CN108409745A - A kind of synthetic method of chloro- 7H- pyrrolo-es [2,3-d] pyrimidines of 4- - Google Patents
A kind of synthetic method of chloro- 7H- pyrrolo-es [2,3-d] pyrimidines of 4- Download PDFInfo
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- YUWMLSSCKNEVHL-UHFFFAOYSA-N O=C(Cc(cc[nH]1)c1N1)NC1=S Chemical compound O=C(Cc(cc[nH]1)c1N1)NC1=S YUWMLSSCKNEVHL-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
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- 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 4 chlorine 7H pyrrolo-es [2,3 d] pyrimidine synthetic method, the compound is synthesis treatment rheumatoid arthritis JAK inhibitor Lusos for Buddhist nun, the important intermediate of tropsch imatinib, the present invention is with chemical compounds I (4,6 dichloro, 5 allyl yl pyrimidines) it is starting material, oxidation reaction, which occurs, with ozone generates compound ii；Then with triethyl orthoformate nucleophilic substitution generation compound III occurs for compound ii；Compound III occurs nucleophilic substitution with ammonia again and generates compounds Ⅳ；Finally itself cyclization generates compound V under acidic environment, and as 4 chlorine 7H pyrrolo-es [2,3 d] pyrimidines, synthetic route is shown below.The synthesis technology raw material of the present invention is cheap to be easy to get, and synthetic route is brief, and high income at low cost is easy to industrialized production.
Description
Technical field
The present invention relates to technical field of compound preparation, more particularly to Luso is for Antibody Production Techniques among Buddhist nun, tropsch imatinib
Field, more specifically, referring to a kind of synthetic method of chloro- 7H- pyrrolo-es [2, the 3-d] pyrimidines of 4-.
Background technology
Rheumatoid arthritis (RheumatiodArthritis, RA) is a kind of chronic characterized by arthrosynovitis
Autoimmune disease.In world wide, the illness rate of RA is about the 1% of population, which is mainly shown as fatigue early period, detests
Food, general debility and fuzzy musculoskeletal symptom, until the appearance of synovitis becomes apparent, this leads to arthralgia, stiff
Hard and swelling.RA drastically influences human health all the time as chronic auto-immune disease, with to RA morbidity machines
Reason further investigation, JAK/STAT are a kind of important cytokine signaling conduction path, the U.S. related to rheumatoid arthritis
Pfizer (Pfizer) company develops small molecule JAKs kinase inhibitor tropsch imatinibs, shows to show in treating RA clinical trials
Write effect.U.S. FDA in 2012, approval tropsch imatinib is for treating moderate to severe active rheumatoid arthritis.This is also
First oral improvement state of an illness antirheumatic drug for the treatment of rheumatoid arthritis is approved for over 10 years.And 2017, U.S.'s gift
Carrying out the Luso of drugmaker will also list for Buddhist nun.
Pyrrolopyrimidine structural compounds are that have preferable physiological activity and pharmacological activity, the chloro- 7H- pyrroles of intermediate 4-
And [2,3-d] pyrimidine is that synthesis treats rheumatoid arthritis JAK inhibitor-Luso for Buddhist nun, the important centre of tropsch imatinib
Body.Reported synthetic method, there are starting material prices it is high, yield is low the problems such as.As tropsch imatinib, Luso are for the successive of Buddhist nun
Listing, both at home and abroad to the need of tropsch imatinib, bulk pharmaceutical chemicals (API) and its chloro- 7H- pyrrolo-es [2, the 3-d] pyrimidines of key intermediate 4-
It asks increasing, designs and what exploitation was efficient, economical, green meets industrialized production synthetic route, with larger economic value
And meaning.
Has pertinent literature report about the synthesis of chloro- 7H- pyrrolo-es [2,3-d] pyrimidine intermediates of 4- at present.Such as：
Pyrrolopyrimidine ketone compound, assimilation is obtained by the reaction using adjacent amino-pyrroles formic acid esters and carbonamidine in Fumeaux et al.
Object prepares target product by chlorination reaction.
Niwas et al. obtains schiff bases using adjacent amino-pyrroles formic acid esters and N,N-dimethylformamide oxalic acid aldehyde reaction
Pyrrolopyrimidine thion is obtained by the reaction in intermediate with amine again, and chloro obtains target product.
