CN111560021B - Degaitinib intermediate and preparation method thereof - Google Patents
Degaitinib intermediate and preparation method thereof Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a Degaitinib (Delgocitinib) intermediate (3S, 4R) -3-methyl-beta-oxo-1, 6-diazaspiro [3,4] octane-1-propionitrile and a preparation method thereof, wherein common compounds are used as starting materials to sequentially perform bromination, acylation, cyclization, substitution, condensation reduction and other reactions, so that the raw materials in the preparation process are easy to obtain, and the preparation method is economical and environment-friendly. Deratinib can be prepared by one-step condensation between the intermediate and 4-chloro-7H-pyrrole [2,3-d ] pyrimidine, thereby providing a new way for preparing the bulk drug.
Description
Technical Field
The invention belongs to the technical field of organic synthesis route design, raw material medicines and intermediate preparation thereof, and particularly relates to a preparation method of an intermediate of an atopic dermatitis treatment medicine Degatinib (Delgocitinib).
Background
Degaitinib (Delgocitinib) is a JAK kinase inhibitor developed jointly by Nicotiana japonica and Torii Pharmaceutical. The composition is approved by the integrated administration (PMDA) of Japanese independent administration for treating atopic dermatitis in month 1 of 2020, and has the trade name of Corectom. Because the medicine is not formally marketed in China and does not have a standard Chinese translated name, the applicant transliterates the medicine into Degatinib. Degaitinib (Delgocitinib) is used as a JAK kinase inhibitor, and can inhibit the overactivation of immune response and slow down inflammatory response caused by a JAK signal pathway.
Degaitinib (Delgocitinib), chemical name (3S, 4R) -3-methyl-beta-oxo-6- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 6-diazaspiro [3,4] octane-1-propionitrile.
International patent WO2011013785 and WO2018117152 et al disclose a process for the preparation of Deratinib and its analogues. The basic idea is that the spiro intermediate protected by benzyl or formyloxybenzyl is subjected to amination reaction with chloro-pyrrolopyrimidine, the obtained intermediate is subjected to deprotection of benzyl or formyloxybenzyl, and amidation reaction with nitrile propionic acid under the action of condensing agent such as 3, 5-dimethylpyrazole to generate the target product Deratinib.
Synthetic scheme by benzyl protection and deprotection:
synthetic scheme for double protection and deprotection by benzyl and formyloxybenzyl:
as can be seen from examining the above synthetic routes, although the literature provides numerous specific methods involving the conversion of lactones to lactams, substitution of pyrrolopyrimidine rings, and condensation of oxopropanenitriles, all synthetic routes involve single or double protection of two nitrogen atoms in a double spiro intermediate, and deprotection thereof. The protection and deprotection play a major role in distinguishing the activity of two nitrogen atoms and reducing possible side reactions, but at the same time, the reaction steps are actually added, so that the total yield is reduced, the cost is increased, and the economic and social benefits are influenced.
Based on the analysis, the invention aims to design and synthesize an intermediate which can be used for preparing the De-high-tinib, and the defects of more steps, higher cost and the like in the existing synthetic route can be overcome through the intermediate, so that the preparation of the De-high-tinib is simpler, more convenient and controllable in cost, and the economic and technical benefits of the raw material medicine can be obviously improved.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, and provides a Degaitinib (Delgocitinib) intermediate and a preparation method thereof according to the green chemical synthesis concept.
