CN108794479A - A kind of synthetic method of 4- chloropyrrolo [2,3-ds - Google Patents
A kind of synthetic method of 4- chloropyrrolo [2,3-ds Download PDFInfo
- Publication number
- CN108794479A CN108794479A CN201710280763.XA CN201710280763A CN108794479A CN 108794479 A CN108794479 A CN 108794479A CN 201710280763 A CN201710280763 A CN 201710280763A CN 108794479 A CN108794479 A CN 108794479A
- Authority
- CN
- China
- Prior art keywords
- degree
- pyrimidine
- reaction
- sulfydryl
- hydroxypyrroles
- 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.)
- Withdrawn
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention relates to a kind of synthetic methods of 4- chloropyrrolo [2,3-ds, the synthetic method is using cyan-acetic ester, bromo acetal, thiocarbamide, sodium ethoxide, hydrogen peroxide as raw material, using DMF, ethyl alcohol, water, phosphorus oxychloride as solvent, target product 4- chloropyrrolo [2,3-ds are obtained by four-step reaction.The invention improves the method that sulfydryl is removed in third step, by using hydrogen peroxide, is first sulfinic acid by sulfhydryl oxidase, then sloughs in acid condition.Reaction condition is mild, environmental-friendly, and safe operation, yield is higher, is suitble to industrialized production.
Description
Technical field
The invention belongs to the field of chemical synthesis, and in particular to arrives a kind of synthetic method of 4- chloropyrrolo [2,3-ds.
Background technology
The biological endogenous substance important as one, pyrimidine heterocyclic, which is widely present in organism, participates in vital movement, because
In the research and development of many medicine and pesticide, pyrimidine heterocyclic compounds play an important role for this.Such as known 4-
Chloropyrrolo [2,3-d be exactly develop the drugs such as many antibacterials, antitumor, anti-centrum worm important source material (CN105218554,
2016.01.06).Therefore it is become more and more active in recent years about the research of substance of this kind.
Currently, the synthetic method of 4- chloropyrrolo [2,3-ds mainly has following three kinds：
1. using cyan-acetic ester, thiocarbamide, sodium ethoxide, 2- chloroacetaldehydes as raw material, using ethyl alcohol, ammonium hydroxide, phosphorus oxychloride as solvent, with
Active nickel is catalyst, and product is obtained by four-step reaction（CN101830904A, 2010.09.15）.To be used in this route compared with
More inflammable catalyst activity nickel removes sulfydryl, very dangerous, is unfavorable for industrialized production.It thanks and wave et al. is answered to improve this
Route, by second step be added catalyst titanium dioxide, by yield improve 11-15% (CN105218554,
2016.01.06).But due to still making catalyst using inflammable active nickel, industrialized production still has security risk.
2. using cyan-acetic ester, bromo acetal, formamidine acetate, sodium hydride, sodium alkoxide as raw material, with ethyl alcohol, DMF,
Phosphorus oxychloride is solvent, and three steps synthesize to obtain product（CN104860950A, 2015.08.26）.The first step will be used in this route
, there are security risk in sodium hydride, when post-processing, and first two steps total recovery only has 40% or so, is also not suitable for industrialized production.
3. with 4,6- dihydroxy-pyrimidines, phosphorus oxychloride, ammonia, methoxyl methyl triphenyl phosphine dichloride, potassium tert-butoxide are raw material,
Using DMF, toluene, THF as solvent, four-step reaction obtains product（US20140256941,2014.09.14）.Part in this route
Raw material is more expensive, and technological operation is more complex, and yield is not high, is also not suitable for industrialized production.
The above route respectively has deficiency, therefore develops a safe operation, and yield is higher, is suitble to the synthesis of industrialized production
Method is necessary.
Invention content
The present invention is using cyan-acetic ester, bromo acetal, thiocarbamide, sodium ethoxide, hydrogen peroxide as raw material, with DMF, water, three
Chlorethoxyfos are solvent, and product is obtained by four-step reaction.This route reaction condition is mild, environmental-friendly, safe operation, yield compared with
Height is suitble to industrialized production.
Its synthetic route such as formula（One）It is shown：
It comprises the concrete steps that：
（1）Using cyan-acetic ester, bromo acetal as starting material, after being dissolved in DMF, potassium carbonate is added, is warming up to 150 degree of left sides
Right reaction is down to room temperature after reaction, is poured into water, dry with chloroform recovery, and vacuum distillation obtains 2- cyano -4,4-
Diethyl acetal ethyl butyrate.