Philip et al. is that starting material is made by bromo, coupling and cyclization using 6- amino-4-hydroxy pyridines
Target product.
In above-mentioned reaction route, the yield of bromo-reaction only has 50%, and the tin being more toxic is used in coupling reaction
Reagent, total recovery only have 17%, are unfavorable for industrialized production.
It is proposed 2- cyano -4,4- diethoxy ethyl butyrates are starting material through cyclisation, intramolecular pass to Philip et al. again
Ring, desulfurization, chloro synthesising target compound.
Though this method has larger improvement compared with the former, its cost of material is still higher, and cyclization and chlorination reaction are received
Rate is low.It follows that either still synthesizing the chloro- 7H- pyrrolo-es [2,3-d] of 4- from pyrimidine ring from pyrrole ring at present
The method of pyrimidine all haves the shortcomings that expensive starting materials, is not easy to obtain and overall yield of reaction is relatively low, makes this kind of synthetic method application
It is restricted, is not suitable for industrialized production.
Xia et al. is using diethyl malonate cheap and easy to get as starting material, through cyclisation, Vilsmeier reactions, SN/Ar
Reaction, Wittings reactions, then itself cyclization obtain target compound.Specific synthetic route is as follows：
This synthetic method, route is brief, and document report often walks that yield is higher, but the by-product that wittings reacts in route
Object triphen oxygen phosphorus is difficult to remove, and is unfavorable for production purifying.
Synthetic method of the country about chloro- 7H- pyrrolo-es [2, the 3-d] pyrimidine intermediates of 4- uses in some document reports
4,6- bis- chloro- 5- allyls yl pyrimidines are starting material, carry out oxidation reaction to starting material first, react last pass with ammonia afterwards
Ring although second step ammonification cyclization document report yield is up to 80% in the synthetic route, but is attempted in multiple specific experiment
Middle yield is but less than 20%, which has that reaction yield is too low, and the synthetic route reaction condition is more complex in addition,
It has used part expensive reagent and cost is higher, has been unfavorable for industrialized production.Its synthetic route is as follows：
By the research to existing 4- chloro- 7H- pyrrolo-es [2,3-d] pyrimidine synthetic method, there is an urgent need for develop one more
Add synthetic route that is economical and eco-friendly and meeting industrialized production.
Invention content
The purpose of the present invention provides the chloro- 7H- pyrrolo-es of a kind of 4- [2,3- aiming at the problems and shortcomings present on
D] pyrimidine synthetic method, this method have synthetic route is brief, easy to operate, at low cost, high income, is easy to industrialized production
The advantages of.
To achieve the goals above, the technical solution adopted by the present invention is：
A kind of synthetic method of chloro- 7H- pyrrolo-es [2, the 3-d] pyrimidines of 4-, this method include the following steps：
A, chemical compounds I and dimethyl sulfoxide (DMSO), triethylamine are passed through ozone at low temperature and carry out ozonization, be added later
Reducing agent occurs reduction reaction and obtains compound ii, and the molar ratio of the chemical compounds I and dimethyl sulfoxide (DMSO) is 1:1, chemical compounds I with
The molar ratio of triethylamine is 1:1.5；The molar ratio of the reducing agent and chemical compounds I is 1:1, the reaction temperature is -40 DEG C, instead
It is 8 hours between seasonable；
B, compound ii is dissolved in solvent, under Catalyzed by p-Toluenesulfonic Acid effect, is condensed with triethyl orthoformate,
Obtain compound III；The solvent is dichloromethane, tetrahydrofuran or absolute ethyl alcohol, and the reaction temperature is 40 DEG C, when reaction
Between be 3 hours, the molar ratio of the compound ii and triethyl orthoformate is 1:1~2, compound ii and p-methyl benzenesulfonic acid rub
You are than being 1:1；
C, SN nucleophilic substitutions are occurred into a solvent for compound III and ammonia and generates compounds Ⅳ；The SN nucleophilics
Substitution reaction substrate is ammonia, and the solvent is absolute ethyl alcohol, methanol, isopropanol or water, and the reaction temperature is 25~60 DEG C,
Reaction time is 3 hours；
D, compounds Ⅳ in acid condition to that intramolecular cyclization occur, the chloro- 7H- pyrrolo-es of compound V i.e. 4- are obtained
[2,3-d] pyrimidine；The acid condition is hydrochloric acid solution or glacial acetic acid, and the concentration of hydrochloric acid solution is 3~6M, the reaction temperature
Degree is 25~50 DEG C, and the reaction time is 4 hours；Its building-up process is as follows：
In step a, the oxidation reaction oxidant is ozone；The reducing agent is sodium thiosulfate, Zn-AcOH, diformazan
Thioether, thiocarbamide or triphenylphosphine；After being passed through ozone, further include：It is passed through nitrogen and drives ozone away；After reduction reaction,
Further include：Organic solvent is steamed, is extracted, washing, is evaporated drying.
