone base (I), comprising:
i. hydromorphone monohydrate (I.H 2 O) suspended in or dissolved in at least one organic solvent, and
separating hydromorphone base (I).
Another aspect of the invention is hydromorphone monohydrate (I.H 2 O)。
Another aspect of the invention is the preparation of hydromorphone monohydrate (I.H 2 O) a process comprising:
a) Dissolving hydromorphone salt in a solvent medium comprising water,
b) Adjusting the pH of the mixture of step a) to 8-10, and
c) Separating hydromorphone monohydrate (I.H) from the mixture of step b) 2 O), wherein
In step b), the pH is adjusted with a weak base.
Definition of the definition
In this document, the following terms are used in the following sense.
Solvent(s)"means a liquid which is used as a reaction medium.
Organic solvents"refers to a solvent that contains primarily organic compounds.
Polar organic solvents"refers to an organic solvent in which its molecules have a large dipole, i.e., include bonds between atoms of different electronegativity. Solvents are considered polar when they have a relative permittivity (previously referred to as dielectric constant) higher than 15.
Relative permittivity"is the ratio of the electric field strength in vacuum to the electric field strength in a given medium. It was previously referred to as the dielectric constant. Thus, the relative permittivity is a dimensionless number.
Polar protic organic solvents"refers to organic polar solvents whose molecules have O-H or N-H bonds.
Polar aprotic solvents"refers to organic polar solvents whose molecules lack O-H or N-H bonds.
Nonpolar organic solvents"refers to an organic solvent whose molecules do not contain bonds between atoms of different electronegativity. Solvents are considered to be nonpolar when they have a relative permittivity (previously referred to as dielectric constant) of less than 15.
Isotopically labeled"refers to a non-radioactive substance whose atom or atoms are enriched with stable isotopes that are not the most abundant isotopes that occur in nature. Suitable stable isotopes for enrichment include isotopes of hydrogen, for example 2 H (commonly referred to as deuterium, D) and 3 h (commonly referred to as tritium, T); isotopes of carbon, e.g. 11 C、 13 C, C and C 14 C, performing operation; isotopes of nitrogen, e.g. 13 N is a single unit 15 N; isotopes of oxygen, e.g. 15 O、 17 O and 18 O。
weak base"is a base that does not completely dissociate when dissolved in water.
Strong base"is a base that completely dissociates when dissolved in water.
FTIR"means Fourier transform infrared spectroscopy.
PXRD"refers to powder X-ray diffraction.
DSC"means differential scanning calorimetry.
TGA"means thermogravimetric analysis.
Pharmaceutically acceptable excipients"refers to any substance other than a pharmacologically active drug or prodrug that can be used to prepare a pharmaceutical composition that is generally safe and non-toxic and approved by or by a regulatory agency.
Drawings
Fig. 1: hydromorphone monohydrate prepared in example 1 (I.H 2 O) FTIR of form a.
Fig. 2: hydromorphone monohydrate prepared in example 1 (I.H 2 O) DSC of form a, which shows an endothermic peak at 112 ℃ due to water loss and an endothermic peak at 276 ℃ due to solid melting.
Fig. 3: hydromorphone monohydrate prepared in example 1 (I.H 2 O) TGA of form a, which shows a 5.8% drop between 98 ℃ and 115 ℃ due to water loss. One molecule of water represents 5.94% of the theoretical molecular weight.
Fig. 4: FTIR of hydromorphone base (I) prepared in example 2.
Fig. 5: DSC of hydromorphone base (I) prepared in example 2, shows an endothermic peak at 275 ℃.
Fig. 6: TGA of hydromorphone base (I) prepared in example 2, which shows no water loss.
Fig. 7: hydromorphone monohydrate prepared in example 1 (I.H 2 O) PXRD of form a.
Fig. 8: FTIR of hydromorphone hydrochloride (i·hcl) with the following peaks 3029, 2960, 2926, 2584, 1716, 1638, 1621, 1312, 976, 736.
Fig. 9: hydromorphone hydrochloride (i.hcl), hydromorphone base (I) and hydromorphone monohydrate (i.h) 2 O) FTIR superimposed form a.