In order to achieve the above purpose, the main technical scheme provided by the invention is as follows: a delatinib intermediate (3S, 4R) -3-methyl-beta-oxo-1, 6-diazaspiro [3,4] octane-1-propionitrile (I), the structure of which is shown as the following formula:
the preparation method of the Degatinib intermediate (3S, 4R) -3-methyl-beta-oxo-1, 6-diazaspiro [3,4] octane-1-propionitrile (I) comprises the following steps: the R-2-chloro-1-propylamine (II) and the 2-bromo-acetamide are subjected to bromination reaction under the action of potassium carbonate to generate N- (R-2-chloro-propyl) -2-amino acetamide (III), the N- (R-2-chloro-propyl) -2-amino acetamide (III) and the 2-nitriloacetamide chloride are subjected to acylation reaction under the action of triethylamine to prepare N- (R-2-chloro-propyl) -N- (2-acetamide) -2-nitriloacetamide (IV), the N- (R-2-chloro-propyl) -N- (2-acetamide) -2-nitriloacetamide (IV) is subjected to cyclization reaction under the action of cesium carbonate to prepare (3S) -N- (2-nitriloacetic acid) -1-aza-2-formamide-3-methyl-cyclobutane (V), the (3S) -N- (2-nitriloacetic acid) -1-aza-2-formamide-3-methyl-cyclobutane (V) and 2-bromoethanol are subjected to substitution reaction under the action of hexamethyldisilazane lithium amide to generate (2R, 3S) -N- (2-nitriloacetic acid) -1-aza-2-formamide-2- (2-hydroxyethyl) -3-methyl-cyclobutane (VI), and the 2R, 3S) -N- (2-nitriloacetic acid) -1-aza-2-formamide-2- (2-hydroxyethyl) -3-methyl-cyclobutane (VI) is subjected to condensation reduction reaction under the action of catalyst diethyl azodicarboxylate, triphenylphosphine and reductant lithium aluminum hydride to prepare the delatinib intermediate (3S, 4R) -3-methyl-beta-oxo-1, 6-diazaspiro [3,4] octane-1-propionitrile (I).
In addition, the invention also provides the following auxiliary technical scheme:
the feed ratio of the bromination reaction is R-2-chloro-1-propylamine (II) (1 equivalent), 2-bromoacetamide (1-1.5 equivalent) and potassium carbonate (1-2 equivalent), preferably R-2-chloro-1-propylamine (II) (1 equivalent), 2-bromoacetamide (1.2 equivalent) and potassium carbonate (1.5 equivalent).
The solvent for the bromination reaction is toluene, xylene, tetrahydrofuran, acetonitrile, n-hexane or n-heptane, preferably n-hexane.
The bromination reaction temperature is 0 to 100 ℃, preferably 60 to 70 ℃.
The acylation reaction is carried out with a charge ratio of N- (R-2-chloro-propyl) -2-aminoacetamide (III) (1 equivalent), 2-nitriloacetamide (1 to 1.5 equivalent) and triethylamine (1 to 3 equivalents), preferably N- (R-2-chloro-propyl) -2-aminoacetamide (III) (1 equivalent), 2-nitriloacetamide (1.2 equivalent) and triethylamine (2 equivalents).
The solvent of the acylation reaction is dichloromethane, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate or isopropyl acetate, preferably dichloromethane.
The temperature of the acylation reaction is 0 to 60 ℃, preferably 30 to 35 ℃.
The feed ratio of the cyclization reaction is N- (R-2-chloro-propyl) -N- (2-acetamide) -2-nitriloacetamide (IV) (1 equivalent) and cesium carbonate (1-3 equivalents), preferably N- (R-2-chloro-propyl) -N- (2-acetamide) -2-nitriloacetamide (IV) (1 equivalent) and cesium carbonate (2 equivalents).
The solvent for the cyclization reaction is N, N-dimethylformamide, N-dimethylacetamide, acetonitrile, toluene or dimethylsulfoxide, preferably dimethylsulfoxide.
The temperature of the cyclization reaction is 0 to 100 ℃, preferably 35 to 45 ℃.
The feed ratio of the substitution reaction is (3S) -N- (2-nitriloacetic acid) -1-aza-2-formamide-3-methyl-cyclobutane (V) (1 equivalent), 2-bromoethanol (1-2 equivalents) and lithium hexamethyldisilazide (1-3 equivalents), preferably (3S) -N- (2-nitriloacetic acid) -1-aza-2-formamide-3-methyl-cyclobutane (V) (1 equivalent), 2-bromoethanol (1.5 equivalents) and lithium hexamethyldisilazide (2 equivalents).
