CN109796453A - A kind of preparation method of 1,7- dimethyl xanthine - Google Patents
A kind of preparation method of 1,7- dimethyl xanthine Download PDFInfo
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Abstract
The present invention provides the preparation method of one kind 1,7- dimethyl xanthine, specifically: firstly, existing in alkali or under the conditions of alkali-free, will react to obtain compound (II) with methylating reagent in compound (III) Yu Yiding solvent；Then, under the conditions of existing for the catalytic hydrogenolysis reagent or lewis acid or lewis acid and silane reducing agent, deprotection obtains 1,7- dimethyl xanthine (I) in compound (III) Yu Yiding solvent.Method of the invention is simple and easy, process stabilizing, easily controllable, post-reaction treatment is convenient, product yield is good, it is with high purity, can economy be advantageously used in industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to the preparation method of one kind 1,7- dimethyl xanthine.
Background technique
Methyl xanthine Alkaloid is a kind of natural alkaloid with xanthine ring structure.Wherein, 1,3,7- front threes
(theobromine is beverage or sweet tea for base xanthine (caffeine), 1,3- dimethyl xanthine (theophylline) and 3,7- dimethyl xanthine
Important composition ingredient in point, structural formula difference are as follows:
Within a very long time, an important member 1 of family, 7- dimethyl xanthine (paraxanthine) is always
It is considered being not present in plant, structural formula is as follows:
Until 1998, Jiang etc. has found paraxanthine from menispermaceous plants sinomenium acutum.It is reported that paraxanthine is
One of the major metabolite of caffeine in vivo.In the crowd of normal edible caffeine group food, paraxanthine in serum
Content be the 2/3 of content of caffeine.1,7- dimethyl xanthine has a series of important physiological actions, such as:
1. being used as emulative non-selection phosphonic acid diester enzyme inhibitor, cAMP intracellular can be improved, activate PKA, inhibit
TNF-alpha and leukotriene synthesis, reduce the generation of inflammation and inherent immunity；
2. being used as non-selective adenosine receptor antagonist, plasma epinephrine and diastole pressure are increased；
3. reducing fat, the presence in blood plasma can increase the content of free fatty acids in blood plasma；
4. being used as Na+/K+The enzyme effect device of pump promotes kalium ion transport into skeletal muscle tissue.Equally also stimulation improves
The content of calcium ion in muscle.
Paraxanthine natural origin is limited, extraction process is complicated.Pass through bioconversion at present for natural materials such as caffeines
Be transformed into paraxanthine low efficiency, it is at high cost, be difficult to industrialize.Preparation method existing research in relation to 1,7- dimethyl xanthine
Report.1991, Fujii etc. in Chem.Pharm.Bull.1991,39,2855-2862 report by hydrolysis 7- methyl gland it is fast
Cyclization takes off the method for benzyl preparation 1,7- dimethyl xanthine again after purine benzyl salt derivative, and reaction route is as follows:
The major defect of above-mentioned route is as follows:
(1) raw material 7- methyl adenine benzyl salt derivative preparation can not amplify, and its raw material commercial-free source of goods；
(2) first step hydrolysis working conditions are harsh, and production is not easy to realize；
(3) it is relatively low to take off benzyl yield for final step.
2017, Zhang etc. reported preparation 1,7- dimethyl on Chem.Commun.2017,53,3637-3640
Another route of xanthine prepares 1,7- dimethyl xanthine by pass pyrimidine ring, and cyclization yield is only 56%, and main former
The auxiliary material commercial-free source of goods, reaction route are as follows:
The chloro- 7- first of 1,3- bis- of other routes such as Monatshefte fur Chemie 1985,116,341-351 report
Base purine method or the equal commercial-free source of goods of methyl-isorhodanate methyl esters primary raw material, and or yield it is low, condition is harsh or uses
To the reagent of severe toxicity, without industrial value.
Therefore, it is urgent to provide supplementary materials preparation 1 cheap and easy to get, easy to operate, suitable for industrialized production, 7- bis-
The synthetic route of methyl xanthine.