（2）2- cyano -4,4- diethyl acetal ethyl butyrates are dissolved in absolute ethyl alcohol, under 0 degree, sodium ethoxide and sulphur is added
Urea, is warming up to reflux, after pyrimidine ring closure reaction, is down to room temperature, acidity is adjusted to hydrochloric acid, be further continued for reacting, pyrroles's cyclization
After reaction, it filters, recrystallization obtains 2- sulfydryl -4- hydroxypyrroles and pyrimidine.
（3）By 2- sulfydryl -4- hydroxypyrroles, simultaneously pyrimidine is dissolved in alkaline aqueous solution, and under 15-20 degree, hydrogen peroxide is added dropwise, will
Sulfhydryl oxidase is sulfinic acid, and concentrated hydrochloric acid tune acidity is then added dropwise again, and after reaction, with ammonium hydroxide tune PH=9-10, filtering obtains
4- hydroxypyrroles and pyrimidine.
（4）By 4- hydroxypyrroles, simultaneously pyrimidine is dissolved in phosphorus oxychloride, is warming up to 85 degree or so reactions, after reaction, is steamed
Extra phosphorus oxychloride is gone, 0 degree is cooled to, is quenched with ice water, with saturated solution of sodium bicarbonate tune PH=7-8, is filtered, recrystallization,
Obtain product 4- chloropyrrolo [2,3-ds.
Step（1）In, the molar ratio of cyan-acetic ester and bromo acetal is 1-5:1, preferably 2:1.Cyanoacetic acid second
The molar ratio of ester and potassium carbonate is 1:0.8-1.5, preferably 1:1.
Step（2）In, the molar ratio of 2- cyano -4,4- diethyl acetal ethyl butyrates and sodium ethoxide is 1:2-4, preferably 1:3.
The molar ratio of 2- cyano -4,4- diethyl acetals ethyl butyrate and thiocarbamide is 1:1-3, preferably 1:1.5.
Step（3）In, alkaline aqueous solution can be that sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide etc. are water-soluble
Liquid, preferably sodium hydroxide.Alkaline aqueous solution concentration 1-30%, preferably 15-20%.2- sulfydryl -4- hydroxypyrroles and pyrimidine with it is used
The molar ratio of alkali is 1:0.5-3, preferably 1:1.The molar ratio of 2- sulfydryl -4- hydroxypyrroles and pyrimidine and hydrogen peroxide is 1:2-6,
It is preferred that 1:3-4.Reaction temperature 5-35 degree, preferably 15-20 degree.
Mainly improved place is step to this route（3）In, active nickel, ammonium hydroxide will be used to remove sulfydryl in common process
Method is changed to use hydrogen peroxide, is first sulfinic acid, the method then removed in acid condition, reaction condition by sulfhydryl oxidase
Mildly, environmental-friendly, safe operation is suitble to industrialized production.
The present invention, by four-step reaction, generates 4- chlorine pyrrolo-es using cyan-acetic ester, bromo acetal as starting material
Pyrimidine is tested, to verify the reliability of synthetic method.The protection content of the present invention is not limited to following case study on implementation.
Case is embodied：
（1）The synthesis of 2- cyano -4,4- diethyl acetal ethyl butyrates：
By 113 grams（1mol）Cyan-acetic ester and 98.5 grams（0.5mol）Bromo acetal dissolves in 450 grams of DMF, adds
138 grams（1mol）Potassium carbonate is warming up to 150 degree or so, after reaction, is cooled to 20 degree or so, 450 grams of water is added, respectively
Twice with 500 grams of chloroform recoveries, saturated salt solution washed once, dry, vacuum distillation, obtain 78.1 grams of 2- cyano -4,4- contractings
Diethanol ethyl butyrate, yield 70%.
（2）The synthesis of 2- sulfydryl -4- hydroxypyrroles and pyrimidine：
By 68.7 grams（0.3mol）2- cyano -4,4- diethyl acetal ethyl butyrates are added in 490ml absolute ethyl alcohols, under 0 degree, then
It is added 61.2 grams（0.9mol）Sodium ethoxide and 34.2 grams（0.45mol）Thiocarbamide, is warming up to reflux, after pyrimidine ring closure reaction,
It is down to room temperature, PH=2-3 is adjusted to concentrated hydrochloric acid, is further continued for reacting at room temperature, after pyrroles's ring closure reaction, filtering, with toluene weight
Crystallization, it is dry, obtain 41 grams of 2- sulfydryl -4- hydroxypyrroles and pyrimidine, yield 82%.