Detailed Description
These methods are shown graphically in the following schemes: the solvent medium comprises an aqueous organic solvent
DSC and TGA experiments at 30-350 ℃ at 10 ℃/min under N 2 And under a stream of air.
Embodiment 1. A process for preparing hydromorphone base (I) comprising:
i. hydromorphone monohydrate (I.H 2 O) suspended or dissolved in at least one organic solvent, and
separating hydromorphone base (I).
Implementation of the embodimentsScheme 2. The method of the above embodiment wherein the organic solvent comprises C 1 -C 8 Primary, secondary or tertiary alcohols of linear or branched alkanes; c (C) 1 -C 5 C of straight-chain or branched carboxylic acids 1 -C 8 Linear or branched alkyl esters; in cyclic or open form with the same or two different C's attached to oxygen 1 -C 6 A linear or branched ether; c substituted by 1 to 4 different or identical halogens 1 -C 8 Linear or branched alkanes, wherein the halogen is selected from Cl, br or I; the same or different C 1 -C 8 Ketones of linear or branched alkane chains; c (C) 1 -C 5 A nitrile; c (C) 5 -C 8 Linear, branched or cyclic alkanes; c (C) 1 -C 3 Mono-, di-or trialkyl-substituted C 5 -C 8 Aromatic or heteroaromatic compounds; or a mixture thereof.
Embodiment 3. The method of any of the above embodiments, wherein the organic solvent comprises methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, t-butanol, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, dichloromethane, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, diethyl ether, 1, 4-dioxane, methyl t-butyl ether, pentane, cyclopentane, hexane, cyclohexane, heptane, toluene, chloroform, or mixtures thereof.
Embodiment 4. The method of any of the preceding embodiments, wherein the organic solvent comprises ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone, methylene chloride, methanol, ethanol, propanol, isopropanol, 1-butanol, isobutanol, t-butanol, pentane, hexane, heptane, toluene, methyl t-butyl ether, diethyl ether, or mixtures thereof.
Embodiment 5. The method of any of the above embodiments, wherein the organic solvent comprises ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone, methanol, heptane, toluene, methyl tert-butyl ether, or mixtures thereof.
Embodiment 6. The method of any of the above embodiments, wherein the organic solvent comprises ethyl acetate, isopropyl acetate, methyl isobutyl ketone, heptane, toluene, methyl t-butyl ether, or mixtures thereof.
Embodiment 7. The method of any of the above embodiments, wherein the organic solvent comprises a polar organic solvent.
Embodiment 8. The method of the above embodiment, wherein the polar organic solvent comprises methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, t-butanol, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, dichloromethane, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, or mixtures thereof.
Embodiment 9. The method of the above embodiment, wherein the organic solvent comprises a polar protic organic solvent.
Embodiment 10. The method of the above embodiment, wherein the polar protic organic solvent comprises methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, t-butanol, or a mixture thereof.
Embodiment 11. The method of embodiment 8, wherein the organic solvent comprises a polar aprotic organic solvent.
Embodiment 12. The method of the above embodiment, wherein the polar aprotic organic solvent comprises methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, methylene chloride, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, or mixtures thereof.
Embodiment 13. The method of any of embodiments 1-6, wherein the organic solvent comprises a non-polar organic solvent.
Embodiment 14. The method of the above embodiment, wherein the non-polar organic solvent comprises diethyl ether, 1, 4-dioxane, methyl tertiary butyl ether, pentane, cyclopentane, hexane, cyclohexane, heptane, toluene, chloroform, or mixtures thereof.
Embodiment 15. The method of any of the above embodiments, wherein the organic solvent comprises less than 5% water.
Embodiment 16. The method of the above embodiment, wherein the organic solvent comprises less than 3% water.
Embodiment 17. The method of the above embodiment, wherein the organic solvent comprises less than 2% water.
Embodiment 18. The method of the above embodiment, wherein the organic solvent comprises less than 1% water.
Embodiment 19. The method of the above embodiment, wherein the organic solvent comprises less than 0.1% water.
Embodiment 20. The method of the above embodiment, wherein the organic solvent comprises less than 0.01% water.
