CN109553603A - A kind of preparation method of antineoplaston medicine pomalidomide - Google Patents
A kind of preparation method of antineoplaston medicine pomalidomide Download PDFInfo
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- CN109553603A CN109553603A CN201811561404.2A CN201811561404A CN109553603A CN 109553603 A CN109553603 A CN 109553603A CN 201811561404 A CN201811561404 A CN 201811561404A CN 109553603 A CN109553603 A CN 109553603A
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- pomalidomide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a kind of preparation methods of antineoplaston medicine pomalidomide, belong to pharmaceutical synthesis field.With 3- nitrophthalic acid and 3- amino piperidine -2,6- dione hydrochloride for raw material, pomalidomide is obtained after two steps such as condensation reaction, nitro reduction.The method that the present invention compares existing literature report, synthesis step is few, reaction condition is mild, easy to operate, and condensation step avoids the use of Heavy Metal Reagent and toxic organic solvents, Determination of Residual Organic Solvents is low, environmental-friendly, integrated artistic is more environmentally protective, and quality is easy to control, the advantages that technology stability is higher is suitble to industrialized production.
Description
Technical field
The present invention relates to technical field of medicine synthesis, and in particular to a kind of preparation side of antineoplaston medicine pomalidomide
Method.
Background technique
Pomalidomide Pomalyst, entitled 3- amino-N- (2, the 6- dioxo -3- piperidyl) phthalyl of chemistry are sub-
Amine, English entitled 3-Amino-N- (2,6-dioxo-3-piperidyl) phthalimide, No. CAS: 19171-19-8, property
Shape: light yellow solid, fusing point: 318.5 DEG C -320.5 DEG C, molecular formula: C13H11N3O4, molecular weight: 273.24, dissolubility: readily soluble
In DMSO.
Pomalidomide is the third generation immunomodulator (IMiD) after Thalidomide, lenalidomide, is treated other anti-
The multiple myeloma patients that are still in progress of the state of an illness after the treatment of cancer medicine show unique anti-infective, immunological regulation, antitumor
The effects of hyperplasia, anti-angiogenesis, and for refractory MM (RRMM) clinical test in show it is full of hope
Curative effect and relative to Thalidomide, the less toxic side effect of lenalidomide.It can enhance T cell and natural killer cells mediates
Immune response, while inhibit monocyte generate pro-inflammatory cytokine (such as TNF-α, IL-6).In addition, pomalidomide can
Inhibit tumor cell proliferation and induce cell apoptosis, also has stronger increasing to the drug resistant multiple myeloma cell line of lenalidomide
Grow inhibiting effect.2 months 2013 8 Nikkei U.S. food and Drug Administration's approval, pomalidomide in U.S.'s Initial Public Offering,
Trade name Pomalyst, it is small, significant in efficacy etc. with toxic side effect for treating recurrent and Refractory Multiple Myeloma
Advantage, market application prospect are wide.
Pomalidomide is the third generation immunomodulator developed by Celegene company, the U.S., is mainly used for treating multiple
Myeloma and myeloproliferative disorders.Therefore, economy, environmental-friendly is developed, the pomalidomide that can be mass produced
Synthesis route is of great practical significance.Therefore, on the basis of with reference to existing synthetic route, a work is studied
Skill mild condition is good, high production efficiency, low in input cost, operation is simple, is easy to industrial synthetic route just
It is very necessary, important data and technique preparation are added for the developing target market of pomalidomide at home, makes at home can its future
The large-scale production of competitiveness is enough provided, and is used widely.
Summary of the invention
In order to solve the deficiencies in the prior art, the present invention provides a kind of preparation sides of antineoplaston medicine pomalidomide
Method.
A kind of preparation method of antineoplaston medicine pomalidomide, which comprises the steps of: adjacent with 3- nitro
Phthalic acid 2 is raw material, by obtaining pomalidomide after the two-step reactions such as condensation reaction, nitro reduction.
Reaction equation is as follows:
Further, in the above-mentioned technical solutions, the condensation step is, by 3- nitrophthalic acid 2 and 3- amino
Piperidine-2,6-diones hydrochloride 3 is condensed to yield compound 4 under the conditions of glacial acetic acid and anhydrous sodium acetate.
Further, in the above-mentioned technical solutions, the 3- nitrophthalic acid 2 and 3- amino piperidine -2,6- diketone
3 equivalent proportion of hydrochloride is 1.5-2.5:1.It is preferably in a proportion of 2:1.
