CN106188064A - A kind of preparation method of N methyl N ((3R, 4R) 4 picoline 3 base) 7H pyrrolo-[2,3 d] pyrimidine 4 amine - Google Patents
A kind of preparation method of N methyl N ((3R, 4R) 4 picoline 3 base) 7H pyrrolo-[2,3 d] pyrimidine 4 amine Download PDFInfo
- Publication number
- CN106188064A CN106188064A CN201610529958.9A CN201610529958A CN106188064A CN 106188064 A CN106188064 A CN 106188064A CN 201610529958 A CN201610529958 A CN 201610529958A CN 106188064 A CN106188064 A CN 106188064A
- Authority
- CN
- China
- Prior art keywords
- base
- pyrrolo
- pyrimidine
- amine
- picoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses a kind of N methyl N ((3R, 4R) 4 picoline 3 base) 7H pyrrolo-[2,3 d] preparation method of pyrimidine 4 amine, the method includes using palladium carbon as catalyst, by N ((3R, 4R) 1 benzyl 4 picoline 3 base) N methyl 7H pyrrolo-[2,3 d] pyrimidine 4 amine takes off benzyl and obtains intermediate N methyl N ((3R, 4R) 4 picoline 3 base) 7H pyrrolo-[2,3 d] pyrimidine 4 amine.Productivity of the present invention is high, and by-product is few, and easy and simple to handle, has both been suitable to laboratory preparation on a small scale, also has been adapted for large-scale industrial production.
Description
Technical field
The invention belongs to field of medicine preparing technology, particularly relate to a kind of N-methyl-N-((3R, 4R)-4-methyl pyrrole
Pyridine-3-base) preparation method of-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.
Background technology
Citric acid expelling pathogens by strengthening vital QI is the little molecule mouth acting on intracellular tyrosine kinase for cloth (tofacitinib citrate)
Take inhibitor, by U.S. FDA in November, 2012 approval for moderate the controlling to severe active rheumatoid arthritis being grown up
Treat.Its indication for treatment the activities of adults phase and to methotrexate (MTX) reaction the best in severe rheumatoid arthritis suffer from
Person, can combine methotrexate for treating the Active rheumatoid arthritis not enough to tumor necrosis factor inhibitors response.
Compound N-methy-N-((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine is
Synthesis citric acid expelling pathogens by strengthening vital QI is for the key intermediate of cloth.Its structural formula is as follows:
The existing relevant report of the synthesis technique of this compound, as patent WO2010123919, WO2007012953 and
WO2002096909, and document " Organic Process Research & Development, 2014,18 (12):
1714-1720 " it is each provided with its synthetic method:
By using catalyst in acid condition, by N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-methyl-
The reaction of 7H-pyrrolo-[2,3-d] pyrimidine-4-amine obtains intermediate N methyl-N-((3R, 4R)-4-picoline-3-base)-7H-
Pyrrolo-[2,3-d] pyrimidine-4-amine.
The synthesis technique that patent WO2010123919, WO2007012953 and WO2002096909 are reported, all uses 20%
Palladium dydroxide/carbon as the catalyst of this step reaction, and need hydrochloric acid or acetic acid to provide sour environment, and more than 16
Hour response time, and the method post processing needs the complex operations such as acid-base neutralization and separatory extraction, due to product pole
Easily deliquescence, it is impossible to filter, be not suitable for industrialized production.Document " Organic Process Research & Development,
2014,18 (12): 1714-1720 " synthesis technique reported uses the catalyst that 10% palladium/carbon reacts as this step, but needs
Acetic acid is wanted to provide sour environment.So, the method post processing is also to need the complex operations such as acid-base neutralization and separatory extraction, and
And, the method products obtained therefrom yield is relatively low, is not suitable for industrialized production.
Summary of the invention
The purpose of the present invention is that and overcomes above-mentioned deficiency, it is provided that N-methyl-N-((3R, 4R)-4-methyl of a kind of improvement
Pyridin-3-yl) preparation method of-7H-pyrrolo-[2,3-d] pyrimidine-4-amine, its reaction condition is gentle, easy and simple to handle, yield
Industrialized production high, applicable.
For reaching above-mentioned purpose, the present invention implements according to techniques below scheme:
A kind of preparation side of N-methyl-N-((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine
Method, it is characterised in that comprise the following steps:
(1) by N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine,
Methanol and palladium carbon join in hydriding reactor；
(2) it is passed through hydrogen, pressurization, heats up, carries out hydrogenation；
(3) after completion of the reaction, filtering and remove palladium removing carbon, filtrate is standby；
(4) carry out filtrate concentrating removing methanol, obtain grease product, be N-methyl-N-((3R, 4R)-4-methyl pyrrole
Pyridine-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.
