CN105906605A - Preparation method of N-(5-(N-t-butyloxycarbonyl-N-methylamino)-2-thenoyl)-L-diethyl glutamate - Google Patents
Preparation method of N-(5-(N-t-butyloxycarbonyl-N-methylamino)-2-thenoyl)-L-diethyl glutamate Download PDFInfo
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- CN105906605A CN105906605A CN201610279653.7A CN201610279653A CN105906605A CN 105906605 A CN105906605 A CN 105906605A CN 201610279653 A CN201610279653 A CN 201610279653A CN 105906605 A CN105906605 A CN 105906605A
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- thenoyl
- tertbutyloxycarbonyl
- methylamino
- preparation
- diethyl phthalate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention provides a preparation method of N-(5-(N-t-butyloxycarbonyl-N-methylamino)-2-thenoyl)-L-diethyl glutamate. The preparation method is characterized by including dissolving N-(5-(N-t-butyloxycarbonyl amino)-2-thenoyl)-L-diethyl glutamate in organic solvent, adding alkali, then adding methylation reagent for methylation, filtering, concentrating filtrate to obtain a crude product, and purifying a pure product to obtain the N-(5-(N-t-butyloxycarbonyl-N-methylamino)-2-thenoyl)-L-diethyl glutamate. The preparation method is mild in reaction condition, easy to operate, high in yield, high in purity of reaction products and suitable for industrial production.
Description
Technical field
The present invention relates to a kind of Raltitrexed intermediate N [5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-thiophene first
Acyl group] preparation method of-Pidolidone diethylester, belong to pharmaceutical technology field.
Background technology
Colorectal cancer (CRC) is the second common tumour being only second to lung cancer in the world.Over nearly 30 years, colorectal cancer is also
One of two kinds of the fastest malignant tumours of China's growth rate are had become as.Raltitrexed (Raltitrexed) is thymus gland synzyme
(Thymidylatesynthase, TS) inhibitor, is a kind of stronger colorectal cancer tumor cell line activity inhibitor, at English
The Guo Deng Western European countries have become the first-line drug for the treatment of Advanced Colon Cancer, and this medicine is also to other cancers such as head and neck neoplasm, front
Row gland cancer, lung cancer, soft tissue sarcoma and leukaemia etc. have certain curative effect.Raltitrexed has the biggest market to need in China
The amount of asking, the raising of its synthetic technology will bring the biggest economic and social benefit.
Raltitrexed is developed by AstraZeneca drugmaker of Britain, takes the lead in 1996 listing in Britain, trade name
Being Tomudex, chemical structural formula is as follows.
The generally route of synthesis Raltitrexed is as follows:
Intermediate N [5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-Pidolidone diethylester is
One of two weight raw materials of synthesis Raltitrexed.According to investigation and analysis comprehensive to existing documents and materials and domestic and international patent etc.,
The synthetic route of this intermediate has following three kinds.
Route 1: with 2-thiophenic acid as raw material route (J.MedChem, 1991,34 (5), 1594-1605)
With triethylamine as alkali, 2-thiophenic acid generates the 2-of Boc protection with diphenyl phosphate azide and the tert-butyl alcohol after reacting
Aminothiophene；Again with sodium hydride as alkali, there is N-methylation reaction with iodomethane, prepare 2-[N-(tertbutyloxycarbonyl)-N-methyl
Amino] thiophene；Under conditions of-78 DEG C and argon shield, 2-[N-(tertbutyloxycarbonyl)-N-methylamino] thiophene is made at LDA
Under with, with dry ice (CO2) reaction, prepare 2-(N-methyl tertbutyl formamido group) thiophene-5-carboxylic acid；It is again through oxalyl chloride effect
It is condensed with Pidolidone diethylester, prepares N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-L-paddy
Propylhomoserin diethylester.
The shortcoming of this route has: need to use the reagent such as sodium hydride, n-BuLi, and reagent price is high, operating condition is strict
(needing to react under low temperature-78 DEG C and argon shield), and there is potential safety hazard, it is difficult to realize industrialized production.
With 2-thiophenic acid as raw material route
Route 2: with 2 thiophene carboxaldehyde as raw material route (China's pharmaceutical chemistry magazine, 2007,17 (6), 368-371)
2 thiophene carboxaldehyde prepares 5-nitro-2 thiophene carboxaldehyde through nitrification；5-nitro-2-thiophene is obtained again by potassium permanganate oxidation
Formic acid；It prepares 5-amino-2-thiophenecarboxylate through over-churning, nitro reduction again；Then methylate instead with iodomethane
Should；5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-thiophenic acid is prepared again through hydrolysis；Last under the effect of DCC with
After the condensation of Pidolidone diethylester, prepare N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-L-paddy
Propylhomoserin diethylester.