Further, the nitro reduction step is that compound 4 adds under DMF/ acetic acid in the mixed solvent, palladium carbon catalysis
Hydrogen reacts to obtain pomalidomide.Preferably, the nitro reduction step be will be dissolved in compound 4 DMF/ acetic acid mixing it is molten
In agent, under palladium carbon catalysis, 30-40 DEG C of reaction temperature, Hydrogen Vapor Pressure 2.5-3.5MPa, reaction obtains pomalidomide 1.Wherein,
Palladium carbon is selected from 5% or 10% palladium carbon, and additional amount is 0.02-0.08 times of 4 weight of compound.
Further, the product pomalidomide is recrystallized to give 99.5% or more sterling of purity by dimethyl sulfoxide.
Advantageous effect of the invention:
1, compared to the method for existing literature report, condensation step avoids making for Heavy Metal Reagent and toxic organic solvents
With Determination of Residual Organic Solvents is low, and environmental-friendly, integrated artistic is more environmentally protective.
2, pomalidomide is after dimethyl sulfoxide recrystallizes, the product of available 99.5% or more purity.
3, synthesis step of the present invention is few, and reaction condition is mild, easy to operate, and convenient post-treatment, technology stability is higher, matter
Amount is easy to control, and is more suitable for industrialized production.
Specific embodiment
Embodiment 1
3- nitrophthalic acid 2 (4.22g, 20.0mmol), 3- amino piperidine -2,6- diketone are added in three-necked bottle
Hydrochlorate 3 (1.64g, 10mmol) and 16mL glacial acetic acid, are heated to 105-115 DEG C, and the anhydrous sodium acetate of 5g, control reaction temperature is added
105-115 DEG C of degree reacts 3-4h.Reaction solution is cooled to 80-90 DEG C, is filtered, filter cake is beaten with water and is washed, and drains, filter cake is used
The dissolution of 18mL n,N-Dimethylformamide, is added 1.5g active carbon, stirs 0.5h, filters, and 350mL water, stirring are instilled in filtrate
2-3h is filtered, and the mashing of filter cake water washes twice, and is drained, by solid in 50-60 DEG C of forced air drying 20-24h, is obtained 2.70g chemical combination
Object 4, yield: 89%.
Take compound 4 (3.03g, 10.0mmol) to be dissolved in 120mL n,N-Dimethylformamide, be added 4mL acetic acid and
0.14g 10%Pd/C is transferred to hydriding reactor, is kept for 30-40 DEG C of reacting liquid temperature, Hydrogen Vapor Pressure 2.5-3.5MPa, reacts 10-
12h, HPLC detect reaction end.Reaction terminates, and diatomite filters off palladium carbon, and 1.2g active carbon is added in filtrate, stirs 0.5h, takes out
It filters, 46mL pure water is added in filtrate, stir 1-2h, filter, the mashing of filter cake water washes twice, 50-60 DEG C of forced air drying 10-
12h obtains 2.59g pomalidomide crude product, yield: 95%.
Pomalidomide method for recrystallizing and refining: pomalidomide crude product (2.73g, 10mmol) is taken to be dissolved in 45mL dimethyl sulfoxide
In, 20-25 DEG C of stirring and dissolving filters off insoluble matter, instills 165mL methanol, stirring and crystallizing 3-4h in filtrate.It filters, filter cake 70-
80 DEG C of pure water mashing are washed 2-3 times, drain, solid is obtained light yellow solid (compound in 50-60 DEG C of vacuum drying 10-12h
1) 2.56g, yield 94%, HPLC: purity 99.55%.Mp:319-322 DEG C.ESI-MS m/z:274.1[M+H]+,
296.1[M+Na]+。1H-NMR (400MHz, DMSO-d6):2.03-2.89(m,4H),5.05-5.09(m,1H),6.54(s,
2H), 7.02 (t, 2H, J=8.0Hz), 7.48 (t, 1H, J=7.6Hz), 11.10 (s, 1H).