In step b, after the completion of the reaction, further include：Organic solvent is steamed, is extracted, washing, is evaporated, column chromatography drying
Chromatogram purification.
Further include step after the completion of the reaction in step c：Solvent evaporated, extraction, drying, are evaporated washing.
In step d, after the completion of the reaction, further include：It filters.
Beneficial effects of the present invention are as follows：
1) present invention is starting material using simple chemical compounds I (4,6- bis- chloro- 5- allyls yl pyrimidines), by ozone oxygen
Change reduction reaction, aldol condensation, SN nucleophilic displacement of fluorine and intramolecular cyclization and obtains the chloro- 7H- pyrrolo-es [2,3-d] of compound V i.e. 4-
Pyrimidine, synthetic route is brief, and high income, total recovery is up to 59%.
2) present invention is not related to the use of expensive reagent, reduces cost.
3) synthesis technology of the invention is related to easy to operate, and condition is easily-controllable, is easy to industrialized production.
Specific implementation mode
In order to which the technology contents of the present invention are expressly understood, it is further described below in conjunction with embodiment：
Embodiment 1
The synthesis of 1.1 compound iis, that is, 2- (4,6- dichloro pyrimidine) acetaldehyde
Into the 50ml three-necked bottles equipped with magnetic agitation, 20ml dichloromethane and 4, bis- chloro- 5- allyls yl pyrimidines of 6- are added
(5.0g, 0.026mol) sequentially adds dimethyl sulfoxide (DMSO) (8g, 0.104mol) and triethylamine (5.5mL, 0.040mol), cooling
To -40 DEG C, it is passed through O3Until reaction solution becomes au bleu, stop leading to O3, use N instead2Continue to be passed through 30min, O in exclusion system3。
Sodium thiosulfate (4.1g, 0.026mol) is added, is warmed to room temperature naturally, starch potassium iodide paper detects (constant indigo plant), it is ensured that is anti-
Answer system that peroxide is not present.60ml water, extraction is added, dichloromethane layer is washed with water 2 times, anhydrous sodium sulfate drying, decompression
It is concentrated to give off-white powder 3.4g, yield 68%.
1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.89(s,1H),4.24(s,2H)。
The synthesis of 1.2 compound iis, that is, 2- (4,6- dichloro pyrimidine) acetaldehyde
Into the 50ml three-necked bottles equipped with magnetic agitation, 20ml dichloromethane and 4, bis- chloro- 5- allyls yl pyrimidines of 6- are added
(5.0g, 0.026mol) sequentially adds dimethyl sulfoxide (DMSO) (8g, 0.104mol) and triethylamine (5.5mL, 0.040mol), cooling
To -40 DEG C, it is passed through O3Until reaction solution becomes au bleu, stop leading to O3, use N instead2Continue to be passed through 30min, O in exclusion system3。
It is warmed to room temperature, solvent evaporated, Zn powder (1.7g, 0.026mol) and acetic acid (15mL) is added, starch potassium iodide paper detection is (constant
It is blue), it is ensured that peroxide is not present in reaction system.It filters, mother liquor is concentrated under reduced pressure to give off-white powder 2.3g, yield 46%.
1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.89(s,1H),4.24(s,2H)。
The synthesis of 1.3 compound iis, that is, 2- (4,6- dichloro pyrimidine) acetaldehyde
Into the 50ml three-necked bottles equipped with magnetic agitation, 20ml dichloromethane and 4, bis- chloro- 5- allyls yl pyrimidines of 6- are added
(5.0g, 0.026mol) sequentially adds dimethyl sulfoxide (DMSO) (8g, 0.104mol) and triethylamine (5.5mL, 0.040mol), cooling
To -40 DEG C, it is passed through O3Until reaction solution becomes au bleu, stop leading to O3, use N instead2Continue to be passed through 30min, O in exclusion system3。
Dimethyl sulphide (1.6g, 0.026mol) is added, is warmed to room temperature naturally, starch potassium iodide paper detects (constant indigo plant), it is ensured that reaction
Peroxide is not present in system.60ml water, extraction is added, dichloromethane layer is washed with water 2 times, anhydrous sodium sulfate drying, and decompression is dense
Contracting obtains off-white powder 3.7g, yield 74%.