The solvent for the substitution reaction is N, N-dimethylformamide, N-dimethylacetamide, acetonitrile, toluene, dimethyl sulfoxide or tetrahydrofuran, preferably tetrahydrofuran.
The temperature of the substitution reaction is-78 to 0 ℃, preferably-70 to-75 ℃.
The charge ratio of the condensation reduction is (2R, 3S) -N- (2-nitriloacetic acid) -1-aza-2-carboxamide-2- (2-hydroxyethyl) -3-methyl-cyclobutane (VI) (1 equivalent), diethyl azodicarboxylate (1 to 3 equivalents), triphenylphosphine (1 to 3 equivalents) and lithium aluminum hydride (4 to 10 equivalents), preferably (2R, 3S) -N- (2-nitriloacetic acid) -1-aza-2-carboxamide-2- (2-hydroxyethyl) -3-methyl-cyclobutane (VI) (1 equivalent), diethyl azodicarboxylate (2 equivalents), triphenylphosphine (2 equivalents) and lithium aluminum hydride (8 equivalents).
The solvent for the condensation reaction in the condensation reduction reaction is acetonitrile, toluene, methylene dichloride, 1, 2-dichloroethane, dioxane or tetrahydrofuran, preferably tetrahydrofuran.
The temperature of the condensation reaction in the condensation reduction reaction is 0 to 100 ℃, preferably 50 to 55 ℃.
The solvent for the reduction reaction in the condensation reduction reaction is acetonitrile, toluene, diethyl ether, isopropyl ether, dioxane or tetrahydrofuran, preferably tetrahydrofuran.
The temperature of the reduction reaction in the condensation reduction reaction is 0 to 100 ℃, preferably 30 to 40 ℃.
According to the Degaitinib intermediate and the preparation method thereof, common compounds are used as starting materials, and the reactions of bromination, acylation, cyclization, substitution, reduction condensation and the like are sequentially carried out, so that the raw materials in the preparation process are easy to obtain, and the preparation method is economical and environment-friendly. The preparation of the intermediate provides a new preparation way for the crude drug.
Detailed Description
The technical scheme of the invention is further described in non-limiting detail below with reference to a plurality of preferred embodiments.
Embodiment one:
to the reaction flask were added R-2-chloro-1-propylamine (II) (4.68 g,50 mmol), 2-bromoacetamide (8.28 g,60 mmol), potassium carbonate (10.35 g,75 mmol) and n-hexane 150mL. Heating to 60-70 ℃ under stirring, and reacting for 10 hours. Filtering, washing the filtrate with water and brine in turn, drying, distilling under reduced pressure to recover the solvent, and obtaining 6.5g of N- (R-2-chloro-propyl) -2-aminoacetamide (III) as pale yellow oily substance with a yield of 86.7%, EI-MS m/z 151[ M+H ]] + 。
Embodiment two:
n- (R-2-chloro-propyl) -2-aminoacetamide (III) (5.18 g,25 mmol), 2-nitriloacetamide chloride (3.1 g,30 mmol), triethylamine (5.05 g,50 mmol) and dichloromethane (100 mL) were added to the reaction flask and reacted at 30-35℃for 4 hours with stirring. Cooled to room temperature, and the organic phase was washed with saturated brine and water, dried and concentrated to give 4.85g of N- (R-2-chloro-propyl) -N- (2-acetamide) -2-nitriloacetamide (IV) as a pale yellow solid in a yield of 89.1%, EI-MS m/z 218[ M+H ]] + 。
Embodiment III:
n- (R-2-chloro-propyl) -N- (2-acetamide) -2-nitriloacetamide (IV) 4.34g,20 mmol), cesium carbonate (14.1 g,40 mmol) and dimethyl sulfoxide 100mL were added to the reaction flaskThe mixture is stirred and reacted for 24 hours at the temperature of 35 to 45 ℃. Cooled to room temperature and the pH is adjusted to neutrality with dilute hydrochloric acid. Extracting with ethyl acetate for 3 times, combining organic phases, washing sequentially with saturated sodium bicarbonate aqueous solution, saturated saline solution and water, drying, concentrating to obtain an off-white solid (3S) -N- (2-nitriloacetic acid) -1-aza-2-carboxamide-3-methyl-cyclobutane (V) 3.62g, yield 89.8%, EI-MS m/z 182[ M+H ]] + 。