Embodiment 21. The method of any of the above embodiments, wherein the organic solvent is an anhydrous organic solvent.
Embodiment 22 the method of any of the above embodiments, wherein in step I, hydromorphone monohydrate (I.H) 2 O)。
Embodiment 23. The method of the above embodiment wherein in step I. Suspension or dissolution of hydromorphone monohydrate (I.H) 2 O)。
Embodiment 24. The method of the above embodiment, wherein in step I hydromorphone monohydrate (I.H) is suspended or dissolved at 25-35 ℃ 2 O)。
Embodiment 25 the method of any one of embodiments 1-22, wherein in step I. Hydromorphone monohydrate (I.H) 2 O)。
Embodiment 26. The method of the above embodiment wherein in step I. The hydromorphone monohydrate (I.H) 2 O)。
Embodiment 27. The method of any of the above embodiments, wherein the separating step ii.) is performed at-5 to 25 ℃.
Embodiment 28. The method of any of the above embodiments, wherein the separating step ii.) is performed at-5 to 15 ℃.
Embodiment 29. The method of any of the above embodiments, wherein the separating step ii.) is performed at 0 to 10 ℃.
Embodiment 30 the method of any one of embodiments 1-29 or 76-88, wherein hydromorphone monohydrate (I.H) is prepared according to embodiments 47-67 2 O)。
Embodiment 31 the method of any one of embodiments 1-29 or 76-88, wherein hydromorphone monohydrate (I.H 2 O) is hydromorphone monohydrate (I.H) as described in embodiments 36-43 or 68-75 2 O)。
Embodiment 32. A crystalline form of hydromorphone base (I) having a DSC endotherm at 275 ± 2 ℃.
Embodiment 33A crystalline form of hydromorphone base (I) of the above embodiment is characterized by comprising the following peaks 3361, 2924, 2797, 1727, 1502, 1314, 946.+ -. 5cm -1 FTIR of (c).
Embodiment 34. A pharmaceutical composition comprising a crystalline form of hydromorphone base (I) according to any one of embodiments 32 to 33 and at least one pharmaceutically acceptable excipient.
Embodiment 35 a crystalline form of hydromorphone base (I) according to any one of embodiments 32 to 33 or a pharmaceutical composition according to embodiment 34 for use in the treatment of pain.
Embodiment 36 hydromorphone monohydrate (I.H 2 O)。
Embodiment 37 hydromorphone monohydrate (I.H) 2 O), which is considered to exclude isotopically labeled derivatives.
Embodiment 38. Hydromorphone monohydrate (I.H) 2 O), wherein the non-primary isotope comprises less than 5 mole percent.
Embodiment 39. Hydromorphone monohydrate (I.H) 2 O), wherein the lower abundance isotope is less than 3% by mole percent.
Embodiment 40. Hydromorphone monohydrate of any of embodiments 36-39 (I.H 2 O), wherein deuterium comprises less than 0.1% of the hydrogen isotope in mole percent.
Embodiment 41 any of embodiments 36-40 in crystalline formHydromorphone monohydrate (I.H) 2 O) characterized by FTIR substantially as shown in figure 1.
Embodiment 42. Hydromorphone monohydrate (I.H. of any of embodiments 36-41 2 O) form A, characterized by comprising the following peaks 3547, 2925, 1721, 1377, 973, 749.+ -. 5cm -1 FTIR of (c).
Embodiment 43 hydromorphone monohydrate (I.H) 2 O) form a characterized by a DSC having two endotherm peaks, one at 112±4 ℃, and a second at 276±2 ℃.
Embodiment 44 hydromorphone monohydrate (I.H) as described in embodiments 36-43 2 O) for the preparation of hydromorphone base (I).
Embodiment 45A pharmaceutical composition comprising hydromorphone monohydrate (I.H) as described in any one of embodiments 36-43 2 O) with at least one pharmaceutically acceptable excipient.
Embodiment 46. Hydromorphone monohydrate (I.H) as described in any one of embodiments 36-43 2 O) or the pharmaceutical composition of embodiment 45 for use in the treatment of pain.
