CN102633802A - Intermediate for synthesizing 2-chloro-7H-pyrrolo (2, 3-d) pyrimidine and preparation method thereof - Google Patents
Intermediate for synthesizing 2-chloro-7H-pyrrolo (2, 3-d) pyrimidine and preparation method thereof Download PDFInfo
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- CN102633802A CN102633802A CN2012101048352A CN201210104835A CN102633802A CN 102633802 A CN102633802 A CN 102633802A CN 2012101048352 A CN2012101048352 A CN 2012101048352A CN 201210104835 A CN201210104835 A CN 201210104835A CN 102633802 A CN102633802 A CN 102633802A
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- VLWHADKTLVXEID-UHFFFAOYSA-N CC(C)(C)OC([n]1c2nc(Cl)nc(Cl)c2cc1)=O Chemical compound CC(C)(C)OC([n]1c2nc(Cl)nc(Cl)c2cc1)=O VLWHADKTLVXEID-UHFFFAOYSA-N 0.000 description 1
- GHXBPCSSQOKKGB-UHFFFAOYSA-N Clc1c(cc[nH]2)c2nc(Cl)n1 Chemical compound Clc1c(cc[nH]2)c2nc(Cl)n1 GHXBPCSSQOKKGB-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to the field of synthesis of medicament intermediates and specifically relates to an intermediate for synthesizing 2-chloro-7H-pyrrolo (2, 3-d) pyrimidine and a preparation method thereof. The preparation method is characterized by taking 2, 4-dichloro-7H-pyrrolo (2, 3-d) pyrimidine as raw material, and reacting with di-tert-butyl dicarbonate; selectively dechlorinating under the condition of hydrogenation under atmospheric pressure to get the intermediate (VIII); and removing a protecting group of the intermediate (VIII) to get the 2-chloro-7H-pyrrolo (2, 3-d) pyrimidine. The 2-chloro-7H-pyrrolo (2, 3-d) pyrimidine is the important pharmaceutical intermediate. The preparation method disclosed by the invention has the advantages that the reaction conditions are mild, the yield in each step is higher, and the total yield can achieve about 63.0%. Furthermore, the post-treatment is simple, the operation is easy, and the preparation method is suitable for industrial large-scale production.
Description
Technical field
The present invention relates to the synthetic field of pharmaceutical intermediate, be specifically related to midbody of 2-chloro-7H-pyrrolo-[2,3-d] pyrimidines (I) and preparation method thereof.
Background technology
2-chloro-7H-pyrrolo-[2,3-d] pyrimidine is a kind of important pharmaceutical intermediate, and the multiple SU11752 of report is all as key intermediate.WO2005/080393 has reported one type of new compound, contained the pharmaceutical composition of these compounds and has used these compounds for treating or prevention and abnormal kinase or imbalance diseases associated or illness, particularly with the method for FAK, AblBcr-Abl, PDGFR, c-Kit, NPM-ALK, Flt-3, JAK2 and c-Met abnormal activation diseases associated or illness.
For the preparation of 2-chloro-7H-pyrrolo-[2,3-d] pyrimidine, bibliographical information related compound method is following:
A kind of compound method of report among the patent WO2010/007114:
Reagent: (a) NaBH
4, palladium, 1,1 '-dinaphthalene-2,2 '-two diphenyl phosphines (BINAP).
Not enough below the compound method of this report exists: catalyzer is somewhat expensive, need carry out purifying products with the preparative high-performance liquid chromatographic appearance, and yield is low, does not possess the feasibility of mass preparation.
Patent WO2005/080393 in addition; Tetra.Lett.42 (2001) 999-1001; Bioorg.Med.Chem.17 (2009) 6926-6936; The compound method of bibliographical information 2-chloro-7H-pyrrolo-[2,3-d] pyrimidines such as Bioorg.Med.Chem.16 (2006) 2173-2176 is following:
Reagent and yield: (b) NH
3, MeOH, yield: about 90%; (c) EtOCH=CHSnBu
3, tetrakis triphenylphosphine palladium, toluene.Perhaps bi triphenyl phosphorus palladium chloride, etamon chloride (Et
4NCl), yield: 46～58%; (d) 3N hydrochloric acid or trifluoroacetic acid, yield: 92%.