Embodiment four:
under the protection of nitrogen, adding (3S) -N- (2-nitriloacetic acid) -1-aza-2-formamide-3-methyl-cyclobutane (V) (1.8 g,10 mmol), 2-bromoethanol (1.88 g,15 mmol) and tetrahydrofuran (50 mL), cooling to-70-75 ℃, adding hexamethyldisilazane lithium amide (3.35 g,20 mmol), stirring for 3 hours, slowly heating to-30 ℃ and continuing the reaction for 1 hour. The temperature is raised to 0 ℃, and saturated ammonium chloride quenches the reaction. Extraction was performed 3 times with ethyl acetate, and the organic phases were combined and washed with water, saturated brine and water in this order. Drying, concentrating, and recrystallizing the obtained residue from N-hexane to obtain off-white solid (2R, 3S) -N- (2-nitriloacetic acid) -1-aza-2-carboxamide-2- (2-hydroxyethyl) -3-methyl-cyclobutane (VI) 2.0g in 88.9% yield, EI-MS m/z:226[ M+H ]] + 。
Fifth embodiment:
in a dry reaction flask were added (2R, 3S) -N- (2-nitriloacetic acid) -1-aza-2-carboxamide-2- (2-hydroxyethyl) -3-methyl-cyclobutane (VI) (1.13 g,5 mmol), diethyl azodicarboxylate (1.74 g,10 mmol), triphenylphosphine (2.62 g,10 mmol) and 100mL tetrahydrofuran under nitrogen, and the mixture was heated to 50-55℃for 10 hours. Cooling to room temperature, adding water, stirring for 1 hour, extracting with dichloromethane three times, combining organic phases, sequentially adding saline water and water, drying and concentrating, dissolving the obtained condensate with 50mL of tetrahydrofuran, cooling to 0 ℃, adding lithium aluminum hydride (1.52 g,40 mmol), stirring for 30 minutes, heating to 30-40 ℃, and continuing stirring for reacting for 2-3 hours. Quenching reaction with saturated ammonium chloride, extracting with dichloromethane three times, combining organic phases, sequentially washing with saturated sodium bicarbonate, saline solution and water, drying, concentrating, and recrystallizing the obtained residue with n-hexane to obtain Deratinib intermediate (3S, 4R) -3-methyl-beta-oxo-room-temperature-energy-reducing agent1, 6-diazaspiro [3,4]]0.75g of octane-1-propionitrile (I) with a yield of 77.3% and EI-MS m/z 194[ M+H ]] + ； 1 H NMR(DMSO-d6)δ3.70(d,J＝18.7Hz,1H),3.65(d,J＝18.7Hz,1H),3.20(brs,1H),3.07(m,1H),2.83(d,J＝12Hz,1H),2.71(m,3H),2.55(m,1H),2.25(m,1H),2.10(m,1H),1.67(m,1H),1.10(d,J＝7.0Hz,3H)。
Example six:
under the protection of nitrogen, adding Degaitinib intermediate (3S, 4R) -3-methyl-beta-oxo-1, 6-diazaspiro [3,4] into a dry reaction bottle]Octane-1-propionitrile (I) (1.93 g,10 mmol), 4-chloro-7H-pyrrole [2,3-d ]]Pyrimidine (1.84 g,12 mmol) and acetonitrile 50mL, potassium carbonate (8.28 g,60 mmol) was added dropwise with stirring in solution in 30mL of water. Heating to 80-85 deg.c and stirring to react for 2-3 hr. Concentrating, recrystallizing the obtained residue with ethanol to obtain 2.7g of Deratinib with a yield of 87.1%, and EI-MS m/z 311[ M+H ]] + ； 1 H NMR(DMSO-d6)δ11.61(brs,1H),8.09(s,1H),7.12(m,1H),6.59(m,1H),4.16(m,1H),4.01(m,3H),3.79(m,1H),3.72(d,J＝18.8Hz,1H),3.67(d,J＝18.6Hz,1H),3.59(dd,J＝8.2,4.0Hz,1H),2.64(m,2H),2.18(m,1H),1.13(d,J＝7.0Hz,3H)。
It should be noted that the foregoing description of the preferred embodiments is merely illustrative of the technical concept and features of the present invention, and is not intended to limit the scope of the invention, as long as the scope of the invention is defined by the claims and their equivalents. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.