Embodiment 47 preparation of hydromorphone monohydrate (I.H 2 O) a process comprising:
a) Dissolving hydromorphone salt in a solvent medium comprising water,
b) Adjusting the pH of the mixture of step a) to 8-10, and
c) Separating hydromorphone monohydrate (I.H) from the mixture of step b) 2 O)。
Embodiment 48. The method of the above embodiment, wherein the hydromorphone salt is hydromorphone hydrochloride (I.HCl), sulfate, 1, 4-benzenedicarboxylate, 1, -triflate, 1-hydroxy-2-naphthalene carboxylate, 3-hydroxy-2-naphthalene carboxylate, alpha-methyl-4- [ (2-oxocyclopentyl) methyl ] phenylacetate, 2',4' -difluoro-4-hydroxy [1,1 '-biphenyl ] -3-carboxylate, 4, 5-diphenyl-2-oxazolopropionate, α -methyl-3-phenoxyphenylacetate, 1-methyl-5- (4-methylbenzoyl) -1H-pyrrole-2-acetate, 2-fluoro- α -methyl [1,1' -biphenyl ] -4-acetate, α -methyl-4- (2-thienylcarbonyl) phenylacetate, (1Z) -5-fluoro-2-methyl-1- (methylsulfinyl) phenyl ] methylene ] -1H-indene-3-acetate, 3-benzoyl- α -methylphenylacetate, 1, 8-diethyl-1, 3,4, 9-tetrahydropyrano [3,4-b ] indole-1-acetate, (α S) -6-methoxy- α -methyl-2-naphthaleneacetate, 2-naphthalenesulfonate, succinate, (2E) -2-butene diacid salt, (2Z) -2-butene diacid salt, 2-hydroxy-1, 2, 3-tricarballyl carboxylate, 4-methylbenzenesulfonate, 2-hydroxypropionate, benzoate, borate, dodecanoate, oxalate, valerate, hydrobromide, (2R, 3R) -2, 3-dihydroxysuccinate, phosphate, acetate, (9Z) -9-octadecenoate, 2, 3-dimethyl-4- [ [ (4-methylphenyl) sulfonyl ] oxy ] benzenesulfonate, 4- [ [ (2, 3-dimethylphenyl) sulfonyl ] oxy ] benzenesulfonate, 4- [ [ [ (4-methylphenyl) sulfonyl ] oxy ] benzenesulfonate, 4- [ (phenylsulfonyl) oxy ] benzenesulfonate, or 3-hydroxy-2, 6-dimethylbenzenesulfonate.
Embodiment 49. The method of the above embodiment, wherein the hydromorphone salt is hydromorphone hydrochloride (i.hcl).
Embodiment 50. The method of any of embodiments 47-49, wherein the solvent medium comprising water comprises at least 50% water.
Embodiment 51. The method of the above embodiment, wherein the solvent medium comprising water comprises at least 75% water.
Embodiment 52. The method of the above embodiment, wherein the solvent medium comprising water comprises at least 85% water.
Embodiment 53. The method of the above embodiment, wherein the solvent medium comprising water comprises at least 95% water.
Embodiment 54. The method of any of embodiments 47-53, wherein the pH is adjusted to 8.2-9.8.
Embodiment 55. The method of the above embodiment, wherein the pH is adjusted to 8.4-9.6.
Embodiment 56. The method of the above embodiment, wherein the pH is adjusted to 8.6-9.4.
Embodiment 57. The method of the above embodiment, wherein the pH is adjusted to 8.8-9.2.
Embodiment 58. The method of any of embodiments 47-57, wherein step c) is performed at-5 to 25 ℃.
Embodiment 59. The method of the above embodiment, wherein step c) is performed at-5 to 15 ℃.
Embodiment 60. The method of the above embodiment, wherein step c) is performed at-2 to 12 ℃.
Embodiment 61. The method of the above embodiment, wherein step c) is performed at 0 to 10 ℃.
Embodiment 62. The method of any of embodiments 47-61, wherein the pH is adjusted with a base.
Embodiment 63. The method of the above embodiment, wherein the base is a weak base.