Summary of the invention
In view of the deficiencies of the prior art, the object of the present invention is to provide a kind of simple and easy, process stabilizing, it is easily controllable,
Post-reaction treatment is convenient, product yield is good, it is with high purity, can economy be advantageously used in industrialized production 1,7- dimethyl yellow it is fast
The preparation method of purine；Raw material of the invention can easily be prepared with bibliography.
To realize the above-mentioned technical purpose, the invention adopts the following technical scheme:
The preparation method of one kind 1,7- dimethyl xanthine, the method comprise the steps of:
Step a: it under the conditions of alkali presence or alkali-free, is reacted in compound (III) Yu Yiding solvent with methylating reagent
To compound (II)；
Step b: under the conditions of felicity condition, deprotection obtains 1,7- dimethyl yellow in compound (III) Yu Yiding solvent
Purine (I)；
Reaction route is as follows:
Wherein, R=benzyl, to methoxy-benzyl, 2,4- dimethoxy-benzyl.
Wherein, in step a, the methylating reagent is iodomethane, dimethyl suflfate, dimethyl carbonate, tripotassium phosphate
One of ester and Methyl triflate are a variety of, preferably dimethyl suflfate and iodomethane；The alkali is sodium bicarbonate, carbon
Sour sodium, saleratus, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide,
Magnesium hydroxide, calcium hydroxide, tert-butyl alcohol magnesium, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, triethylamine, diethylamine, diformazan
Amine, trimethylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1,8- diazabicyclo [5.4.0]
One of 11 carbon -7- alkene, 1,5- diazabicyclo [4.3.0] nonyl- 5- alkene or 1,4- diazabicylo [2.2.2] octane
Or a variety of, preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropyl
One of base ethylamine or 4-dimethylaminopyridine are a variety of；
The solvent be selected from benzene, toluene, chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, isopropyl acetate,
2- butanone, acetone, 1,2- dimethyl -2- imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N, N- bis-
Methylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyridine, methanol, ethyl alcohol,
Isopropanol, n-butanol, ethylene glycol, the tert-butyl alcohol, tert-pentyl alcohol, polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, diethyl two
Diethylene glycol dimethyl ether, 1,2- propylene glycol, diethoxymethane, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- methyl
One of tetrahydrofuran, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, chloroform, ethyl acetate or water are a variety of；
Preferably toluene, acetonitrile, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N- methylpyrrole
One of alkanone, tetrahydrofuran, 2- methyltetrahydrofuran, diethoxymethane or water are a variety of.
Wherein, the molar feed ratio of the methylating reagent and compound (III) are 2-20:1, preferably 2-5:1；It is described
The molar ratio of alkali and compound (III) are 2-20:1, preferably 2-5:1；0-150 is selected from described in the reaction temperature of step 1
DEG C, preferably 20-100 DEG C；Reaction time 0.5-36 hour, preferably 1-24 hour.
Wherein, in step b, the felicity condition can be given for catalytic hydrogenolysis condition such as Pd-C/ hydrogen donor, palladium black/hydrogen
Give body, Raney Ni/hydrogen donor or Pd (OH)2One of/hydrogen donor is a variety of；Preferably Pd- C/ hydrogen donor, Pd
(OH)2/ hydrogen donor or palladium black/hydrogen donor；The felicity condition may be lewis acid such as acetic acid, trifluoroacetic acid, three
One of fluorine methanesulfonic acid, sulfuric acid, hydrochloric acid, alchlor, Boron tribromide, boron chloride or boron trifluoride are a variety of, preferably
One of trifluoroacetic acid, hydrochloric acid, alchlor or Boron tribromide are a variety of；When being elected as catalytic hydrogenolysis condition, the metal
The mass ratio that feeds intake with compound (II) is 0.005-0.5:1, preferably 0.01-0.2:1；When being elected as lewis acid condition,
The molar ratio of the acid and compound (II) are 1-20:1, preferably 1-5:1；When being elected as lewis acid, it can also add
Enter silane reducing agent such as triethylsilane, tri isopropyl silane, tri-phenyl-silane, dimethylphenylsilaneand, 1,1,3,3- tetramethyl
One of base disiloxane is a variety of, and the molar ratio of the silane reducing agent and compound (II) are 0.5- 20:1, excellent
It is selected as 0.8-5:1.
