CN110407807A - A kind of preparation method of lenalidomide - Google Patents
A kind of preparation method of lenalidomide Download PDFInfo
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- CN110407807A CN110407807A CN201910530172.2A CN201910530172A CN110407807A CN 110407807 A CN110407807 A CN 110407807A CN 201910530172 A CN201910530172 A CN 201910530172A CN 110407807 A CN110407807 A CN 110407807A
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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 present invention provides a kind of preparation methods of lenalidomide.The preparation method of the lenalidomide includes the step of preparing -3 nitrobenzene methyl of intermediate 2- halogen methyl and intermediate 3- amino piperidine -2,6- diketone, and the step of preparing lenalidomide using the two intermediates.The preparation method step of the lenalidomide is simple, and yield is higher, and cost is relatively low, is conducive to industrialized production.
Description
Technical field
The invention belongs to anti-tumor drug synthesis technical fields, and in particular to a kind of preparation method of lenalidomide.
Background technique
Lenalidomide is the research and development of Gelgene company, the U.S. for treating the novel immune of lethal hematologic disease and cancer
Adjust oral preparation.Lenalidomide is the derivative of new generation of Thalidomide, and clinical data shows that its drug effect is Thalidomide
100 times, and do not find its toxicity with aberration inducing, therefore, lenalidomide is to treat Huppert's disease curative effect most at present
For significant drug, the patient more than 50% can be obviously prolonged its time-to-live after taking the drug.
A kind of preparation method of lenalidomide is disclosed in international monopoly WO2005005409.The preparation method is with 2- bromine first
Base -3- nitro-benzoic acid methyl ester and L-Glutamine methyl esters obtain intermediate 2- ((1- amino -5- methoxy through condensation reaction
Base -1,5- dioxo pentane -2- base amino) methyl) -3- methyl toluate, then successively pass through cyclization, racemization, nitro also
It is former and etc. to prepare target product lenalidomide, it is detailed in following reaction process.
But preparation method the shortcomings that there are yields is lower, purification difficult, it is unfavorable for large-scale industrial production.
Summary of the invention
The present invention provides a kind of preparation method of lenalidomide, to solve the above problem.
To solve the above problems, The technical solution adopted by the invention is as follows:
A kind of preparation method of lenalidomide, includes the following steps:
(1) 2- methyl-3-nitro methyl benzoate shown in formula (1) is reacted with halogenating agent, is made shown in formula (2)
- 3 nitrobenzene methyl of 2- halogen methyl, the halogenating agent be sodium hypochlorite or sodium hypobromite,
Wherein, X is Cl or Br；
(2) by D shown in formula (3), L-Glutamine is reacted with thionyl chloride and methanol, and paddy ammonia shown in formula (4) is made
Amide methyl ester,
(3) glutamine methyl esters shown in the formula (4) is reacted with dimethyl dicarbonate butyl ester, N- shown in formula (5) is made
Boc- glutamic acid methyl ester,
(4) N-Boc- glutamic acid methyl ester shown in the formula (5) is subjected to molecule in the presence of condensing agent and catalyst
Boc-protected 3- amino piperidine -2,6- diketone shown in formula (6) is made in interior cyclization,
(5) boc-protected 3- amino piperidine -2,6- diketone shown in the formula (6) is reacted with hydrochloric acid, is made formula (7)
Shown in 3- amino piperidine -2,6- diketone,
(6) by -3 nitre of 2- halogen methyl shown in 3- amino piperidine -2,6- diketone shown in the formula (7) and the formula (2)
Yl benzoic acid methyl esters reacts under the conditions of weak base, and 3- (7- nitro -3- oxo -1H- iso-indoles -2- base) shown in formula (8) is made
Piperidines -2,6- diketone,
(7) by (7- nitro -3- oxo -1H- iso-indoles -2- base) piperidine-2,6-diones of 3- shown in the formula (8) and also
Former agent reaction, is made lenalidomide 3- (7- amino -3- oxo -1H- iso-indoles -2- base) piperidines -2,6- bis- shown in formula (9)
Ketone,
The preparation method of lenalidomide according to the present invention, in the step (4), the condensing agent is N, and N- bis- is different
Propyl carbodiimide, the catalyst are n-hydroxysuccinimide.