The shortcoming of this route is to need, through red fuming nitric acid (RFNA) nitrification and potassium permanganate oxidation, have one on workshop is amplified and produced
Fixed security risk.
With 2 thiophene carboxaldehyde as raw material route
Route 3: with 2,5-thiophenedicarboxylic acid is raw material (CN1486985A, 2004)
With 2,5-thiophenedicarboxylic acid and Pidolidone diethylester are initiation material, with DCC as condensation reagent, prepare corresponding single
Condensation product；Again with diphenyl phosphate azide, the tert-butyl alcohol and triethylamine as reaction condition, rearrangement reaction is occurred to prepare N-[5-[N-
(tertbutyloxycarbonyl) amino]-2-Thenoyl]-Pidolidone diethylester；Last with NaOH, potassium carbonate and the tetrabutyl
Ammonium bromide is condition, prepares N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-thiophene with iodomethane generation methylation reaction
Fen formoxyl]-Pidolidone diethylester.
The shortcoming of this route be with iodomethane methylate this step reaction condition wayward, especially when iodine,
Reaction system mutability is miscellaneous, so causing purification difficult.
With 2,5-thiophenedicarboxylic acid is raw material route
Summary of the invention
It is an object of the invention to provide the Raltitrexed intermediate N [5-[N-of a kind of simple to operate, applicable industrialized production
(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl] preparation method of-Pidolidone diethylester, to make up existing skill
The deficiency of art.
In order to achieve the above object, the invention provides a kind of N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-
Thenoyl] preparation method of-Pidolidone diethylester, it is characterised in that including: by N-[5-[N-(tertbutyloxycarbonyl) ammonia
Base]-2-Thenoyl]-Pidolidone diethylester dissolve in organic solvent, add alkali, stirring, add methylating reagent
Carry out methylation reaction, filter, filtrate is concentrated to give crude product, sterling is purified and obtains N-[5-[N-(tertbutyloxycarbonyl)-N-
Methylamino]-2-Thenoyl]-Pidolidone diethylester.
Preferably, described organic solvent is acetonitrile or ethyl acetate.
Preferably, described alkali is cesium carbonate, potassium carbonate or sodium carbonate.
Preferably, described N-[5-[N-(tertbutyloxycarbonyl) amino]-2-Thenoyl]-Pidolidone diethylester and
The mol ratio of alkali is 1: 1.0～4.5.
Preferably, described N-[5-[N-(tertbutyloxycarbonyl) amino]-2-Thenoyl]-Pidolidone diethylester and
The mol ratio of iodomethane is 1: 1.5～3.5.
Preferably, the reaction temperature of described methylation reaction is room temperature.
Preferably, the reaction time of described methylation reaction is 30 minutes.
Preferably, described method of purification includes: by dissolving crude product in ethyl acetate, does through washing, separatory, organic layer
Dry and concentrate.
Preferably, described methylating reagent is halomethane.
It is highly preferred that described methylating reagent is iodomethane.
Preferably, before adding methylating reagent, now it is dissolved in organic solvent.
Compared with prior art, the invention has the beneficial effects as follows:
Reaction condition of the present invention is gentle, easy and simple to handle, yield is high, and product purity is high, is suitable for industrialized production.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate the present invention
Rather than restriction the scope of the present invention.In addition, it is to be understood that after having read the content that the present invention lectures, people in the art
The present invention can be made various changes or modifications by member, and these equivalent form of values fall within the application appended claims equally and limited
Scope.N-[5-[N-(tertbutyloxycarbonyl) amino]-2-Thenoyl] the Pidolidone diethyl used in following example
EsterPrepare by Chinese patent (CN1486985A) method。
Embodiment 1:
A kind of system of N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl] Pidolidone diethylester
Preparation Method, concretely comprises the following steps: by N-[5-[N-(tertbutyloxycarbonyl) amino]-2-Thenoyl]-Pidolidone diethylester
(210g, 0.5mol) is dissolved in acetonitrile (2000mL), adds cesium carbonate (240g, 0.74mol), stirs 10 minutes, then will be dissolved in
The iodomethane (178.6g, 1.26mol) of acetonitrile (100mL) is added dropwise to reactant liquor, adds room temperature and carries out methylation reaction 30 minutes.