Wherein, in step b, the solvent is selected from benzene, toluene, chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, acetic acid second
Ester, isopropyl acetate, 2- butanone, acetone, 1,2- dimethyl -2- imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl
Phosphamide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyrrole
Pyridine, methanol, ethyl alcohol, isopropanol, n-butanol, ethylene glycol, the tert-butyl alcohol, tert-pentyl alcohol, polyethylene glycol, glycol monoethyl ether, ethylene glycol
Dimethyl ether, diethylene glycol dimethyl ether, 1,2- propylene glycol, diethoxymethane, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether,
Tetrahydrofuran, 2- methyltetrahydrofuran, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, chloroform, acetic acid, hydrochloric acid, three
One of fluoroacetic acid or water are a variety of；Preferably toluene, acetonitrile, methanol, ethyl alcohol, glycol dimethyl ether, N, N- dimethyl methyl
One of amide, N-Methyl pyrrolidone, tetrahydrofuran, 2- methyltetrahydrofuran, hydrochloric acid, trifluoroacetic acid or water are a variety of.
Wherein, in step b, 0-150 DEG C, preferably 20-120 DEG C is selected from described in reaction temperature；Reaction time, 0.5-36 was small
When, preferably 1-24 hours.
Compared with prior art, the invention has the following advantages: supplementary material of the invention is cheap and easy to get or be easy to make
Standby, reaction condition is mild, good, the high income of selectivity；By crystallization purifying intermediate and product, column is avoided to chromatograph, is suitble to industry
Change.
Specific embodiment
The present invention is further illustrated below with reference to embodiment, following implementation only describes this by way of example
Invention.These embodiments are not meant to be limited the present invention.It is obvious that those of ordinary skill in the art can be
In the scope of the present invention and essence, various flexible and modification is carried out to the present invention.It is to be understood that this invention is intended to cover
The accommodation and modification for including in the appended claims.
Raw material 3- substituted benzyl xanthine used in the present invention can refer to Green Chem.2012,14,296-
299, the documents such as J.Med.Chem.2009,52,6433-6446 are easily prepared.
The synthesis of 1 3- of embodiment (4- methoxy-benzyl) xanthine
Raw material 6- amino -1- (4- methoxy-benzyl) pyrimidine can refer to Green Chem.2012,14,296-299 synthesis.
6- amino -1- (4- methoxy-benzyl) pyrimidine (10g, 40.4mmol) is suspended in water (100mL), and acetic acid is added
(100mL), is warming up to 65-75 DEG C.Sodium nitrite (5.5g, 80mmol) aqueous solution (20mL) is added.It is cooled to 20-30 DEG C, is stirred
It mixes 1 hour.It is cooled to 0-10 DEG C, it is phonetic to obtain violet solid 6- amino -1- (4- methoxy-benzyl) -5- nitroso for filtering after drying
Pyridine 10g, yield 90%.
6- amino -1- (4- methoxy-benzyl) -5- nitrous yl pyrimidines (10g, 36.4mmol) be suspended in ammonium hydroxide (10%,
In 100mL), it is warming up to 50-60 DEG C, Na is added portionwise2S2O4(19g, 109.2mmol).50-60 DEG C is heated 2 hours, is cooled to
20-30℃.Filtering obtains celadon solid 5,6- diaminostilbene-(4- methoxy-benzyl)-pyrimidine 8.59g, yield after drying
90%.
5,6- diaminostilbenes-(4- methoxy-benzyl)-pyrimidine (10g, 38.1mmol) is suspended in triethyl orthoformate
In (100g, 675mmol), it is warming up to 110-120 DEG C, is stirred 8 hours.It is cooled to 20-30 DEG C.It is solid to obtain yellow for filtering after drying
Body 3- (4- methoxy-benzyl) xanthine 9.34g, yield 90%.1H NMR(500 MHz,DMSO-d6)3.71(s,3H),5.05
(s, 2H), 6.85 (d, 2H, J=8.5Hz), 7.30 (d, 2H, J=8.5Hz), 7.98 (s, 1), 11.01 (s, 1), 13.42 (s,
1H)。
Similar operation can be used to synthesize 3- (2,4- dimethoxy-benzyl) xanthine.1H NMR(500MHz, DMSO-
d6) δ 3.71 (s, 3H), 3.78 (s, 3H), 5.05 (s, 2H), 6.41 (dd, 1H, J=8.1,2.4Hz), 6.44 (d, 1H, J=
2.3Hz), 7.08 (d, 1H, J=8.1Hz), 7.98 (s, 1), 11.01 (s, 1), 13.42 (s, 1 H).