Embodiment 64. The method of the above embodiment, wherein the weak base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, ammonium hydroxide, methylamine, ethylamine, dimethylamine, diethylamine, triethylamine, diisopropylethylamine, sodium acetate, potassium acetate, sodium formate, potassium formate, or mixtures thereof.
Embodiment 65. The method of the above embodiment, wherein the weak base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, ammonium hydroxide, triethylamine, diisopropylethylamine, sodium acetate, potassium acetate, sodium formate, potassium formate, and mixtures thereof.
Embodiment 66. Hydromorphone monohydrate of any of embodiments 36-46 (I.H 2 O) form a characterized by PXRD comprising the following peaks: 11.2 and 15.1.+ -. 0.2 degrees 2. Theta. Are referred to as form A.
Embodiment 67 hydromorphone monohydrate (I.H) 2 O) form a characterized by PXRD comprising the following peaks: 11.2, 15.1 and 25.4.+ -. 0.2 degrees 2-theta, referred to as form a.
Embodiment 68. Hydromorphone monohydrate (I.H) 2 O) form a characterized by PXRD comprising the following peaks: 11.2, 15.1, 16.5, 25.4 and 25.7±0.2 degrees 2θ, referred to as form a.
Embodiment 69 hydromorphone monohydrate (I.H) 2 O) form a characterized by PXRD comprising the following peaks: 11.2, 12.3, 15.1, 16.5, 25.4 and 25.7.+ -. 0.2 degrees 2-theta, referred to as form a.
Embodiment 70. Hydromorphone monohydrate (I.H) of the above embodiment 2 O) form a characterized by PXRD comprising the following peaks: 11.2, 12.3, 15.1, 16.5, 23.2, 25.4 and 25.7±0.2 degrees 2θ, referred to as form a.
Embodiment 71. Hydromorphone monohydrate (I.H) 2 O) form a characterized by PXRD comprising the following peaks: 11.2, 12.3, 13.9, 15.1, 16.5, 23.2, 24.8, 25.4, 25.7 and 28.1 ± 0.2 degrees 2θ, referred to as form a.
Embodiment 72. Hydromorphone monohydrate (I.H) 2 O) form a characterized by PXRD comprising the following peaks: 11.2, 12.3, 13.9, 15.1, 16.5, 18.9, 19.3, 23.2, 24.8, 25.4, 25.7 and 28.1 ± 0.2 degrees 2θ, referred to as form a.
Embodiment 73. Hydromorphone monohydrate (I.H) 2 O) form a characterized by PXRD comprising the following peaks: 11.2, 12.3, 13.9, 15.1, 16.5, 18.9, 19.3, 23.2, 23.6, 24.8, 25.4, 25.7, 28.1, 31.4 and 31.8±0.2 degrees 2θ, referred to as form a.
Embodiment 74. The method of any of embodiments 1-31 wherein the organic solvent comprises ethyl acetate, toluene, or a mixture thereof.
Embodiment 75. The method of the above embodiment, wherein the organic solvent comprises ethyl acetate.
Embodiment 76 the method of embodiment 74, wherein the organic solvent comprises toluene.
Embodiment 77 the method of any of embodiments 1-31 or 74-76 wherein in step I. Hydromorphone monohydrate (I.H 2 O) suspending or dissolving for 30 minutes to 48 hours.
Embodiment 78. The method of the above embodiment wherein hydromorphone monohydrate (I.H 2 O) suspending or dissolving in step i.
Embodiment 79. The above embodimentThe method wherein in step i. hydromorphone monohydrate (I.H 2 O) suspending or dissolving for 1.5 to 24 hours.
Embodiment 80. The method of the above embodiment, wherein in step I. Hydromorphone monohydrate (I.H 2 O) suspending or dissolving for 1.5 to 12 hours.
Embodiment 81. The method of the above embodiment wherein in step I. Hydromorphone monohydrate (I.H 2 O) suspending or dissolving for 1.5 to 6 hours.
Embodiment 82. The method of the above embodiment, wherein in step I. Hydromorphone monohydrate (I.H 2 O) suspending or dissolving for 1.5 to 4 hours.