1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.89(s,1H),4.24(s,2H)。
The synthesis of 1.4 compound iis, that is, 2- (4,6- dichloro pyrimidine) acetaldehyde
Into the 50ml three-necked bottles equipped with magnetic agitation, 20ml dichloromethane and 4, bis- chloro- 5- allyls yl pyrimidines of 6- are added
(5.0g, 0.026mol) sequentially adds dimethyl sulfoxide (DMSO) (8g, 0.104mol) and triethylamine (5.5mL, 0.040mol), cooling
To -40 DEG C, it is passed through O3Until reaction solution becomes au bleu, stop leading to O3, use N instead2Continue to be passed through 30min, O in exclusion system3。
Thiocarbamide (2.0g, 0.026mol) is added, is warmed to room temperature naturally, starch potassium iodide paper detects (constant indigo plant), it is ensured that reaction system
There is no peroxide.60ml water, extraction is added, dichloromethane layer is washed with water 2 times, and anhydrous sodium sulfate drying is concentrated under reduced pressure
To off-white powder 4.4g, yield 88%.
1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.89(s,1H),4.24(s,2H)。
The synthesis of 1.5 compound iis, that is, 2- (4,6- dichloro pyrimidine) acetaldehyde
Into the 50ml three-necked bottles equipped with magnetic agitation, 20ml dichloromethane and 4, bis- chloro- 5- allyls yl pyrimidines of 6- are added
(5.0g, 0.026mol) sequentially adds dimethyl sulfoxide (DMSO) (8g, 0.104mol) and triethylamine (5.5mL, 0.040mol), cooling
To -40 DEG C, it is passed through O3Until reaction solution becomes au bleu, stop leading to O3, use N instead2Continue to be passed through 30min, O in exclusion system3。
Triphenylphosphine (6.8g, 0.026mol) is added, is warmed to room temperature naturally, starch potassium iodide paper detects (constant indigo plant), it is ensured that reaction
Peroxide is not present in system.60ml water, extraction is added, dichloromethane layer is washed with water 2 times, anhydrous sodium sulfate drying, and decompression is dense
Contracting obtains off-white powder 3.2g, yield 65%.
1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.89(s,1H),4.24(s,2H)。
Embodiment 2
The synthesis of 2.1 i.e. 4, the 6- of compound III, bis- chloro- 5- (2,2- diethoxy ethyl) pyrimidines
Into the 100ml three-necked bottles equipped with magnetic agitation, addition 2- (4,6- dichloro pyrimidine) acetaldehyde (5.4g,
0.028mol), triethyl orthoformate (8.5g, 0.057mol), p-methyl benzenesulfonic acid (0.27g, 0.028mol), is dissolved in 30mL dichloros
Methane, system are heated to 40 DEG C, insulation reaction 3h.4mL triethylamines are added into reaction system, concentrate reaction system, second is added
Acetoacetic ester extracts, and washes 2 times, separates organic phase, and anhydrous sodium sulfate drying is evaporated；Use petroleum ether and ethyl acetate ratio for 5:1
Column chromatography chromatogram purifying is carried out, colourless oil liquid 4.1g, yield 55% are obtained.
1H NMR (400MHz, CDCl3) δ 8.60 (s, 1H), 4.76 (t, J=5.7Hz, 1H), 3.62-3.69 (m, 2H),
3.36-3.44 (m, 2H), 3.20 (d, J=5.7Hz, 2H), 1.08 (t, J=7.0Hz, 6H).