The preparation of 2 1,7- dimethyl xanthine of embodiment
3- benzyl xanthine (10g, 41.3mmol) is dissolved in DMF (100mL), addition potassium carbonate (17.1 g,
123.9mmol), iodomethane (17.6g, 123.9mmol).100-110 DEG C is warming up to react 4 hours.It is cooled to 20-30 DEG C, it is dense
Methylene chloride/water liquid separation is added after contracting.Off-white powder 3- benzyl -1,7- is beaten to obtain with methyl tertiary butyl ether(MTBE) after organic phase concentration
Dimethyl xanthine 10g, yield 90%.
3- benzyl -1,7- dimethyl xanthine (10g, 37.2mmol) is suspended in toluene (150mL), and alchlor is added
(10g, 74.4mmol).It is warming up to 80 DEG C to react 1 hour, TLC shows fully reacting.It is cooled to 0-10 DEG C, water is added dropwise
(150mL) is stirred 2 hours.Off-white powder 1 is beaten to obtain with ethyl alcohol after filtering, 7- dimethyl xanthine 5.7g, yield 85%,
Purity 98%.1H-NMR(400MHz,DMSO- d6):δ11.82(s,1H),7.90(s,1H),3.84(s,3H),3.16(s,
3H)。
The preparation of 3 1,7- dimethyl xanthine of embodiment
3- benzyl xanthine (10g, 41.3mmol) is dissolved in DMF (100mL), addition potassium carbonate (17.1 g,
123.9mmol), iodomethane (17.6g, 123.9mmol).100-110 DEG C is warming up to react 4 hours.It is cooled to 20-30 DEG C, it is dense
Methylene chloride/water liquid separation is added after contracting.Off-white powder 3- benzyl -1,7- is beaten to obtain with methyl tertiary butyl ether(MTBE) after organic phase concentration
Dimethyl xanthine 10g, yield 90%.
3- benzyl -1,7- dimethyl xanthine (10g, 37.2mmol) is suspended in toluene (150mL), and Boron tribromide is added
(18.6g, 74.4mmol).It is warming up to 80 DEG C to react 2 hours, TLC shows fully reacting.It is cooled to 0-10 DEG C, water is added dropwise
(150mL) is stirred 2 hours.Off-white powder 1 is beaten to obtain with ethyl alcohol after filtering, 7- dimethyl xanthine 6.0g, yield 90%,
Purity 98%.
The preparation of 4 1,7- dimethyl xanthine of embodiment
3- (4- methoxy-benzyl) xanthine (10g, 36.7mmol) is dissolved in acetonitrile (100mL), and sodium hydroxide is added
(5.87g, 146.8mmol), dimethyl suflfate (18.5g, 146.8mmol).80-90 DEG C is warming up to react 4 hours.It is cooled to
20-30 DEG C, methylene chloride/water liquid separation is added after concentration.Off-white powder is beaten to obtain with methyl tertiary butyl ether(MTBE) after organic phase concentration
3- (4- methoxy-benzyl) -1,7- dimethyl xanthine, 9.4 g, yield 85%.