Claims (11)
1. A preparation method of a Degaitinib (Delgocitinib) intermediate (3S, 4R) -3-methyl-b-oxo-1, 6-diazaspiro [3,4] octane-1-propionitrile, wherein the chemical structural formula of the intermediate is as follows:
the preparation method is characterized by comprising the following steps: the R-2-chloro-1-propylamine (compound II) and 2-bromo-acetamide undergo bromination reaction in a solvent under the action of potassium carbonate to generate a compound (III); the compound (III) and 2-nitrile acetyl chloride are subjected to acylation reaction in a solvent under the action of triethylamine to prepare a compound (IV); the compound (IV) is subjected to cyclization reaction in a solvent under the action of cesium carbonate to prepare a compound (V); the compound (V) and 2-bromoethanol undergo substitution reaction in a solvent under the action of hexamethyldisilazide lithium to generate a compound (VI); the compound (VI) is subjected to condensation reduction reaction in a solvent under the action of catalyst diethyl azodicarboxylate and triphenylphosphine and reductant lithium aluminum hydride to prepare a Degaitinib intermediate (3S, 4R) -3-methyl-b-oxo-1, 6-diazaspiro [3,4] octane-1-propionitrile [ compound (I) ];
2. the process for the preparation of the delatinib intermediate (3 s, 4R) -3-methyl-b-oxo-1, 6-diazaspiro [3,4] octane-1-propionitrile according to claim 1, characterized in that the bromination reaction feed ratio is R-2-chloro-1-propylamine: 2-bromoacetamide: potassium carbonate = 1 equivalent: 1 to 1.5 equivalents: 1 to 2 equivalents.
3. Degatinib intermediate (3S, 4R) -3-methyl-b-oxo-1, 6-diazaspiro [3,4] as claimed in claim 1]The preparation method of the octane-1-propionitrile is characterized in that the solvent for bromination reaction is toluene, xylene, tetrahydrofuran, acetonitrile, n-hexane or n-heptane; the temperature of the bromination reaction is 0-100 o C。
4. The process for the preparation of the delatinib intermediate (3 s, 4R) -3-methyl-b-oxo-1, 6-diazaspiro [3,4] octane-1-propionitrile as claimed in claim 1, characterized in that the acylation reaction charge ratio is N- (R-2-chloro-propyl) -2-aminoacetamide: 2-nitriloacetyl chloride: triethylamine = 1 equivalent: 1 to 1.5 equivalents: 1 to 3 equivalents.