Being filtered to remove inorganic salts, and wash filter cake with a small amount of ethyl acetate, filtrate reduced in volume obtains crude product, and crude product uses ethyl acetate again
(500mL) dissolving, washed once with water (300mL), separatory, organic phase anhydrous magnesium sulfate is dried, and filtering and concentrating is done, and obtains product
190g, purity is more than 95%, yield 88%. 1 HNMR(CDCl 3 ): δ 1.24 (t, 3H), 1.29 (t, 3H), 1.57 (s, 9H), 2.18
(m,2H), 2.47 (t, 2H), 3.18 (s, 1H), 3.38 (s, 3H), 4.11 (q.2H), 4.22 (q, 2H), 4.93 (m, 1H), 6.45 (d, J=4.2Hz, 1H), 7.42 (d, J=4.2Hz, 1H).
Embodiment 2:
A kind of system of N-[5-[water (tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-Pidolidone diethylester
Preparation Method, concretely comprises the following steps: by N-[5-[N-(tertbutyloxycarbonyl) amino]-2-Thenoyl]-Pidolidone diethylester
(210g, 0.5mol) is dissolved in acetonitrile (2000mL), adds potassium carbonate (207g, 1.5mol), is stirred vigorously 10 minutes, then by molten
Iodomethane (178.6g, 1.26mol) in acetonitrile (100mL) is added dropwise to reactant liquor, adds room temperature and carries out methylation reaction 30 points
Clock.Being filtered to remove inorganic salts, and wash filter cake with a small amount of ethyl acetate, filtrate reduced in volume obtains crude product, and crude product uses acetic acid second again
Ester (500mL) dissolves, and washs with water (300mL), separatory, and organic phase anhydrous magnesium sulfate is dried, and filtering and concentrating is done, through column chromatography
Obtaining product 64.8g, purity is more than 95%, yield 30%. b HNMR(CDCl 3 ): δ 1.24 (t, 3H), 1.29 (t, 3H), 1.57 (s, 9H), 2.18 (m, 2H), 2.47 (t, 2H), 3.18 (s, 1H), 3.38 (s, 3H), 4.11 (q, 2H), 4.22 (q, 2H), 4.93 (m, 1H), 6.45 (d, J=4.2Hz, 1H), 7.42 (d, J=4.2Hz, 1H).
Embodiment 3:
A kind of system of N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl] Pidolidone diethylester
Preparation Method, concretely comprises the following steps: by N-[5-[N-(tertbutyloxycarbonyl) amino]-2-Thenoyl] Pidolidone diethylester
(210g, 0.5mol) is dissolved in acetonitrile (2000mL), adds sodium carbonate (159g, 1.5mol), is stirred vigorously 10 minutes, then by molten
Iodomethane (178.6g, 1.26mol) in acetonitrile (100mL) is added dropwise to reactant liquor, adds room temperature and carries out methylation reaction 30 points
Clock.Being filtered to remove inorganic salts, and wash filter cake with a small amount of ethyl acetate, filtrate reduced in volume obtains crude product, and crude product uses acetic acid second again
Ester (500mL) dissolves, and washs with water (300mL), separatory, and organic phase anhydrous magnesium sulfate is dried, and filtering and concentrating is done, through column chromatography
Obtaining product 43g, purity is more than 95%, yield 20%. 1 HNMR(CDCl 3 ): δ 1.24 (t, 3H), 1.29 (t, 3H), 1.57 (s, 9H), 2.18 (m, 2H), 2.47 (t, 2H), 3.18 (s, 1H), 3.38 (s, 3H), 4.11 (q, 2H), 4.22 (q, 2H), 4.93 (m, 1H), 6.45 (d, J=4.2Hz, 1H), 7.42 (d, J=4.2Hz, 1H).
Embodiment 4:
A kind of system of N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-Pidolidone diethylester
Preparation Method, concretely comprises the following steps: by N-[5-[N-(tertbutyloxycarbonyl) amino]-2-Thenoyl]-Pidolidone diethylester
(210g, 0.5mol) is dissolved in ethyl acetate (2000mL), adds cesium carbonate (240g, 0.74mol), is stirred vigorously 10 minutes,
The iodomethane (178.6g, 1.26mol) that will be dissolved in ethyl acetate (100mL) again is added dropwise to reactant liquor, adds room temperature and carries out methyl
Change reaction 30 minutes.Being filtered to remove inorganic salts, and wash filter cake with a small amount of ethyl acetate, filtrate reduced in volume obtains crude product, crude product
Dissolving with ethyl acetate (500mL), wash with water (300mL), separatory, organic phase anhydrous magnesium sulfate is dried, filtering and concentrating
Dry, obtain product 54g through column chromatography, purity is more than 95%, yield 25%. 1 HNMR(CDCl 3 ): δ 1.24 (t, 3H), 1.29 (t, 3H), 1.57 (s, 9H), 2.18 (m, 2H), 2.47 (t, 2H), 3.18 (s, 1H), 3.38 (s, 3H), 4.11 (q, 2H), 4.22 (q, 2H), 4.93 (m, 1H), 6.45 (d, J=4.2Hz, 1H), 7.42 (d, J=4.2Hz.1H).