Embodiment 83 the method of embodiment 79 wherein in step I. Hydromorphone monohydrate (I.H 2 O) suspending or dissolving for 4 to 24 hours.
Embodiment 84. The method of the above embodiment, wherein in step I. Hydromorphone monohydrate (I.H 2 O) suspending or dissolving for 8 to 24 hours.
Embodiment 85. The method of the above embodiment, wherein in step I. Hydromorphone monohydrate (I.H 2 O) suspending or dissolving for 12 to 24 hours.
Embodiment 86 the method of the above embodiment wherein in step i. hydromorphone monohydrate (I.H 2 O) suspending or dissolving for 17 to 22 hours.
Examples
Test 1 powder X-ray diffraction analysis (PXRD) was performed as follows:
sample preparation: to obtain a powder diffraction pattern of the resulting solid, about 20mg of sample was prepared in a standard sample holder using two pieces of polyacetate foil.
Data acquisition: cuK alpha 1 rays on a Bruker D8 advanced series 2 theta/theta powder diffraction SystemA powder diffraction pattern is obtained in a transmissive geometry. The system is equipped with->Single photon counting PSD, germanium monochromator, 90-bit automatic replacement sample stage, fixed divergent slit and radial Soiler.
The procedure used was: data were collected using DIFFRAC Plus XRD Commander V.2.5.1 and evaluated using High Score Plus 4.9 (Malvern Panalytical).
Measurement conditions: samples were measured in 1 hour measurements at room temperature in the range of 4 ° -40 ° 2θ degrees using an angular step of 0.033 ° and a time per step of 2930.45 seconds.
EXAMPLE 1 preparation of hydromorphone monohydrate (I.H) from hydromorphone hydrochloride (I.HCl) 2 O).
1.002g (3.11 mmol) of I.HCl was dissolved in 10mL of water under nitrogen flow and cooled to 0/10 ℃. 0.278g (2.62 mmol) of sodium carbonate was added in portions with stirring to adjust the pH to 9.0. The mixture was stirred at 0/10℃for 3 hours. The resulting suspension was filtered, the solid was washed with cold water and dried in vacuo (55 mbar) at 50 ℃. Yield 0.774g (82% yield) of I.H 2 O。
FTIR (fig. 1): 3547. 2925, 1721, 1377, 973, 749cm -1
The DSC endotherm, water loss and I endotherm at 112℃and 276℃are shown in FIG. 2, respectively.
TGA 5.8%, 98 ℃ -115 ℃ water loss is shown in figure 3.
MW I·H 2 O:303.36。
MW H 2 O:18.02。
I·H 2 O had 5.94% water.
PXRD form a, as shown in fig. 7, has the following peaks:
example 2: from hydromorphone monohydrate (I.H in ethyl acetate 2 O)
Preparing hydromorphone base (I).
At 20/25℃under a nitrogen flowNext, will be 0.306g I.H 2 O (1.00 mmol) was suspended in 1.5mL anhydrous ethyl acetate for 2 hours. After cooling to 0/10℃for 1 hour, the resulting suspension was filtered and the solid was washed 2 times with 1mL of cold ethyl acetate. The solid was dried under vacuum at 50℃to give 0.257g (89% yield) of I.
FTIR (fig. 4): 3361. 2924, 2797, 1727, 1502, 1314, 946cm -1 . DSC, at 275 ℃, as shown in FIG. 5.
Example 3: from hydromorphone monohydrate (I.H) 2 O)
Preparing hydromorphone base (I).
0.100g of hydromorphone monohydrate (I.H) was reacted under nitrogen at 20/25 ℃ 2 O) (0.33 mmol) was suspended in 0.5mL of anhydrous solvent as set forth in the table below for 2 hours. After cooling to 0/10℃for 1 hour, the resulting suspension was filtered and the solid was washed 4 times with 0.5mL of the corresponding cold solvent. The solid was dried under vacuum at 50 ℃. The results are reported in the following table:
EXAMPLE 4 preparation of hydromorphone monohydrate (I.H) from hydromorphone hydrochloride (I.HCl) 2 O).