（3）The synthesis of 4- hydroxypyrroles and pyrimidine：
By 33.4 grams（0.2mol）2- sulfydryl -4- hydroxypyrroles and pyrimidine are added in 76 gram 20% of sodium hydrate aqueous solution, entirely
After molten, under temperature control 15-20 degree, 84 gram 30% of hydrogen peroxide is added dropwise, stirs 2 hours, 44 grams of concentrated hydrochloric acids are added dropwise, are stirred for 1 hour
Afterwards, PH=9-10 is adjusted with ammonium hydroxide, filtered, washed, it is dry, obtain 23.4 grams of 4- hydroxypyrroles and pyrimidine, yield 83%.
（4）The synthesis of 4- chloropyrrolo [2,3-ds：
By 56.4 grams（0.4mol）Simultaneously pyrimidine is dissolved in phosphorus oxychloride 4- hydroxypyrroles, is heated to 85 degree or so, after reaction,
Extra phosphorus oxychloride is distilled out, 0 degree or so is cooled to, is quenched with ice water, with saturated solution of sodium bicarbonate tune PH=7-8, mistake
Filter, is recrystallized with methanol-water, dry, obtains 56.1 grams of 4- chloropyrrolo [2,3-ds, yield 88%.
Claims (8)
1. a kind of synthetic method of 4- chloropyrrolo [2,3-ds, it is characterised in that include following steps：
（1）Using cyan-acetic ester, bromo acetal as starting material, after being dissolved in DMF, potassium carbonate is added, is warming up to 150 degree of left sides
Right reaction is down to room temperature, is poured into water until reaction terminates, dry with chloroform recovery, and vacuum distillation obtains cyano -4 2-,
4- diethyl acetal ethyl butyrates；
（2）2- cyano -4,4- diethyl acetal ethyl butyrates are dissolved in absolute ethyl alcohol, under 0 degree, sodium ethoxide and thiocarbamide is added,
It is warming up to reflux, after pyrimidine ring closure reaction, is down to room temperature, acidity is adjusted to hydrochloric acid, be further continued for reacting, pyrroles's ring closure reaction
After, it filters, recrystallization obtains 2- sulfydryl -4- hydroxypyrroles and pyrimidine；
（3）By 2- sulfydryl -4- hydroxypyrroles, simultaneously pyrimidine is dissolved in alkaline aqueous solution, under 15-20 degree, hydrogen peroxide is added dropwise, by sulfydryl
It is oxidized to sulfinic acid, concentrated hydrochloric acid tune acidity is then added dropwise again, after reaction, with ammonium hydroxide tune PH=9-10, filtering obtains 4- hydroxyls
Base pyrrolopyrimidine；
（4）By 4- hydroxypyrroles, simultaneously pyrimidine is dissolved in phosphorus oxychloride, is warming up to 85 degree or so reactions and is boiled off more after reaction
Remaining phosphorus oxychloride is cooled to 0 degree, is quenched with ice water, with saturated solution of sodium bicarbonate tune PH=7-8, filters, and recrystallization obtains
Product 4- chloropyrrolo [2,3-ds.
2. according to claim 1, step（1）In, the molar ratio of cyan-acetic ester and bromo acetal is 1-5:1, it is excellent
Select 2:1；The molar ratio of cyan-acetic ester and potassium carbonate is 1:0.8-1.5, preferably 1:1.
3. according to claim 1, step（2）In, the molar ratio of 2- cyano -4,4- diethyl acetal ethyl butyrate and sodium ethoxide
It is 1:2-4, preferably 1:3；The molar ratio of 2- cyano -4,4- diethyl acetals ethyl butyrate and thiocarbamide is 1:1-3, preferably 1:1.5.
4. according to claim 1, step（3）In, alkaline aqueous solution can be sodium hydroxide, potassium hydroxide, lithium hydroxide,
The aqueous solutions such as calcium hydroxide, preferably sodium hydroxide.
5. according to claim 1, step（3）In, alkaline aqueous solution concentration 1-30%, preferably 15-20%.
6. according to claim 1, step（3）In, 2- sulfydryl -4- hydroxypyrroles and pyrimidine and alkali used
Molar ratio is 1:0.5-3, preferably 1:1.