Embodiment 2
3- nitrophthalic acid 2 (42.2g, 200.0mmol), 3- amino piperidine -2,6- diketone are added in three-necked bottle
Hydrochloride 3 (16.4g, 100mmol) and 80mL glacial acetic acid, are heated to 105-115 DEG C, and the anhydrous sodium acetate of 50g is added, and control is anti-
105-115 DEG C of temperature is answered, 3-4h is reacted.Reaction solution is cooled to 80-90 DEG C, is filtered, filter cake is beaten with water and is washed, and is drained, will be filtered
Cake 180mL n,N-Dimethylformamide dissolves, and 15g active carbon is added, and stirs 0.5h, filters, and 500mL water is instilled in filtrate,
2-3h is stirred, is filtered, the mashing of filter cake water washes twice, and drains, by solid in 50-60 DEG C of forced air drying 20-24h, obtains 27.1g
Compound 4, yield: 89%.
Take compound 4 (30.3g, 100.0mmol) to be dissolved in 800mLN, in dinethylformamide, be added 300mL acetic acid and
1.4g 10%Pd/C is transferred to hydriding reactor, is kept for 30-40 DEG C of reacting liquid temperature, Hydrogen Vapor Pressure 2.5-3.5MPa, reacts 10-12h,
HPLC detects reaction end.Reaction terminates, and diatomite filters off palladium carbon, and 12g active carbon is added in filtrate, stirs 0.5h, filters, filter
800mL pure water is added in liquid, stirs 1-2h, filters, the mashing of filter cake water washes twice, and 50-60 DEG C of forced air drying 10-12h is obtained
25.94g pomalidomide crude product, yield: 95%.
Pomalidomide method for recrystallizing and refining: pomalidomide crude product (27.3g, 100mmol) is taken to be dissolved in 900mL dimethyl sulfoxide
In, 20-25 DEG C of stirring and dissolving filters off insoluble matter, instills 300mL methanol, stirring and crystallizing 3-4h in filtrate.It filters, filter cake 70-
80 DEG C of pure water mashing are washed 2-3 times, are drained, and solid is obtained light yellow solid pool Ma Du in 50-60 DEG C of vacuum drying 10-12h
Amine 25.6g, yield 94%, HPLC: purity 99.62%.Mp:319-322 DEG C.ESI-MS m/z:274.1[M+H]+,
296.1[M+Na]+。1H-NMR(400MHz,DMSO-d6):2.03-2.89(m,4H),5.05-5.09(m,1H),6.54(s,
2H), 7.02 (t, 2H, J=8.0Hz), 7.48 (t, 1H, J=7.6Hz), 11.10 (s, 1H).
Embodiment 3
3- nitrophthalic acid 2 (4.22kg, 20.0mol), 3- amino piperidine -2,6- diketone are added in three-necked bottle
Hydrochlorate 3 (1.64kg, 10mol) and 16L glacial acetic acid are heated to 105-115 DEG C, and 500g anhydrous sodium acetate, control reaction temperature is added
105-115 DEG C of degree reacts 3-4h.Reaction solution is cooled to 80-90 DEG C, is filtered, filter cake is beaten with water and is washed, and drains, filter cake is used
The dissolution of 18L n,N-Dimethylformamide, is added 550g active carbon, stirs 0.5h, filters, and 35L water is instilled in filtrate, stirs 2-
3h is filtered, and the mashing of filter cake water washes twice, and is drained, by solid in 50-60 DEG C of forced air drying 20-24h, is obtained 2.73kg chemical combination
Object 4, yield: 90%.
It takes compound 4 (3.03kg, 10.0mol) to be dissolved in 12L n,N-Dimethylformamide, 4L acetic acid and 140g is added
10%Pd/C is transferred to hydriding reactor, is kept for 30-40 DEG C of reacting liquid temperature, Hydrogen Vapor Pressure 2.5-3.5MPa, reacts 10-12h, HPLC
Detect reaction end.Reaction terminates, and diatomite filters off palladium carbon, and 1.2kg active carbon is added in filtrate, stirs 0.5h, filters, filtrate
Middle addition 46L pure water stirs 1-2h, filters, and the mashing of filter cake water washes twice, and 50-60 DEG C of forced air drying 10-12h is obtained
2.62kg pomalidomide crude product, yield: 96%.