The synthesis of 2.2 i.e. 4, the 6- of compound III, bis- chloro- 5- (2,2- diethoxy ethyl) pyrimidines
Into the 100ml three-necked bottles equipped with magnetic agitation, addition 2- (4,6- dichloro pyrimidine) acetaldehyde (5.4g,
0.028mol), triethyl orthoformate (8.5g, 0.057mol), p-methyl benzenesulfonic acid (0.27g, 0.028mol), is dissolved in 30mL tetrahydrochysenes
Furans, system are heated to 40 DEG C, insulation reaction 3h.4mL triethylamines are added into reaction system, concentrate reaction system, second is added
Acetoacetic ester extracts, and washes 2 times, separates organic phase, and anhydrous sodium sulfate drying is evaporated；Use petroleum ether and ethyl acetate ratio for 5:1
Column chromatography chromatogram purifying is carried out, colourless oil liquid 5.9g, yield 79% are obtained.
1H NMR (400MHz, CDCl3) δ 8.60 (s, 1H), 4.76 (t, J=5.7Hz, 1H), 3.62-3.69 (m, 2H),
3.36-3.44 (m, 2H), 3.20 (d, J=5.7Hz, 2H), 1.08 (t, J=7.0Hz, 6H).
The synthesis of 2.3 i.e. 4, the 6- of compound III, bis- chloro- 5- (2,2- diethoxy ethyl) pyrimidines
Into the 100ml three-necked bottles equipped with magnetic agitation, addition 2- (4,6- dichloro pyrimidine) acetaldehyde (5.4g,
0.028mol), triethyl orthoformate (8.5g, 0.057mol), p-methyl benzenesulfonic acid (0.27g, 0.028mol), it is anhydrous to be dissolved in 30mL
Ethyl alcohol, system are heated to 40 DEG C, insulation reaction 3h.4mL triethylamines are added into reaction system, concentrate reaction system, second is added
Acetoacetic ester extracts, and washes 2 times, separates organic phase, and anhydrous sodium sulfate drying is evaporated；Use petroleum ether and ethyl acetate ratio for 5:1
Column chromatography chromatogram purifying is carried out, colourless oil liquid 6.2g, yield 84% are obtained.
1H NMR (400MHz, CDCl3) δ 8.60 (s, 1H), 4.76 (t, J=5.7Hz, 1H), 3.62-3.69 (m, 2H),
3.36-3.44 (m, 2H), 3.20 (d, J=5.7Hz, 2H), 1.08 (t, J=7.0Hz, 6H).
The synthesis of 2.4 i.e. 4, the 6- of compound III, bis- chloro- 5- (2,2- diethoxy ethyl) pyrimidines
Into the 100ml three-necked bottles equipped with magnetic agitation, addition 2- (4,6- dichloro pyrimidine) acetaldehyde (5.4g,
0.028mol), triethyl orthoformate (4.2g, 0.028mol), p-methyl benzenesulfonic acid (0.27g, 0.028mol), it is anhydrous to be dissolved in 30mL
Ethyl alcohol, system are heated to 40 DEG C, insulation reaction 3h.4mL triethylamines are added into reaction system, concentrate reaction system, second is added
Acetoacetic ester extracts, and washes 2 times, separates organic phase, and anhydrous sodium sulfate drying is evaporated；Use petroleum ether and ethyl acetate ratio for 5:1
Column chromatography chromatogram purifying is carried out, colourless oil liquid 3.9g, yield 53% are obtained.
1H NMR (400MHz, CDCl3) δ 8.60 (s, 1H), 4.76 (t, J=5.7Hz, 1H), 3.62-3.69 (m, 2H),
3.36-3.44 (m, 2H), 3.20 (d, J=5.7Hz, 2H), 1.08 (t, J=7.0Hz, 6H).
Embodiment 3
The synthesis of the 3.1 compounds Ⅳs, that is, chloro- 5- of 4- amino -6- (2,2- diethoxies ethyl) pyrimidine
In the 100ml three-necked bottles equipped with magnetic agitation, by 4,6-, bis- chloro- 5- (2,2- diethoxy ethyl) pyrimidine (5g,
30mL absolute ethyl alcohols 0.019mol) are dissolved in, 60 DEG C is warming up to, is continually fed into NH3Stir 3h.Reaction solution concentrates, and 30mL second is added
Acetoacetic ester, organic phase are washed 2 times, and anhydrous sodium sulfate drying is evaporated to obtain 3.4g products, yield 73%.
1H NMR (400MHz, DMSO) δ 8.09 (s, 1H), 7.01 (br, 2H), 4.67 (t, J=5.5Hz, 1H), 3.59-
3.68 (m, 2H), 3.39-3.47 (m, 2H), 2.88 (d, J=5.5Hz, 2H), 1.06 (t, J=7.0Hz, 6H).