The preparation method of lenalidomide according to the present invention, in the step (6), the weak base is concentrated ammonia liquor.
The preparation method of lenalidomide according to the present invention, in the step (7), the reducing agent is vulcanized sodium.
The mode of reduction nitro commonly used in the prior art is catalytic hydrogenation method, but traditional hydrogenator is mixed because using with air
It forms the hydrogen of explosive mixture and reacts at high temperature under high pressure, heavy explosion easily occurs in production and causes considerable safety
Accident.And preparation method provided by the present invention then avoids the security risk of hydrogenation reaction, is more advantageous to industrialized production, together
When the nitro reduction step yield it is also higher.
In conclusion by adopting the above-described technical solution, the beneficial effects of the present invention are:
Used starting material 2- methyl-3-nitro methyl benzoate and D, L-Glutamine is cheap and easy to get, drops significantly
Low production cost；
Entire preparation flow step is shorter, and safety easy to operate, is suitble to industrial production；
Obtained target product lenalidomide yield is higher.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.
Embodiment 1
(1) preparation of -3 nitrobenzene methyl of 2- chloromethyl
2- methyl-3-nitro methyl benzoate 0.02mol is dissolved in chloroform, halogenating agent sodium hypochlorite 0.04mol is added, adds
Heat reflux is for 24 hours.After cooling, add distilled water, liquid separation, water phase is extracted twice with chloroform, is merged chloroform, is washed with sodium bicarbonate solution
It washs, then is washed with saturated sodium-chloride, anhydrous sodium sulfate is dry.After being spin-dried for, -3 nitre of 2- chloromethyl is crystallized 2 times to obtain in petroleum ether
Yl benzoic acid methyl esters, yield 71%.
The preparation of glutamine methyl esters
By 1mol D, L-Glutamine is dissolved in 2L anhydrous methanol, is kept for 0 DEG C or less thionyl chloride 2mol is added dropwise, dripped
8h is heated to reflux after finishing.It is evaporated methanol, 200g faint yellow solid is obtained and obtains 191g paddy ammonia after the washing of methylate tertbutyl ether
Amide methyl ester hydrochloride salt as white solid.
The preparation of N-Boc- glutamic acid methyl ester
The glutamine methyl ester hydrochloride that step (2) obtains is dissolved in 2L distilled water, 200g saleratus, 1L is added
Methanol and 250g dimethyl dicarbonate butyl ester, react 15h at room temperature.It is extracted 3 times with methyl tertiary butyl ether(MTBE) again, merges organic phase, successively
It is washed with diluted acid, saturated sodium bicarbonate, saturated sodium-chloride, it is dry to reuse anhydrous sodium sulfate.It is spin-dried for, obtains N-Boc- paddy ammonia
Sour methyl esters, yield 95%.
(4) preparation of boc-protected 3- amino piperidine -2,6- diketone
N-Boc- glutamic acid methyl ester obtained in 0.1mol step (3) is weighed, 300mL anhydrous tetrahydro furan is dissolved in, is added
Condensing agent N, N- diisopropylcarbodiimide, catalyst n-HOSu NHS are heated to reflux 48h.It is spin-dried for tetrahydrofuran, is added
200mL distilled water is extracted in two times with 300mL methyl tertiary butyl ether(MTBE), then successively using diluted acid, saturated sodium bicarbonate, saturation chlorine
Change sodium washing, anhydrous sodium sulfate is dry.It is spin-dried for, obtains 20g white solid, the recrystallization 2 in ethyl acetate/petroleum ether (30/70)
It is secondary, obtain white solid 15.1g, yield 66.2%.
(5) preparation of 3- amino piperidine -2,6- diketone
3- amino piperidine -2,6- diketone prepared by step (4) is dissolved in 200mL methyl tertiary butyl ether(MTBE), is cooled and maintained at 0
DEG C, it is passed through hydrogen chloride gas, reacts 20min, white solid is precipitated, is filtered, drying obtains 9.5g white solid, yield is
90%.