7. according to claim 1, step（3）In, simultaneously the molar ratio of pyrimidine and hydrogen peroxide is 1 to 2- sulfydryl -4- hydroxypyrroles:
2-6, preferably 1:3-4.
8. according to claim 1, step（3）In, reaction temperature 5-35 degree, preferably 15-20 degree.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710280763.XA CN108794479A (en) | 2017-04-26 | 2017-04-26 | A kind of synthetic method of 4- chloropyrrolo [2,3-ds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710280763.XA CN108794479A (en) | 2017-04-26 | 2017-04-26 | A kind of synthetic method of 4- chloropyrrolo [2,3-ds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108794479A true CN108794479A (en) | 2018-11-13 |
Family
ID=64069086
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710280763.XA Withdrawn CN108794479A (en) | 2017-04-26 | 2017-04-26 | A kind of synthetic method of 4- chloropyrrolo [2,3-ds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108794479A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109824675A (en) * | 2019-04-09 | 2019-05-31 | 唐山师范学院 | A kind of synthetic method of 4- chloropyrrolo [2,3-d |
| CN112645956A (en) * | 2020-12-29 | 2021-04-13 | 天津全和诚科技有限责任公司 | Preparation method of prodrug intermediate of thymidine phosphorylase inhibitor |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103709164A (en) * | 2013-12-04 | 2014-04-09 | 浙江工业大学 | Synthetic method for adenine |
-
2017
- 2017-04-26 CN CN201710280763.XA patent/CN108794479A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103709164A (en) * | 2013-12-04 | 2014-04-09 | 浙江工业大学 | Synthetic method for adenine |
Non-Patent Citations (1)
| Title |
|---|
| JIAE KIM,等: "Pre-steady state kinetic analysis of cyclobutyl derivatives of 2’-deoxyadenosine 5’-triphosphate as inhibitors of HIV-1 reverse transcriptase", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109824675A (en) * | 2019-04-09 | 2019-05-31 | 唐山师范学院 | A kind of synthetic method of 4- chloropyrrolo [2,3-d |
| CN112645956A (en) * | 2020-12-29 | 2021-04-13 | 天津全和诚科技有限责任公司 | Preparation method of prodrug intermediate of thymidine phosphorylase inhibitor |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106349245B (en) | A kind of phosphoric acid Xi Gelieting impurity and its preparation method and application | |
| CN106699756B (en) | The synthetic method of beta lactamase restrainer AVM hereinafter Batan | |
| ZA200500745B (en) | Process for preparing the calcium salt of resuvastatin | |
| CN105541844B (en) | Simple preparation method of high-purity linagliptin | |
| CN106749194A (en) | A kind of preparation method for a pyrimidine | |
| CN108794479A (en) | A kind of synthetic method of 4- chloropyrrolo [2,3-ds | |
| CN105669642A (en) | Revaprzan hydrochloride preparation method | |
| CN106674084B (en) | A kind of preparation method of 2- isopropyl oxygroup -5- methyl -4- (piperidin-4-yl) aniline dihydrochloride | |
| CN105175446B (en) | Preparation method of minodronic acid for treating osteoporosis | |
| CN101565428B (en) | Preparation method of prulifloxacin | |
| CN104447758B (en) | The synthesis technique of pyrazolo [3,4 d] pyrimidines | |
| CN101778824A (en) | Process for producing toluidine compound | |
| CN101973982A (en) | Production method of fasudil hydrochloride | |
| CN106397416B (en) | A kind of preparation method of Tegafur | |
| CN106366034B (en) | A kind of preparation method of 3-Pyridineacetic Acid hydrochloride | |
| CN105837635B (en) | A kind of preparation method for being used to treat the minodronic acid of osteoporosis | |
| CN105418507A (en) | Preparation method for 1-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine | |
| CN104910068A (en) | 2-cyano isonicotinic acid hydrazide 1.5 p-toluenesulfonate synthetic method | |
| CN114230525B (en) | Preparation method of 2-amino-4, 6-dimethoxypyrimidine | |
| CN106632483A (en) | Tenofovir disoproxil preparation method | |
| CN115572747B (en) | Topiroxostat preparation method | |
| CN112920182B (en) | Preparation method of palbociclib | |
| CN109369642B (en) | Related substance of a kind of Eliquis and its preparation method and application | |
| CN110452165B (en) | Preparation method of 2-methylpyridine-4-formic acid | |
| CN105218554A (en) | The synthesis technique of 4-chlorine pyrrolo-[2,3-D] pyrimidine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20181113 |