The synthesis of the 3.2 compounds Ⅳs, that is, chloro- 5- of 4- amino -6- (2,2- diethoxies ethyl) pyrimidine
In the 100ml three-necked bottles equipped with magnetic agitation, by 4,6-, bis- chloro- 5- (2,2- diethoxy ethyl) pyrimidine (5g,
It 0.019mol) is dissolved in 30mL methanol, 60 DEG C is warming up to, is continually fed into NH3Stir 3h.Reaction solution concentrates, and 30mL acetic acid second is added
Ester, organic phase are washed 2 times, and anhydrous sodium sulfate drying is evaporated to obtain 3.3g products, yield 70%.
1H NMR (400MHz, DMSO) δ 8.09 (s, 1H), 7.01 (br, 2H), 4.67 (t, J=5.5Hz, 1H), 3.59-
3.68 (m, 2H), 3.39-3.47 (m, 2H), 2.88 (d, J=5.5Hz, 2H), 1.06 (t, J=7.0Hz, 6H).
The synthesis of the 3.3 compounds Ⅳs, that is, chloro- 5- of 4- amino -6- (2,2- diethoxies ethyl) pyrimidine
In the 100ml three-necked bottles equipped with magnetic agitation, by 4,6-, bis- chloro- 5- (2,2- diethoxy ethyl) pyrimidine (5g,
30mL isopropanols 0.019mol) are dissolved in, 60 DEG C is warming up to, is continually fed into NH3Stir 3h.Reaction solution concentrates, and 30mL acetic acid is added
Ethyl ester, organic phase are washed 2 times, and anhydrous sodium sulfate drying is evaporated to obtain 3.7g products, yield 79%.
1H NMR (400MHz, DMSO) δ 8.09 (s, 1H), 7.01 (br, 2H), 4.67 (t, J=5.5Hz, 1H), 3.59-
3.68 (m, 2H), 3.39-3.47 (m, 2H), 2.88 (d, J=5.5Hz, 2H), 1.06 (t, J=7.0Hz, 6H).
The synthesis of the 3.4 compounds Ⅳs, that is, chloro- 5- of 4- amino -6- (2,2- diethoxies ethyl) pyrimidine
In the 100ml three-necked bottles equipped with magnetic agitation, 4,6- bis- chloro- 5- (2,2- diethoxy ethyl) pyrimidine is added
(5g, 0.019mol), ammonium hydroxide 30mL is warming up to 60 DEG C of stirring 3h.The extraction of 30mL ethyl acetate is added, organic phase is washed 2 times, nothing
Aqueous sodium persulfate is dried, and is evaporated to obtain 4.1g products, yield 87%.
1H NMR (400MHz, DMSO) δ 8.09 (s, 1H), 7.01 (br, 2H), 4.67 (t, J=5.5Hz, 1H), 3.59-
3.68 (m, 2H), 3.39-3.47 (m, 2H), 2.88 (d, J=5.5Hz, 2H), 1.06 (t, J=7.0Hz, 6H).
The synthesis of the 3.5 compounds Ⅳs, that is, chloro- 5- of 4- amino -6- (2,2- diethoxies ethyl) pyrimidine
In the 100ml three-necked bottles equipped with magnetic agitation, 4,6- bis- chloro- 5- (2,2- diethoxy ethyl) pyrimidine is added
(5g, 0.019mol), ammonium hydroxide 30mL is warming up to 40 DEG C of stirring 3h.The extraction of 30mL ethyl acetate is added, organic phase is washed 2 times, nothing
Aqueous sodium persulfate is dried, and is evaporated to obtain 3.8g products, yield 81%.
1H NMR (400MHz, DMSO) δ 8.09 (s, 1H), 7.01 (br, 2H), 4.67 (t, J=5.5Hz, 1H), 3.59-
3.68 (m, 2H), 3.39-3.47 (m, 2H), 2.88 (d, J=5.5Hz, 2H), 1.06 (t, J=7.0Hz, 6H).