Not enough below the compound method of this report exists: the organotin reagent toxicity that second step used is bigger, and price is higher; The palladium catalyst price of using is higher, and yield has only about 50%, and midbody needs column chromatography purification, does not possess the feasibility of mass preparation.
Summary of the invention
The purpose of this invention is to provide a kind of efficient, compound method of possessing 2-chloro-7H-pyrrolo-[2, the 3-d] pyrimidine that mass preparation is worth.Mainly solve existing 2-chloro-7H-pyrrolo-[2,3-d] the pyrimidine yield be low, midbody is difficult to purifying, can't scale operation etc. technical problem.
Preparing method of the present invention is with 2, and 4-two chloro-7H-pyrazole, pyrroles also [2,3-d] pyrimidine are raw material, obtains compound (VII) with the tert-Butyl dicarbonate reaction; Second step, the selectivity dechlorination obtained a new intermediate (VIII) under the condition of atmospheric hydrogenation; The 3rd step sloughed the protection base and obtains compound (I).
Midbody compound structure of the present invention (VIII) is as follows:
The preparation method of midbody compound of the present invention is following:
Preparing compound VI by compound VI is that the condition of e step is: under alkaline condition, catalyzer is 4-Dimethylamino pyridine (DMAP), reacts with tert-Butyl dicarbonate.
Preparing compound VIII by compound VI I is that the condition of f step is: under normal pressure, palladium carbon is catalyzer, feeds hydrogen.
In the e step, preferred triethylamine of said alkali or N, N-diisopropylethylamine (DIPEA).Temperature of reaction is preferably 20～60 ℃.Reaction solvent is preferably from ETHYLE ACETATE (EA), THF (THF), methylene dichloride (DCM), 1,2-ethylene dichloride or N, dinethylformamide.Compound VI: tert-Butyl dicarbonate: alkali: the mol ratio of 4-Dimethylamino pyridine preferred 1: 1.0～1.5: 1.0～3.0: 0.1～0.5.
In the f step, reaction solvent is preferably from EA, THF or DCM.Preferred acid binding agent, the preferred N of said acid binding agent, N-diisopropylethylamine (DIPEA), triethylamine, the Na of adding
2CO
3Perhaps NaHCO
3
During by midbody of the present invention (VIII) preparation compound I, only need add sour deprotection and get final product.
The present invention adopts midbody compound (VIII) preparation compound (I), comprising:
Above-mentioned being reflected under the acidic conditions carried out, preferred trifluoroacetic acid of said acid (TFA) or concentrated hydrochloric acid, or reaction feeds hydrogen chloride gas.
Preferred acid is trifluoroacetic acid.
Midbody compound VIII: preferred 1: 2.0～1: 10.0 of the mol ratio of trifluoroacetic acid.
The preferred methylene dichloride of the reaction solvent of above-mentioned reaction.
The present invention discloses the method for a kind of preparation 2-chloro-7H-pyrrolo-[2,3-d] pyrimidines (I) on the basis of invention midbody (VIIII):
Preparing method's reaction conditions of the present invention is relatively gentleer, and per step productive rate is all than higher, and total recovery can reach about 63.0%.And aftertreatment is simple, and is easy to operate, is fit to industrialized production.
Embodiment
Embodiment 1
Compound VI I's is synthetic
Compound VI (1000g, 5.32mol, 1.0eq.), triethylamine (2240mL, 15.6mol, 3.0eq.) and DMAP (65g, 0.532mol 0.1eq.) are dissolved in 5L EA.Under ice bath, to wherein dripping tert-Butyl dicarbonate (1160g, 5.32mol, EA 1.0eq.) (500mL) solution.Add back stirring at room 0.5h.Reaction finishes.With the solvent evaporate to dryness, recrystallization (sherwood oil PE/EA) obtains compound VI I white solid 1374g, yield: 90%.