2.0g (6.23 mmol) of I.HCl are dissolved in 20mL of water under nitrogen and cooled to 0/10 ℃. Sodium carbonate (0.766 g,7.22 mmol) was added in portions with stirring at 0/10℃to adjust the pH to 9.0. The mixture was stirred at 0/10℃for 2.5 hours. The resulting suspension was filtered and the solid was washed several times with cold water to completely remove NaCl. The solid was dried under vacuum (55 mbar) at 50℃to give 1.754g (92.8% yield) of I.H 2 O. FTIR matched the monohydrate obtained in example 1.
Example 5: from hydromorphone monohydrate (I.H) 2 O) preparation of hydromorphone base (I).
0. g I.H was treated under nitrogen flow at 30/35 ℃ 2 O (2.96 mmol) was suspended in 4.5mL toluene for 19 hours. After cooling to 0/10℃for 1 hour, the resulting suspension was filtered and the solid was washed 2 times with 2mL of toluene.The solid was dried under vacuum at 50℃to give 0.788g (88% yield) of I. FTIR matched hydromorphone base (I) obtained in example 2.
Reference to the literature
CSUK, r. et al Towards an Efficient Preparation of hydrophorphone. Synthesis 2012, vol.44, n°18, pages 2840-2842 DOI:10.1055/s-0031-1291151.
ERBING, e. Et al General, simple, and Chemoselective Catalysts for the Isomerization of Allylic Alcohols: the Importance of the Halide Ligand. Chem. Eur. J.2016, vol.22, N.degree.44, pages 15659-15663 DOI: 10.1002/chem.201603025.
FISCHER, R.et al Zum Nachweis narkotisch wirkender Substanzen in biologischem Material Mikrochim Acta 1949, vol.34, N.3, pages 257-268.DOI:10.1007/BF01412693.
GOMEZ, AB. Et al Transmission metal-catalyzed redox isomerization of codeine and morphine in Water RSA adv.2014, vol.4, N20, pages 39519-39522 DOI:10.1039/C4RA07735K.
MAZUREK, j. Et al Two orthorhombic polymorphs of hydrommorphone acta cryst.2016, vol.72, n°5, pages 730-733. DOI:10.1107/S2056989016006563.
MERK INDEX,2006,O'Neil,M.J.(ed.).The Merck Index-An Encyclopedia of Chemicals,Drugs,and Biologicals.Whitehouse Station,NJ:Merck and Co.,Inc.,2006.,p.121.
MURPHY, B. Et al Conversion of Thebaine to Oripavine and Other Useful Intermediates for the Semisynthesis of Opiate-developed Agents: synthesis of Hydromatorphine Adv Synth. Catalyst 2014, vol.256, N.degree.11-12, pages 2679-2687. DOI:10.1002/adsc.201400445.
RAPOPORT, h. et al, the preparation of some dihydro ketones in the morphine series by Oppenauer oxidation j. Org. Chem.1950, vol.15, n°5, pages 1103-1107. DOI:10.1021/jo01151a029.
WANG, m. et al The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: a Bifunctional Opioid from a Set of "Tail Wags Dog" experimenters.molecular 2020, vol 25, n° 11,2640; DOI:10.3390/molecules25112640.

Claims (32)

1. A process for preparing hydromorphone base (I), comprising:
i. hydromorphone monohydrate (I.H 2 O) suspended or dissolved in at least one organic solvent, and
separating hydromorphone base (I).
2. The process of claim 1, wherein the organic solvent comprises methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, t-butanol, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, dichloromethane, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, diethyl ether, 1, 4-dioxane, methyl t-butyl ether, pentane, cyclopentane, hexane, cyclohexane, heptane, toluene, chloroform, or mixtures thereof.