The synthesis of the 3.6 compounds Ⅳs, that is, chloro- 5- of 4- amino -6- (2,2- diethoxies ethyl) pyrimidine
In the 100ml three-necked bottles equipped with magnetic agitation, 4,6- bis- chloro- 5- (2,2- diethoxy ethyl) pyrimidine is added
(5g, 0.019mol), ammonium hydroxide 30mL, is stirred at room temperature 3h.The extraction of 30mL ethyl acetate is added, organic phase is washed 2 times, anhydrous slufuric acid
Sodium is dried, and is evaporated to obtain 3.2g products, yield 68%.
1H NMR (400MHz, DMSO) δ 8.09 (s, 1H), 7.01 (br, 2H), 4.67 (t, J=5.5Hz, 1H), 3.59-
3.68 (m, 2H), 3.39-3.47 (m, 2H), 2.88 (d, J=5.5Hz, 2H), 1.06 (t, J=7.0Hz, 6H).
Embodiment 4
4.1 compounds V are the synthesis of chloro- 7H- pyrrolo-es [2,3-d] pyrimidines of 4-
The chloro- 5- of 4- amino -6- (2,2- diethoxy ethyl) pyrimidine (10.0g, 0.041mol) is dissolved in 30mL 3M hydrochloric acid
In, 50 DEG C, insulated and stirred 4h are heated to, there is solid precipitation in system, is filtered, gained filter cake dries to obtain the solid 4.9g of white, receives
Rate 78%.
1H NMR (400MHz, DMSO-d6) δ 12.59 (s, 1H), 8.61 (s, 1H), 7.71 (d, J=3.5Hz, 1H),
6.62 (d, J=3.5Hz, 1H).
4.2 compounds V are the synthesis of chloro- 7H- pyrrolo-es [2,3-d] pyrimidines of 4-
The chloro- 5- of 4- amino -6- (2,2- diethoxy ethyl) pyrimidine (10.0g, 0.041mol) is dissolved in 30mL 6M hydrochloric acid
In, 50 DEG C, insulated and stirred 4h are heated to, there is solid precipitation in system, is filtered, gained filter cake dries to obtain white solid 5.8g,
Yield 92%.
1H NMR(400MHz,DMSO-d6) δ 12.59 (s, 1H), 8.61 (s, 1H), 7.71 (d, J=3.5Hz, 1H), 6.62
(d, J=3.5Hz, 1H).
4.3 compounds V are the synthesis of chloro- 7H- pyrrolo-es [2,3-d] pyrimidines of 4-
The chloro- 5- of 4- amino -6- (2,2- diethoxy ethyl) pyrimidine (10.0g, 0.041mol) is dissolved in 30mL glacial acetic acids,
50 DEG C, insulated and stirred 4h are heated to, there is solid precipitation in system, is filtered, gained filter cake dries to obtain white solid 3.9g, yield
62%.
1H NMR (400MHz, DMSO-d6) δ 12.59 (s, 1H), 8.61 (s, 1H), 7.71 (d, J=3.5Hz, 1H),
6.62 (d, J=3.5Hz, 1H).
4.4 compounds V are the synthesis of chloro- 7H- pyrrolo-es [2,3-d] pyrimidines of 4-
The chloro- 5- of 4- amino -6- (2,2- diethoxy ethyl) pyrimidine (10.0g, 0.041mol) is dissolved in 30mL 6M hydrochloric acid
In, 4h is stirred at room temperature, there is solid precipitation in system, filters, gained filter cake dries to obtain white solid 4.7g, yield 75%.
1H NMR(400MHz,DMSO-d6) δ 12.59 (s, 1H), 8.61 (s, 1H), 7.71 (d, J=3.5Hz, 1H), 6.62
(d, J=3.5Hz, 1H).
In conclusion the synthetic method of chloro- 7H- pyrrolo-es [2, the 3-d] pyrimidines of 4- of the present invention have synthetic route it is brief,
It is easy to operate, at low cost, yield is high, is easy to the advantages of industrialized production.
The present invention is described in detail above, its object is to allow the skilled worker for being familiar with the field that can understand this
The content of invention is simultaneously implemented, and it is not intended to limit the scope of the present invention, all Spirit Essence institutes according to the present invention
The equivalent change or modification of work should all cover within the scope of the present invention.