1H?NMR(400M?Hz，CDCl3)δ(ppm)7.72(d，J＝3.3，1H)，6.66(d，J＝3.3，1H)，1.71(s，9H)。
Synthesizing of compound VIII
In the reaction flask of 10L, and adding compound VI I (619g, 2.148mol, 1.0eq.), and triethylamine (239.1g, 2.363mol, 1.1 eq.), (10%, 12.8g), EA (7.5L) feeds hydrogen to palladium carbon under normal pressure.After having reacted, filter, concentrate, recrystallization (PE/EA) obtains compound VIII white solid 736g, yield: 70%, and purity: 99%.LC-MS(ESI+APCI)Calcd?for?C6H4ClN3：253.69；found[M+H]+254。
1H?NMR(400M?Hz，CDCl3)δ(ppm)8.85(s，1H)，7.69(d，J＝4.1，1H)，6.61(d，J＝4.0，1H)，1.71(s，9H)。
Synthesizing of compound I
The 10L four-hole bottle, and the adding compound VIII (630g, 2.48mol, 1.0eq.), DCM (2.7L), adding TFA under ice bath (857g, 7.51mol, 3.0eq.).After room temperature reaction 3h. concentrates after adding, pour in the frozen water, constantly stir, have solid to separate out, transfer to neutrality, filter, dry and obtain compound I white solid 397g, yield with the NaOH aqueous solution: 100%, purity: 99%.
1H?NMR(400M?Hz，DMSO-d6)δ(ppm)12.36(br，1H)，7.61(dd，J＝2.4，3.4，1H)，6.64(dd，J＝1.7，3.5，1H)；LC-MS(ESI+APCI)Calcd?for?C6H4ClN3：153.57；found[M+H]+154.1。
Embodiment 2
Compound VI I's is synthetic
Compound VI (1000g, 5.32mol, 1.0eq.), DIPEA (672g, 5.2mol, 1.0eq.) and DMAP (325g, 2.66mol 0.5eq.) are dissolved in 5L THF.Under ice bath, to wherein dripping tert-Butyl dicarbonate (1624g, 7.448mol, THF 1.4eq.) (600mL) solution.Add back stirring at room 1h.Reaction finishes.With the solvent evaporate to dryness, recrystallization (sherwood oil PE/EA) obtains compound VI I white solid 1351g, yield: 88.5%.
1H?NMR(400M?Hz，CDCl3)δ(ppm)7.72(d，J＝3.3，1H)，6.66(d，J＝3.3，1H)，1.71(s，9H)。
Embodiment 3
Synthesizing of compound I
In the 10L reaction flask, add the 1250mL concentrated hydrochloric acid, 1L methyl alcohol, add compound VIII under stirring (630g, 2.48mol 1.0eq.), exit, and the water-bath temperature control is below 30 ℃ in batches.After adding, reacted 3 hours.After concentrating, pour in the frozen water, constantly stir, have solid to separate out, transfer to neutrality with the NaOH aqueous solution, filter, oven dry obtains compound I white solid 389g, yield: 98.0%, and purity: 99%.
1H?NMR(400M?Hz，DMSO-d6)δ(ppm)12.36(b?r，1H)，7.61(dd，J＝2.4，3.4，1H)，6.64(dd，J＝1.7，3.5，1H)。
Claims (10)
1. the compound of structural formula (VIII):
2. the preparation method of the compound of a claim 1 (VIII) comprising:
Wherein preparing compound VI I by compound VI is under alkaline condition, and catalyzer is the 4-Dimethylamino pyridine, compound VI and tert-Butyl dicarbonate reaction; Preparing compound VIII by compound VI I is that palladium carbon is catalyzer, feeds hydrogen.
3. the preparation method of claim 2, when wherein preparing compound VI I by compound VI, alkali is triethylamine or N, the N-diisopropylethylamine.
4. the preparation method of claim 2, when wherein preparing compound VI I by compound VI, temperature of reaction is 20～60 ℃.