3- (4- methoxy-benzyl) -1,7- dimethyl xanthine (10g, 33.3mmol) is dissolved in trifluoroacetic acid (100 mL)
In, it is warming up to back flow reaction 20 hours, TLC shows fully reacting.It is cooled to 20-30 DEG C, with methylene chloride/water point after concentration
Liquid, sodium bicarbonate wash organic phase.Off-white powder 1,7- dimethyl xanthine 5.1g, yield are beaten to obtain with ethyl alcohol after concentration
85%, purity 97%.1H-NMR(400MHz,DMSO-d6):δ11.82 (s,1H),7.90(s,1H),3.84(s,3H),3.16
(s,3H)。
The preparation of 5 1,7- dimethyl xanthine of embodiment
3- (2,4- dimethoxy-benzyl)-xanthine (10g, 33.1mmol) is dissolved in toluene (100mL), and the tert-butyl alcohol is added
Sodium (8.0g, 82.8mmol), Methyl triflate (13.6g, 82.8mmol).100-110 DEG C is warming up to react 4 hours.Drop
Methylene chloride/water liquid separation is added to 20-30 DEG C in temperature after concentration.Off-white color is beaten to obtain with methyl tertiary butyl ether(MTBE) after organic phase concentration
Solid 3- (2,4- dimethoxy-benzyl) -1,7- dimethyl xanthine 10.4g, yield 95%.
3- (2,4- dimethoxy-benzyl) -1,7- dimethyl xanthine (10g, 30.3mmol) is dissolved in trifluoroacetic acid
In (100mL), it is added triethylsilane (7.0g, 60.6mmol).20-30 DEG C is reacted 24 hours, and TLC shows fully reacting.It is dense
With being beaten after contracting, off-white powder 1,7- dimethyl xanthine 4.6g, yield 85%, purity are beaten to obtain with ethyl alcohol after filtering
98%.1H-NMR(400MHz,DMSO-d6):δ11.82(s, 1H),7.90(s,1H),3.84(s,3H),3.16(s,3H)。
The preparation of 6 1,7- dimethyl xanthine of embodiment
3- benzyl xanthine (10g, 41.3mmol) is dissolved in tetrahydrofuran (100mL), addition potassium hydroxide (11.6g,
206.5mmol), iodomethane (29.3g, 206.5mmol).100-110 DEG C is warming up to react 4 hours.It is cooled to 20-30 DEG C, it is dense
Methylene chloride/water liquid separation is added after contracting.Off-white powder 3- benzyl -1,7- is beaten to obtain with methyl tertiary butyl ether(MTBE) after organic phase concentration
Dimethyl xanthine 10g, yield 90%.
3- benzyl -1,7- dimethyl xanthine (10g, 37.2mmol) is dissolved in hydrochloric acid (100mL), and tri-phenyl-silane is added
(29.8mmol).It is warming up to 110 DEG C to react 12 hours, TLC shows fully reacting.It is cooled to 0-10 DEG C, is added dropwise water (150mL),
Stirring 2 hours.Off-white powder 1,7- dimethyl xanthine 5.7g, yield 85%, purity 98% are beaten to obtain with ethyl alcohol after filtering.1H-NMR(400MHz,DMSO- d6):δ11.82(s,1H),7.90(s,1H),3.84(s,3H),3.16(s,3H)。
The preparation of 7 1,7- dimethyl xanthine of embodiment
3- benzyl xanthine (10g, 41.3mmol) is dissolved in n,N-dimethylacetamide (100mL), and 4- diformazan ammonia is added
Yl pyridines (15.1g, 123.9mmol), iodomethane (17.6g, 123.9mmol).100-110 DEG C is warming up to react 4 hours.Cooling
To 20-30 DEG C, methylene chloride/water liquid separation is added after concentration.After organic phase concentration with methyl tertiary butyl ether(MTBE) be beaten off-white color is solid
10.2 g of body 3- benzyl -1,7- dimethyl xanthine, yield 92%.
3- benzyl -1,7- dimethyl xanthine (10g, 37.2mmol) is suspended in glycol dimethyl ether (100mL), is added three
Boron bromide (18.6g, 74.4mmol) and dimethylphenylsilaneand (25.3g, 186mmoL), 20-30 DEG C is reacted 24 hours, TLC
Show fully reacting.It is cooled to 0-10 DEG C, is added dropwise water (150mL), is stirred 2 hours.After filtering with ethyl alcohol be beaten off-white color is solid
Body 1,7- dimethyl xanthine 5.6g, yield 84%, purity 98%.1H-NMR(400MHz,DMSO-d6):δ11.82(s,1H),
7.90(s,1H),3.84(s,3H), 3.16(s,3H)。
The preparation of 8 1,7- dimethyl xanthine of embodiment
3- benzyl xanthine (10g, 41.3mmol) is dissolved in N, and in N- diethylformamide (100mL), potassium carbonate is added
(17.1g, 123.9mmol), iodomethane (17.6g, 123.9mmol).110 DEG C of 100- are warming up to react 4 hours.It is cooled to 20-
30 DEG C, methylene chloride/water liquid separation is added after concentration.Off-white powder 3- benzyl is beaten to obtain with methyl tertiary butyl ether(MTBE) after organic phase concentration
Base -1,7- dimethyl xanthine 9.8g, yield 88%.