5. According to claim 1, the intermediate of Degatinib3S, 4R) -3-methyl-b-oxo-1, 6-diazaspiro [3,4]]The preparation method of the octane-1-propionitrile is characterized in that the acylation reaction solvent of dichloromethane, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate or isopropyl acetate; the temperature of the acylation reaction is 0-60 DEG C o C。
6. The process for the preparation of the delatinib intermediate (3 s, 4R) -3-methyl-b-oxo-1, 6-diazaspiro [3,4] octane-1-propionitrile as claimed in claim 1, characterized in that the cyclization reaction feed ratio is N- (R-2-chloro-propyl) -N- (2-acetamide) -2-nitriloacetamide: cesium carbonate = 1 equivalent: 1 to 3 equivalents.
7. Degatinib intermediate (3S, 4R) -3-methyl-b-oxo-1, 6-diazaspiro [3,4] as claimed in claim 1]The preparation method of the octane-1-propionitrile is characterized in that the solvent of the cyclization reaction is N, N-dimethylformamide, N-dimethylacetamide, acetonitrile, toluene or dimethyl sulfoxide; the temperature of the cyclization reaction is 0-100 o C。
8. The process for the preparation of the delatinib intermediate (3S, 4 r) -3-methyl-b-oxo-1, 6-diazaspiro [3,4] octane-1-propionitrile as claimed in claim 1, characterized in that the substitution reaction feed ratio is (3S) -N- (2-nitriloacetic acid) -1-aza-2-carboxamide-3-methyl-cyclobutane: 2-bromoethanol: lithium hexamethyldisilazide=1 equivalent: 1-2 equivalents: 1 to 3 equivalents.
9. Degatinib intermediate (3S, 4R) -3-methyl-b-oxo-1, 6-diazaspiro [3,4] as claimed in claim 1]The preparation method of the octane-1-propionitrile is characterized in that the solvent of the substitution reaction is N, N-dimethylformamide, N-dimethylacetamide, acetonitrile, toluene, dimethyl sulfoxide or tetrahydrofuran; the temperature of the substitution reaction is-78-0 o C。
10. A process for the preparation of the delatinib intermediate (3 s,4 r) -3-methyl-b-oxo-1, 6-diazaspiro [3,4] octane-1-propionitrile according to claim 1, characterized in that the charge ratio of the condensation reduction is (2 r,3 s) -N- (2-nitriloacetic acid) -1-aza-2-carboxamide-2- (2-hydroxyethyl) -3-methyl-cyclobutane: diethyl azodicarboxylate: triphenylphosphine: lithium aluminum tetrahydroate = 1 equivalent: 1-3 equivalents: 1-3 equivalents: 4-10 equivalents.
11. The process for the preparation of the delatinib intermediate (3 s,4 r) -3-methyl-b-oxo-1, 6-diazaspiro [3,4] octane-1-propionitrile as claimed in claim 1, characterized in that the solvent of the condensation reaction in the condensation reduction reaction is acetonitrile, toluene, dichloromethane, 1, 2-dichloroethane, dioxane or tetrahydrofuran; the temperature of the condensation reaction in the condensation reduction reaction is 0-100 ℃; the solvent for the reduction reaction in the condensation reduction reaction is acetonitrile, toluene, diethyl ether, isopropyl ether, dioxane or tetrahydrofuran; the temperature of the reduction reaction in the condensation reduction reaction is 0-100 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011013785A1 (en) * | 2009-07-31 | 2011-02-03 | 日本たばこ産業株式会社 | Nitrogen-containing spiro-ring compound and medicinal use of same |
| WO2018117152A1 (en) * | 2016-12-21 | 2018-06-28 | 日本たばこ産業株式会社 | Method for producing 7h-pyrrolo[2,3-d]pyrimidine derivative and synthetic intermediate of same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011013785A1 (en) * | 2009-07-31 | 2011-02-03 | 日本たばこ産業株式会社 | Nitrogen-containing spiro-ring compound and medicinal use of same |
| WO2018117152A1 (en) * | 2016-12-21 | 2018-06-28 | 日本たばこ産業株式会社 | Method for producing 7h-pyrrolo[2,3-d]pyrimidine derivative and synthetic intermediate of same |
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