Claims (10)
1. the preparation of N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-Pidolidone diethylester
Method, it is characterised in that including: by N-[5-[N-(tertbutyloxycarbonyl) amino]-2-Thenoyl]-Pidolidone diethylester
Dissolve in organic solvent, add alkali, stirring, add methylating reagent and carry out methylation reaction, filter, filtrate decompression is dense
Contracting obtains crude product, sterling is purified and obtains N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-L-paddy
Propylhomoserin diethylester.
2. N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-L-paddy ammonia as claimed in claim 1
The preparation method of diethyl phthalate, it is characterised in that described organic solvent is acetonitrile or ethyl acetate.
3. N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-L-paddy ammonia as claimed in claim 1
The preparation method of diethyl phthalate, it is characterised in that described alkali is cesium carbonate, potassium carbonate or sodium carbonate.
4. N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-L-paddy ammonia as claimed in claim 1
The preparation method of diethyl phthalate, it is characterised in that described N-[5-[N-(tertbutyloxycarbonyl) amino]-2-Thenoyl]-
The mol ratio of Pidolidone diethylester and alkali is 1:1.0~4.5。
5. N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-L-paddy ammonia as claimed in claim 1
The preparation method of diethyl phthalate, it is characterised in that described N-[5-[N-(tertbutyloxycarbonyl) amino]-2-Thenoyl]-
The mol ratio of Pidolidone diethylester and iodomethane is 1:1.5~3.5。
6. N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-L-paddy ammonia as claimed in claim 1
The preparation method of diethyl phthalate, it is characterised in that the reaction temperature of described methylation reaction is room temperature.
7. N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-L-paddy ammonia as claimed in claim 1
The preparation method of diethyl phthalate, it is characterised in that the reaction time of described methylation reaction is 30 minutes.
8. N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-L-paddy ammonia as claimed in claim 1
The preparation method of diethyl phthalate, it is characterised in that described method of purification includes: by dissolving crude product in ethyl acetate, through water
Wash, separatory, organic layer are dried and concentrate.
9. N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-L-paddy ammonia as claimed in claim 1
The preparation method of diethyl phthalate, it is characterised in that described methylating reagent is halomethane.
10. N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-Thenoyl]-L-paddy ammonia as claimed in claim 1
The preparation method of diethyl phthalate, it is characterised in that before adding methylating reagent, be now dissolved in organic solvent.
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| CN201610279653.7A CN105906605A (en) | 2016-04-29 | 2016-04-29 | Preparation method of N-(5-(N-t-butyloxycarbonyl-N-methylamino)-2-thenoyl)-L-diethyl glutamate |
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| CN201610279653.7A CN105906605A (en) | 2016-04-29 | 2016-04-29 | Preparation method of N-(5-(N-t-butyloxycarbonyl-N-methylamino)-2-thenoyl)-L-diethyl glutamate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1486985A (en) * | 2002-09-30 | 2004-04-07 | 首都师范大学 | Synthesis of anticancer medicine Raltiprexed |
| CN102127063A (en) * | 2011-01-06 | 2011-07-20 | 深圳市普迈达科技有限公司 | New synthesis technology of anti-cancer drug Raltitrexed |
-
2016
- 2016-04-29 CN CN201610279653.7A patent/CN105906605A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1486985A (en) * | 2002-09-30 | 2004-04-07 | 首都师范大学 | Synthesis of anticancer medicine Raltiprexed |
| CN102127063A (en) * | 2011-01-06 | 2011-07-20 | 深圳市普迈达科技有限公司 | New synthesis technology of anti-cancer drug Raltitrexed |
Non-Patent Citations (3)
| Title |
|---|
| SHENG-LI CAO等: "New Synthesis of Thymidylate Synthase Inhibitor Raltitrexed", 《SYNTHETIC COMMUNICATIONS》 * |
| 曹胜利 等: "N-Boc-氨基噻吩的相转移催化N-烷基化", 《应用化学》 * |
| 郝明春 等: "抗癌药雷替曲塞的合成", 《中国药物化学杂志》 * |
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Application publication date: 20160831 |