3- benzyl -1,7- dimethyl xanthine (10g, 37.2mmol) is suspended in ethyl alcohol (150mL), 30 DEG C of 20- additions
10% Pd-C (1g), at this temperature hydrogenation stirring 2 hours.It is cooled to 0-10 DEG C, is added dropwise water (150mL), is stirred 2 hours.
Off-white powder 1,7- dimethyl xanthine 4.6g, yield 70%, purity 98% are beaten to obtain with ethyl alcohol after filtering.1H-NMR
(400MHz,DMSO-d6):δ11.82(s,1H), 7.90(s,1H),3.84(s,3H),3.16(s,3H)。
The preparation of 9 1,7- dimethyl xanthine of embodiment
3- benzyl xanthine (10g, 41.3mmol) is dissolved in N-Methyl pyrrolidone (100mL), and triethylamine is added
(123.9mmol), iodomethane (17.6g, 123.9mmol).100-110 DEG C is warming up to react 4 hours.It is cooled to 20-30 DEG C,
Methylene chloride/water liquid separation is added after concentration.It is beaten to obtain benzyl -1 off-white powder 3- with methyl tertiary butyl ether(MTBE) after organic phase concentration,
7- dimethyl xanthine 10g, yield 90%.
3- benzyl -1,7- dimethyl xanthine (10g, 37.2mmol) is suspended in N-Methyl pyrrolidone (150 mL),
The palladium black (2g) of 20-30 DEG C of addition 10%, hydrogenation stirring 12 hours at this temperature, TLC shows fully reacting.It is cooled to 0-10
DEG C, it is added dropwise water (150mL), stirs 2 hours.Off-white powder 1 is beaten to obtain with ethyl alcohol after filtering, 7- dimethyl xanthine 5.9g,
Yield 88%, purity 98%.1H-NMR(400 MHz,DMSO-d6):δ11.82(s,1H),7.90(s,1H),3.84(s,3H),
3.16(s,3H)。
The preparation of 10 1,7- dimethyl xanthine of embodiment
3- benzyl xanthine (10g, 41.3mmol) is dissolved in 2- methyltetrahydrofuran (100mL), and diisopropyl second is added
Base amine (123.9mmol), iodomethane (17.6g, 123.9mmol).100-110 DEG C is warming up to react 4 hours.It is cooled to 20-30
DEG C, methylene chloride/water liquid separation is added after concentration.Off-white powder 3- benzyl is beaten to obtain with methyl tertiary butyl ether(MTBE) after organic phase concentration
Base -1,7- dimethyl xanthine 10.2g, yield 92%.
3- benzyl -1,7- dimethyl xanthine (10g, 37.2mmol) is suspended in n,N-Dimethylformamide (150 mL)
In, the Pd (OH) of 20-30 DEG C of addition 10%2- C (0.2g), at this temperature hydrogenation stirring 24 hours, TLC display have been reacted
Entirely.It is cooled to 0-10 DEG C, is added dropwise water (150mL), is stirred 2 hours.Off-white powder 1,7- diformazan is beaten to obtain with ethyl alcohol after filtering
Base xanthine 5.7g, yield 85%, purity 98%.1H-NMR (400MHz,DMSO-d6):δ11.82(s,1H),7.90(s,
1H),3.84(s,3H),3.16(s,3H)。
Claims (10)
1. one kind 1, the preparation method of 7- dimethyl xanthine, which is characterized in that the method comprises the steps of: step a:
Under the conditions of alkali presence or alkali-free, react to obtain compound (II) with methylating reagent in compound (III) Yu Yiding solvent；
Step b: under the conditions of existing for the catalytic hydrogenolysis reagent or lewis acid or lewis acid and silane reducing agent, compound
(III) deprotection obtains 1,7- dimethyl xanthine (I) in Yu Yiding solvent；
Reaction route is as follows:
Wherein, R=benzyl, to methoxy-benzyl, 2,4- dimethoxy-benzyl.