Claims (5)
1. a kind of synthetic method of chloro- 7H- pyrrolo-es [2, the 3-d] pyrimidines of 4-, which is characterized in that this method includes the following steps：
A, chemical compounds I and dimethyl sulfoxide (DMSO), triethylamine are passed through ozone at low temperature and carry out ozonization, reduction is added later
Agent occurs reduction reaction and obtains compound ii, and the molar ratio of the chemical compounds I and dimethyl sulfoxide (DMSO) is 1:1, chemical compounds I and three second
The molar ratio of amine is 1:1.5；The molar ratio of the reducing agent and chemical compounds I is 1:1, the reaction temperature is -40 DEG C, when reaction
Between be 8 hours；
B, compound ii is dissolved in solvent, under Catalyzed by p-Toluenesulfonic Acid effect, is condensed, obtains with triethyl orthoformate
Compound III；The solvent is dichloromethane, tetrahydrofuran or absolute ethyl alcohol, and the reaction temperature is 40 DEG C, and the reaction time is
3 hours, the molar ratio of the compound ii and triethyl orthoformate was 1:1~2, the molar ratio of compound ii and p-methyl benzenesulfonic acid
It is 1:1；
C, SN nucleophilic substitutions are occurred into a solvent for compound III and ammonia and generates compounds Ⅳ；The SN nucleophilic displacement of fluorine
Reaction substrate is ammonia, and the solvent is absolute ethyl alcohol, methanol, isopropanol or water, and the reaction temperature is 25~60 DEG C, reaction
Time is 3 hours；
D, compounds Ⅳ in acid condition to that intramolecular cyclization occur, the chloro- 7H- pyrrolo-es of compound V i.e. 4- [2,3- are obtained
D] pyrimidine；The acid condition is hydrochloric acid solution or glacial acetic acid, and the concentration of hydrochloric acid solution is 3~6M, and the reaction temperature is
25~50 DEG C, the reaction time is 4 hours；Its building-up process is as follows：
2. synthetic method according to claim 1, which is characterized in that in step a, the oxidation reaction oxidant is smelly
Oxygen；The reducing agent is sodium thiosulfate, Zn-AcOH, dimethyl sulphide, thiocarbamide or triphenylphosphine；After being passed through ozone, also
Including：It is passed through nitrogen and drives ozone away；After reduction reaction, further include：Organic solvent is steamed, is extracted, washing, is evaporated drying.
3. synthetic method according to claim 1, which is characterized in that in step b, after the completion of the reaction, further include：It steams
Go out organic solvent, extract, washing, is evaporated drying, column chromatography chromatogram purifying.
4. synthetic method according to claim 1, which is characterized in that further include step after the completion of the reaction in step c
Suddenly：Solvent evaporated, extraction, drying, are evaporated washing.
5. synthetic method according to claim 1, which is characterized in that in step d, after the completion of the reaction, further include：It takes out
Filter.
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| CN111423445A (en) * | 2020-05-11 | 2020-07-17 | 安徽赛迪生物科技有限公司 | Synthetic method of 4-chloro-5, 7-dihydro-6H-pyrrolo [2, 3-D ] pyrimidine-6-ketone |
| CN111454215A (en) * | 2020-04-28 | 2020-07-28 | 爱斯特（成都）生物制药股份有限公司 | Process for synthesizing 2- (4, 6-dichloropyrimidin-5-yl) acetaldehyde by continuous flow ozone oxidation |
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| CN107011347A (en) * | 2017-04-18 | 2017-08-04 | 华东师范大学 | A kind of synthetic method of 4 chlorine 7H pyrrolo-es [2,3 d] pyrimidines |
| CN107827893A (en) * | 2017-11-10 | 2018-03-23 | 常州齐晖药业有限公司 | A kind of preparation method of 4 chlorine 7H pyrrolo-es [2,3 d] pyrimidines |
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Cited By (3)
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| CN111454215A (en) * | 2020-04-28 | 2020-07-28 | 爱斯特（成都）生物制药股份有限公司 | Process for synthesizing 2- (4, 6-dichloropyrimidin-5-yl) acetaldehyde by continuous flow ozone oxidation |
| CN111454215B (en) * | 2020-04-28 | 2023-07-07 | 爱斯特（成都）生物制药股份有限公司 | Process for synthesizing 2- (4, 6-dichloropyrimidine-5-yl) acetaldehyde by continuous flow ozone oxidation |
| CN111423445A (en) * | 2020-05-11 | 2020-07-17 | 安徽赛迪生物科技有限公司 | Synthetic method of 4-chloro-5, 7-dihydro-6H-pyrrolo [2, 3-D ] pyrimidine-6-ketone |
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