Further, the pressure of hydrogenation is 0.5-1.5 MPa.
Further, the pressure of hydrogenation is 0.8-1.2MPa.
Further, temperature 50-70 DEG C of hydrogenation.
Further, the temperature of hydrogenation is 55-65 DEG C.
Further, the time of hydrogenation is 5-8 h.
Further, methanol and N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-methyl-7H-pyrrolo-[2,
3-d] mass ratio of pyrimidine-4-amine is 1:1-100:1.
Further, methanol and N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-methyl-7H-pyrrolo-[2,
3-d] mass ratio of pyrimidine-4-amine is 5:1-20:1.
Further, palladium carbon and N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-methyl-7H-pyrrolo-[2,
3-d] mass ratio of pyrimidine-4-amine is 0.01:1-1:1.
Further, palladium carbon and N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-methyl-7H-pyrrolo-[2,
3-d] mass ratio of pyrimidine-4-amine is 0.05:1-0.5:1.
Compared with prior art, the invention have the benefit that
The synthesis technique use palladium carbon of the present invention is as catalyst, without any acid reagent, by N-((3R, 4R)-1-benzyl
Base-4-picoline-3-base)-N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine takes off benzyl and obtains intermediate N methyl-N-
((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.The present invention need not the post processing of complexity
Process, easy and simple to handle, productivity is high, and by-product is few, has both been suitable to laboratory preparation on a small scale, also has been adapted for large-scale industrial production.
Figure of description
Fig. 1 is the HPLC experimental result picture of product obtained by the production technology using the present invention；
The HPLC experimental result picture of product obtained by the production technology that Fig. 2 is reported by using document.
Detailed description of the invention
The invention will be further described with specific embodiment below in conjunction with the accompanying drawings, the illustrative examples invented at this with
And explanation is used for explaining the present invention, but not as a limitation of the invention.
Embodiment 1
By N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine
105.0 g, 10% palladium carbon 26.3 g, methanol 1000 mL join in hydriding reactor.It is passed through hydrogen, keeps pressure 1 MPa, temperature
60 DEG C, react 6 h.After palladium removing carbon is removed in filtration, concentrate and remove methanol, obtain grease product.
Embodiment 2
By N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine 100
G, 10% palladium carbon 28 g, methanol 1000 mL join in hydriding reactor.It is passed through hydrogen, keeps pressure 0.8 MPa, temperature 65 DEG C, instead
Answer 8 h.After palladium removing carbon is removed in filtration, concentrate and remove methanol, obtain grease product.
Embodiment 3
By N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine 100
G, 10% palladium carbon 30 g, methanol 1000 mL join in hydriding reactor.It is passed through hydrogen, keeps pressure 1.2 MPa, temperature 60 C, instead
Answer 7 h.After palladium removing carbon is removed in filtration, concentrate and remove methanol, obtain grease product.
Contrast experiment
According to document " Organic Process Research & Development, 2014,18 (12): 1714-1720 "
N-methyl-N-((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2, the 3-d] pyrimidine-4-amine synthesis technique of report closes
Becoming this compound, step is as follows: by N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-methyl-7H-pyrrolo-[2,
3-d] pyrimidine-4-amine 16g, 20% palladium dydroxide carbon 2.4g, water 16mL, isopropanol 64mL, acetic acid 2.8g add hydriding reactor.It is passed through
Hydrogen, keeps pressure 0.5MPa, temperature 50 C, reacts 12h.Filtering after being down to room temperature, filtrate is stirred with 15%NaOH solution 30mL
0.5h, decompression distillation is to weight.It is down to room temperature, adds 2-methyltetrahydrofuran 100mL, separatory extraction 2-methyltetrahydrofuran
Layer.Concentrate dry, add 100mL toluene making beating 1h.Filter, obtain solid 10.0g, yield 85%.
The technique described in embodiment 1 is used to prepare N-methyl-N-((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-
[2,3-d] pyrimidine-4-amine, obtains grease product 77.0g, yield 100%.
Products obtained therefrom in the embodiment of the present invention 1 is designated as sample 1, products obtained therefrom will be prepared according to literature procedure and be designated as
Sample 2, is respectively adopted high performance liquid chromatography by sample 1 and sample 2 and detects its purity, acquired results as depicted in figs. 1 and 2,
The purity of sample 1 is 96.79%；The purity of sample 2 is 85.36%.