5. the preparation method of claim 2, when wherein preparing compound VI I by compound VI, reaction solvent is selected from ETHYLE ACETATE, THF, methylene dichloride, 1,2-ethylene dichloride or N, dinethylformamide.
6. the preparation method of claim 2, when wherein preparing compound VI I by compound VI, compound VI: tert-Butyl dicarbonate: alkali: the mol ratio of 4-Dimethylamino pyridine is 1: 1.0～1.5: 1.0～3.0: 0.1～0.5.
7. the preparation method of claim 2, when wherein preparing compound VIII by compound VI I, reaction solvent is selected from ETHYLE ACETATE, THF or methylene dichloride.
8. the preparation method of claim 2 when wherein preparing compound VIII by compound VI I, adds acid binding agent, and acid binding agent is N, N-diisopropylethylamine, triethylamine, Na
2CO
3Perhaps NaHCO
3
9. the preparation method of the compound of a structural formula (I) comprising:
Reaction adds trifluoroacetic acid or concentrated hydrochloric acid, or reaction feeds hydrogen chloride gas.
10. the preparation method of claim 9, wherein to add acid be trifluoroacetic acid in reaction, and compound VIII: the mol ratio of trifluoroacetic acid is 1: 2～1: 10, and reaction solvent is a methylene dichloride.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105949196A (en) * | 2016-05-18 | 2016-09-21 | 南京富润凯德生物医药有限公司 | Preparation method of MER/FLT3 dual-inhibitor intermediate |
| CN107722012A (en) * | 2016-08-11 | 2018-02-23 | 斯福瑞（南通）制药有限公司 | The method for preparing 4 chlorine 7H pyrrolo-es [2,3 d] pyrimidines |
| KR102228668B1 (en) * | 2019-10-08 | 2021-03-17 | (주)부흥산업사 | Manufacturing method of methylpiperidine amino pyrrolo pyrimidine |
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| WO2005107760A1 (en) * | 2004-04-30 | 2005-11-17 | Irm Llc | Compounds and compositions as inducers of keratinocyte differentiation |
| CN101981036A (en) * | 2008-02-06 | 2011-02-23 | 诺瓦提斯公司 | Pyrrolo [2, 3-D] pyridines and use thereof as tyrosine kinase inhibitors |
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Patent Citations (3)
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| WO2005107760A1 (en) * | 2004-04-30 | 2005-11-17 | Irm Llc | Compounds and compositions as inducers of keratinocyte differentiation |
| CN101981036A (en) * | 2008-02-06 | 2011-02-23 | 诺瓦提斯公司 | Pyrrolo [2, 3-D] pyridines and use thereof as tyrosine kinase inhibitors |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105949196A (en) * | 2016-05-18 | 2016-09-21 | 南京富润凯德生物医药有限公司 | Preparation method of MER/FLT3 dual-inhibitor intermediate |
| CN105949196B (en) * | 2016-05-18 | 2018-06-29 | 南京富润凯德生物医药有限公司 | A kind of preparation method of MER/FLT3 double inhibitors intermediate |
| CN107722012A (en) * | 2016-08-11 | 2018-02-23 | 斯福瑞（南通）制药有限公司 | The method for preparing 4 chlorine 7H pyrrolo-es [2,3 d] pyrimidines |
| CN107722012B (en) * | 2016-08-11 | 2020-05-29 | 斯福瑞（南通）制药有限公司 | Process for preparing 4-chloro-7H-pyrrolo [2,3-d ] pyrimidines |
| KR102228668B1 (en) * | 2019-10-08 | 2021-03-17 | (주)부흥산업사 | Manufacturing method of methylpiperidine amino pyrrolo pyrimidine |
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Address after: 210061 Nanjing high tech Industrial Development Zone, Jiangsu Province Road, No. 10 Patentee after: PHARMABLOCK (NANJING) R&D CO., LTD. Address before: 210061 Nanjing high tech Industrial Development Zone, Jiangsu Province Road, No. 10 Patentee before: Nanjing Medical Stone and Medicine Research and Development Co., Ltd. |