3. The method of any of the preceding claims, wherein the organic solvent comprises a polar organic solvent.
4. The process of the preceding claim, wherein the polar organic solvent is ethyl acetate.
5. The method of claim 1, wherein the organic solvent comprises a non-polar organic solvent.
6. The process of the preceding claim, wherein the non-polar organic solvent is toluene.
7. The process of any one of the preceding claims, wherein the organic solvent is an anhydrous organic solvent.
8. The process of any of the preceding claims, wherein in step i. hydromorphone monohydrate (i.h 2 O)。
9. The process of the preceding claim, wherein in step i. hydromorphone monohydrate (i.h 2 O)。
10. The process of the preceding claim, wherein in step I. Hydromorphone monohydrate (i.h 2 O)。
11. The method of any one of the preceding claims, wherein the separation step ii.) is performed at-5-25 ℃.
12. The method of the preceding claim, wherein the separation step ii.) is carried out at 0-10 ℃.
13. Hydromorphone monohydrate (I.H) 2 O)。
14. Hydromorphone monohydrate (i·h) of claim 13 2 O), which is in crystalline form, is characterized by a DSC having two endotherm peaks, one at 112±4 ℃, and the second at 276±2 ℃, referred to as form a.
15. Hydromorphone monohydrate (i·h) according to any one of claims 13 to 14 2 O) crystalline form characterized by FTIR comprising the following peaks: 3547. 2925, 1721, 1377, 973, 749.+ -. 5cm -1 Referred to as form a.
16. Hydromorphone monohydrate (i.h) according to any one of claims 13 to 15 2 O) crystalline form characterized by PXRD comprising the following peaks: 11.2 and 15.1.+ -. 0.2 degrees 2. Theta. Are referred to as form A.
17. Hydromorphone monohydrate (i·h) according to the preceding claim 2 O) crystalline formsCharacterized by PXRD comprising the following peaks: 11.2, 15.1 and 25.4, ±0.2 degrees 2θ, referred to as form a.
18. Hydromorphone monohydrate (i·h) according to the preceding claim 2 O) crystalline form characterized by PXRD comprising the following peaks: 11.2, 12.3, 13.9, 15.1, 16.5, 18.9, 19.3, 23.2, 23.6, 24.8, 25.4, 25.7, 28.1, 31.4 and 31.8±0.2 degrees 2θ, referred to as form a.
19. Preparation of hydromorphone monohydrate (I.H) 2 O) a process comprising:
a) Dissolving hydromorphone salt in a solvent medium comprising water,
b) Adjusting the pH of the mixture of step a) to 8-10, and
c) Separating hydromorphone monohydrate (I.H) from the mixture of step b) 2 O);
Wherein:
step c) is carried out at-5 to 25 ℃.
20. The method of claim 19, wherein the solvent medium comprising water comprises at least 50% water.
21. The method of the preceding claim, wherein the solvent medium comprising water comprises at least 95% water.
22. The method of any one of claims 19 or 21, wherein the pH is adjusted to 8.2-9.8.
23. The method of the preceding claim, wherein the pH is adjusted to 8.8-9.2.
24. The method of any one of claims 19-23, wherein in step b), the pH is adjusted with a weak base.
25. The process of the preceding claim, wherein the weak base is selected from sodium carbonate, potassium carbonate, cesium carbonate, ammonium hydroxide, methylamine, ethylamine, dimethylamine, diethylamine, triethylamine, diisopropylethylamine, sodium acetate, potassium acetate, sodium formate, potassium formate, or mixtures thereof.
26. The process of the preceding claim, wherein the weak base is sodium carbonate.
27. The method of any one of claims 19-26, wherein the hydromorphone salt is hydromorphone hydrochloride (I-HCl).
28. The method of any one of claims 19-27, wherein step c) is performed at 0-10 ℃.
29. The process according to any one of claims 1 to 12, wherein hydromorphone monohydrate (i.h) is obtained according to any one of claims 19 to 26 2 O)。
30. The method according to any one of claims 1-12, wherein hydromorphone monohydrate (i.h 2 O) is hydromorphone monohydrate (i.h) according to any one of claims 13-18 2 O)。
31. Hydromorphone monohydrate (i·h) according to any one of claims 13 to 18 2 O), for use in therapy.
32. Use according to the preceding claim of hydromorphone monohydrate (i·h 2 O), wherein the therapy is pain management.
CN202180076350.4A 2020-11-13 2021-11-12 Synthesis of hydromorphone base Pending CN116457359A (en)

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