As can be seen here, the synthesis technique use palladium carbon of the present invention is as catalyst, without any acid reagent, by N-
((3R, 4R)-1-benzyl-4-picoline-3-base)-N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine takes off benzyl and obtains centre
Body N-methyl-N-((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.The present invention need not multiple
Miscellaneous last handling process, easy and simple to handle, productivity is high, and by-product is few, has both been suitable to laboratory preparation on a small scale, also has been adapted for extensive work
Industry metaplasia is produced.
Technical scheme is not limited to the restriction of above-mentioned specific embodiment, every does according to technical scheme
The technology deformation gone out, within each falling within protection scope of the present invention.
Claims (10)
1. the preparation of N-methyl-N-((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine
Method, it is characterised in that comprise the following steps:
(1) by N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine,
Methanol and palladium carbon join in hydriding reactor；
(2) it is passed through hydrogen, pressurization, heats up, carries out hydrogenation；
(3) after completion of the reaction, filtering and remove palladium removing carbon, filtrate is standby；
(4) carry out filtrate concentrating removing methanol, obtain grease product, be N-methyl-N-((3R, 4R)-4-methyl pyrrole
Pyridine-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.
N-methyl-N-the most according to claim 1 ((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2,3-d]
The preparation method of pyrimidine-4-amine, it is characterised in that the pressure of hydrogenation is 0.5-1.5 MPa.
N-methyl-N-the most according to claim 1 ((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2,3-d]
The preparation method of pyrimidine-4-amine, it is characterised in that the pressure of hydrogenation is 0.8-1.2MPa.
N-methyl-N-the most according to claim 1 ((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2,3-d]
The preparation method of pyrimidine-4-amine, it is characterised in that temperature 50-70 DEG C of hydrogenation.
N-methyl-N-the most according to claim 1 ((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2,3-d]
The preparation method of pyrimidine-4-amine, it is characterised in that the temperature of hydrogenation is 55-65 DEG C.
N-methyl-N-the most according to claim 1 ((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2,3-d]
The preparation method of pyrimidine-4-amine, it is characterised in that the time of hydrogenation is 5-8 h.
N-methyl-N-the most according to claim 1 ((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2,3-d]
The preparation method of pyrimidine-4-amine, it is characterised in that methanol and N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-first
The mass ratio of base-7H-pyrrolo-[2,3-d] pyrimidine-4-amine is 1:1-100:1.
N-methyl-N-the most according to claim 1 ((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2,3-d]
The preparation method of pyrimidine-4-amine, it is characterised in that methanol and N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-first
The mass ratio of base-7H-pyrrolo-[2,3-d] pyrimidine-4-amine is 5:1-20:1.
N-methyl-N-the most according to claim 1 ((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2,3-d]
The preparation method of pyrimidine-4-amine, it is characterised in that palladium carbon and N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-first
The mass ratio of base-7H-pyrrolo-[2,3-d] pyrimidine-4-amine is 0.01:1-1:1.
N-methyl-N-the most according to claim 1 ((3R, 4R)-4-picoline-3-base)-7H-pyrrolo-[2,3-d]
The preparation method of pyrimidine-4-amine, it is characterised in that palladium carbon and N-((3R, 4R)-1-benzyl-4-picoline-3-base)-N-first
The mass ratio of base-7H-pyrrolo-[2,3-d] pyrimidine-4-amine is 0.05:1-0.5:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610529958.9A CN106188064A (en) | 2016-07-07 | 2016-07-07 | A kind of preparation method of N methyl N ((3R, 4R) 4 picoline 3 base) 7H pyrrolo-[2,3 d] pyrimidine 4 amine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610529958.9A CN106188064A (en) | 2016-07-07 | 2016-07-07 | A kind of preparation method of N methyl N ((3R, 4R) 4 picoline 3 base) 7H pyrrolo-[2,3 d] pyrimidine 4 amine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106188064A true CN106188064A (en) | 2016-12-07 |
Family
ID=57472368