Pomalidomide method for recrystallizing and refining: taking pomalidomide crude product (2.73kg, 10mol) to be dissolved in 45L dimethyl sulfoxide,
20-25 DEG C of stirring and dissolving filters off insoluble matter, instills 1.65L methanol, stirring and crystallizing 3-4h in filtrate.It filters, filter cake 70-80
It the mashing of DEG C pure water washing 2-3 times, drains, solid is obtained into light yellow solid pomalidomide in 50-60 DEG C of vacuum drying 10-12h
2.57kg, yield 94%HPLC: purity 99.78%.Mp:319-322 DEG C.ESI-MS m/z:274.1[M+H]+, 296.1
[M+Na]+。1H-NMR(400MHz,DMSO-d6): 2.03-2.89 (m, 4H), 5.05-5.09 (m, 1H), 6.54 (s, 2H), 7.02
(t, 2H, J=8.0Hz), 7.48 (t, 1H, J=7.6Hz), 11.10 (s, 1H).
Embodiment above describes basic principles and main features of the invention and advantages.The technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (6)
1. a kind of preparation method of antineoplaston medicine pomalidomide, which is characterized in that reaction equation is as follows:
Include the following steps: with 3- nitrophthalic acid 2 to be moored after condensation reaction, nitro-reduction reaction for raw material
Horse degree amine 1.
2. a kind of preparation method of antineoplaston medicine pomalidomide according to claim 1, it is characterised in that: the condensation is anti-
It should operate are as follows: by 3- nitrophthalic acid 2 and 3- amino piperidine -2,6- dione hydrochloride 3 in glacial acetic acid and anhydrous sodium acetate
Under the conditions of be condensed to yield compound 4.
3. a kind of preparation method of antineoplaston medicine pomalidomide according to claim 1, it is characterised in that: the nitro is also
Origin operation is to restore compound 4 under palladium carbon and hydrogen atmosphere and obtain pomalidomide 1.
4. a kind of preparation method of antineoplaston medicine pomalidomide according to claim 1 or in 2, it is characterised in that: the contracting
Closing step step is, in glacial acetic acid solvent, by 2eq 3- nitrophthalic acid 2,1eq 3- amino piperidine -2,6- diketone
Hydrochlorate 3 and anhydrous sodium acetate are heated to 105 DEG C of -115 DEG C of reactions, compound 4 are obtained after processing.
5. a kind of preparation method of antineoplaston medicine pomalidomide according to claim 1 or in 3, it is characterised in that: the nitre
Base reduction step is that DMF/ acetic acid in the mixed solvent will be dissolved in compound 4, under palladium carbon catalysis, 30-40 DEG C of reaction temperature,
Hydrogen Vapor Pressure 2.5-3.5MPa, reaction obtain pomalidomide 1.
6. a kind of preparation method of antineoplaston medicine pomalidomide according to claim 1, it is characterised in that: the pool Ma Du
Amine is recrystallized to give 99.5% or more sterling of purity by dimethyl sulfoxide.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114605381A (en) * | 2020-12-03 | 2022-06-10 | 南京海辰药业股份有限公司 | Preparation method of pomalidomide |
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| CN104387366A (en) * | 2014-10-30 | 2015-03-04 | 南京恒通医药开发有限公司 | Preparation method of pomalidomide |
| CN104926786A (en) * | 2014-03-21 | 2015-09-23 | 合肥久诺医药科技有限公司 | Method for preparing 3-nitro-N-(2,6-dioxo-3-piperidinyl) phthalimide |
| CN105348257A (en) * | 2014-08-20 | 2016-02-24 | 河北菲尼斯生物技术有限公司 | Pomalidomide preparation method |
| CN107325075A (en) * | 2016-04-29 | 2017-11-07 | 正大天晴药业集团股份有限公司 | A kind of preparation method of pomalidomide |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103819454A (en) * | 2014-03-13 | 2014-05-28 | 南京华威医药科技开发有限公司 | Preparation method of N-(2, 6-dioxo-3-piperidyl) phthalimide compound |
| CN104926786A (en) * | 2014-03-21 | 2015-09-23 | 合肥久诺医药科技有限公司 | Method for preparing 3-nitro-N-(2,6-dioxo-3-piperidinyl) phthalimide |
| CN105348257A (en) * | 2014-08-20 | 2016-02-24 | 河北菲尼斯生物技术有限公司 | Pomalidomide preparation method |
| CN104387366A (en) * | 2014-10-30 | 2015-03-04 | 南京恒通医药开发有限公司 | Preparation method of pomalidomide |
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| CN114605381A (en) * | 2020-12-03 | 2022-06-10 | 南京海辰药业股份有限公司 | Preparation method of pomalidomide |
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