(6) preparation of 3- (7- nitro -3- oxo -1H- iso-indoles -2- base) piperidine-2,6-diones
By the 3- of the 2- chloromethyl -3- nitrobenzene methyl of 0.1mol step (1) preparation and 16.5g step (5) preparation
Amino piperidine -2,6- diketone is dissolved in 200mLDMF, and concentrated ammonia liquor 5mL is added, is heated to reflux 2h.It is cooled to room temperature, imports ice water
In, faint yellow solid is precipitated, filtering, distilled water washes twice, then dries, and obtains 21.7g reaction product, yield 75%.
(7) preparation of lenalidomide 3- (7- amino -3- oxo -1H- iso-indoles -2- base) piperidine-2,6-diones
3- (7- nitro -3- oxo -1H- iso-indoles -2- base) piperidines -2,6- diketone of 14.5g step (6) preparation is weighed,
It is dissolved in 200mL dehydrated alcohol, 7.8g reducing agent vulcanized sodium is added, 1h is reacted at room temperature, is spin-dried for ethyl alcohol, obtains 12.8g white solid,
Yield is 98%.
Claims (4)
1. a kind of preparation method of lenalidomide, which comprises the steps of:
(1) 2- methyl-3-nitro methyl benzoate shown in formula (1) is reacted with halogenating agent, 2- halogen first shown in formula (2) is made
- 3 nitrobenzene methyl of base, the halogenating agent be sodium hypochlorite or sodium hypobromite,
Wherein, X is Cl or Br；
(2) by D shown in formula (3), L-Glutamine is reacted with thionyl chloride and methanol, and glutamine shown in formula (4) is made
Methyl esters,
(3) glutamine methyl esters shown in the formula (4) is reacted with dimethyl dicarbonate butyl ester, N-Boc- shown in formula (5) is made
Glutamic acid methyl ester,
(4) N-Boc- glutamic acid methyl ester shown in the formula (5) is subjected to intramolecular pass in the presence of condensing agent and catalyst
Boc-protected 3- amino piperidine -2,6- diketone shown in formula (6) is made in ring,
(5) boc-protected 3- amino piperidine -2,6- diketone shown in the formula (6) is reacted with hydrochloric acid, is made shown in formula (7)
3- amino piperidine -2,6- diketone,
(6) by -3 nitrobenzene of 2- halogen methyl shown in 3- amino piperidine -2,6- diketone shown in the formula (7) and the formula (2)
Methyl formate reacts under the conditions of weak base, and 3- (7- nitro -3- oxo -1H- iso-indoles -2- base) piperidines-shown in formula (8) is made
2,6- diketone,
(7) by (7- nitro -3- oxo -1H- iso-indoles -2- base) piperidine-2,6-diones of 3- shown in the formula (8) and reducing agent
Lenalidomide 3- (7- amino -3- oxo -1H- iso-indoles -2- base) piperidines -2,6- diketone shown in formula (9) is made in reaction,
2. the preparation method of lenalidomide according to claim 1, it is characterised in that: in the step (4), the condensation
Agent is N, and N- diisopropylcarbodiimide, the catalyst is n-hydroxysuccinimide.
3. the preparation method of lenalidomide according to claim 1 or 2, it is characterised in that: described in the step (6)
Weak base is concentrated ammonia liquor.
4. the preparation method of lenalidomide according to claim 1 or 2, it is characterised in that: described in the step (7)
Reducing agent is vulcanized sodium.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101665484A (en) * | 2009-07-20 | 2010-03-10 | 上海皓元生物医药科技有限公司 | Method for preparing lenalidomide |
| CN104311536A (en) * | 2014-10-24 | 2015-01-28 | 上海应用技术学院 | Method for preparing lenalidomide |
| CN105440012A (en) * | 2014-08-07 | 2016-03-30 | 天津法莫西医药科技有限公司 | Lenalidomide and lenalidomide intermediate preparation method |
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- 2019-06-19 CN CN201910530172.2A patent/CN110407807A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101665484A (en) * | 2009-07-20 | 2010-03-10 | 上海皓元生物医药科技有限公司 | Method for preparing lenalidomide |
| CN105440012A (en) * | 2014-08-07 | 2016-03-30 | 天津法莫西医药科技有限公司 | Lenalidomide and lenalidomide intermediate preparation method |
| CN104311536A (en) * | 2014-10-24 | 2015-01-28 | 上海应用技术学院 | Method for preparing lenalidomide |
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Application publication date: 20191105 |