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610529958.9A Pending CN106188064A (en) | 2016-07-07 | 2016-07-07 | A kind of preparation method of N methyl N ((3R, 4R) 4 picoline 3 base) 7H pyrrolo-[2,3 d] pyrimidine 4 amine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106188064A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101233138A (en) * | 2005-07-29 | 2008-07-30 | 辉瑞产品公司 | Pyrrolo[2,3-d]pyrimidine derivatives, their intermediates and synthesis |
| WO2010123919A2 (en) * | 2009-04-20 | 2010-10-28 | Auspex Pharmaceuticals, Llc | Piperidine inhibitors of janus kinase 3 |
| CN104761555A (en) * | 2015-03-21 | 2015-07-08 | 河北国龙制药有限公司 | Tofacitinib intermediate preparation method and method for preparing tofacitinib or its salt by using tofacitinib intermediate preparation method |
-
2016
- 2016-07-07 CN CN201610529958.9A patent/CN106188064A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101233138A (en) * | 2005-07-29 | 2008-07-30 | 辉瑞产品公司 | Pyrrolo[2,3-d]pyrimidine derivatives, their intermediates and synthesis |
| WO2010123919A2 (en) * | 2009-04-20 | 2010-10-28 | Auspex Pharmaceuticals, Llc | Piperidine inhibitors of janus kinase 3 |
| CN104761555A (en) * | 2015-03-21 | 2015-07-08 | 河北国龙制药有限公司 | Tofacitinib intermediate preparation method and method for preparing tofacitinib or its salt by using tofacitinib intermediate preparation method |
Non-Patent Citations (1)
| Title |
|---|
| YOGESH S. PATIL，等: "An Improved and Efficient Process for the Preparation of Tofacitinib Citrate", 《ORG. PROCESS RES. DEV.》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105367557A (en) | Method for preparing cycloxylidin | |
| CN106966947B (en) | A kind of preparation method of vildagliptin | |
| CN108947891A (en) | The method for safely preparing a Mo Fanselin and its tartrate using triphosgene | |
| CN103833593B (en) | A kind of preparation method of N-(the 9-fluorenylmethyloxycarbonyl)-O-tert-butyl group-TYR | |
| CN106518755B (en) | A kind of method synthesizing 2,3- dichloropyridine | |
| CN102584825B (en) | Method for synthesizing valaciclovir hydrochloride | |
| CN108276414B (en) | A kind of preparation method of citric acid tropsch imatinib | |
| KR101746672B1 (en) | Catalyst for dehydrogenation reaction, the method for synthesizing the same and the decomposition method of form acid using the same | |
| CN103880745B (en) | A kind of chemical synthesis process of the bromo- 1,2,3,4- tetrahydroisoquinoline -1- formic acid of 6- | |
| CN106518754B (en) | A method of preparing 2,3- dichloropyridine | |
| CN106188064A (en) | A kind of preparation method of N methyl N ((3R, 4R) 4 picoline 3 base) 7H pyrrolo-[2,3 d] pyrimidine 4 amine | |
| CN107162987A (en) | The Industrialized synthesis method and midbody compound of a kind of rilpivirine | |
| CN106146560B (en) | A kind of refining methd of high-purity phosphoric acid specially azoles amine | |
| CN106608853B (en) | The preparation method of dipeptidy peptidase in inhibitors | |
| CN106946764A (en) | A kind of method for preparing the tartrate crystal formation B of piperazine Ma Selin half | |
| CN102304102B (en) | Preparation method of 1-methyl piperazine | |
| CN112645813B (en) | Preparation method of (R) -3-cyclohexene carboxylic acid | |
| CN101270119B (en) | Technique for purifying spherosinin from leguminosae pointvetch or milk vetch | |
| CN107880063A (en) | A kind of synthetic method of dauricine | |
| CN102260255B (en) | Simple and convenient synthesis method of 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-3-isobutyl-2H-benzo[a] quinolizidine-2-ketone | |
| CN104557561B (en) | A kind of preparation method of N1, N1-diisopropyl ethylenediamine or its salt | |
| CN102702196B (en) | Method for synthesizing 3-methyl-7-diazaindene | |
| CN106380484A (en) | New crystal form of tenofovir alafenamide and preparation method thereof | |
| CN107879966A (en) | A kind of preparation method of sitafloxacin key intermediate | |
| CN105669539B (en) | A kind of preparation process of 2- amino -3- fluorine pyridines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20161208 Address after: 454950 Wuzhi County in Henan province Jiaozuo City Yingbin Road No. 686 Sinopharm Rongsheng Pharmaceutical Co. Ltd. Applicant after: SINOPHARM RONGSHENG PHARMACEUTICAL CO., LTD. Applicant after: Shanghai Institute of pharmaceutical industry Address before: 454950 Wuzhi County in Henan province Jiaozuo City Yingbin Road No. 686 Sinopharm Rongsheng Pharmaceutical Co. Ltd. Applicant before: SINOPHARM RONGSHENG PHARMACEUTICAL CO., LTD. |
|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20161207 |