2. a kind of preparation method of 1,7- dimethyl xanthine according to claim 1, which is characterized in that in step a,
The methylating reagent is one in iodomethane, dimethyl suflfate, dimethyl carbonate, trimethyl phosphate and Methyl triflate
Kind is a variety of, preferably dimethyl suflfate and iodomethane.
3. a kind of preparation method of 1,7- dimethyl xanthine according to claim 1, which is characterized in that in step a,
The alkali be sodium bicarbonate, sodium carbonate, saleratus, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, potassium phosphate, sodium hydroxide,
Potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, tert-butyl alcohol magnesium, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide,
Triethylamine, diethylamine, dimethylamine, trimethylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1,
11 carbon -7- alkene of 8- diazabicyclo [5.4.0], 1,5- diazabicyclo [4.3.0] nonyl- 5- alkene or 1,4- diazabicylo
One of [2.2.2] octane is a variety of, preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, tertiary fourth
One of potassium alcoholate, triethylamine, diisopropyl ethyl amine or 4-dimethylaminopyridine are a variety of.
4. a kind of preparation method of 1,7- dimethyl xanthine according to claim 1, which is characterized in that in step a,
The solvent be selected from benzene, toluene, chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, isopropyl acetate, 2- butanone,
Acetone, 1,2- dimethyl -2- imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N, N- dimethyl formyl
Amine, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyridine, methanol, ethyl alcohol, isopropanol, just
Butanol, ethylene glycol, the tert-butyl alcohol, tert-pentyl alcohol, polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether,
1,2- propylene glycol, diethoxymethane, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- methyltetrahydrofuran,
One of n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, chloroform, ethyl acetate or water are a variety of；Preferably first
Benzene, acetonitrile, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, four
One of hydrogen furans, 2- methyltetrahydrofuran, diethoxymethane or water are a variety of.
5. a kind of preparation method of 1,7- dimethyl xanthine according to claim 1, which is characterized in that in step a,
The molar feed ratio of the methylating reagent and compound (III) are 2-20:1, preferably 2-5:1；The alkali and compound
(III) molar ratio is 2-20:1, preferably 2-5:1；0-150 DEG C is selected from described in the reaction temperature of step 1, preferably
20-100℃；Reaction time 0.5-36 hour, preferably 1-24 hour.
6. a kind of preparation method of 1,7- dimethyl xanthine according to claim 1, which is characterized in that in step b,
The catalytic hydrogenolysis reagent is Pd-C/ hydrogen donor, palladium black/hydrogen donor, Raney Ni/hydrogen donor or Pd (OH)2/ hydrogen is given
One of body is a variety of；Preferably Pd-C/ hydrogen donor, Pd (OH)2/ hydrogen donor or palladium black/hydrogen donor；The metal
The mass ratio that feeds intake with compound (II) is 0.005-0.5:1, preferably 0.01-0.2:1.
7. a kind of preparation method of 1,7- dimethyl xanthine according to claim 1, which is characterized in that in step b,
The lewis acid be acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid, alchlor, Boron tribromide, boron chloride or
One of boron trifluoride is a variety of, preferably one of trifluoroacetic acid, hydrochloric acid, alchlor or Boron tribromide or a variety of；
The molar ratio of the lewis acid and compound (II) are 1-20:1, preferably 1-5:1.
8. a kind of preparation method of 1,7- dimethyl xanthine according to claim 1, which is characterized in that in step b,
The silane reducing agent is triethylsilane, tri isopropyl silane, tri-phenyl-silane, dimethylphenylsilaneand, 1,1,3,3- tetra-
One of tetramethyldisiloxane is a variety of, and the molar ratio of the silane reducing agent and compound (II) are 0.5-20:1,
Preferably 0.8-5:1.
9. a kind of preparation method of 1,7- dimethyl xanthine according to claim 1, which is characterized in that in step b,
The solvent be selected from benzene, toluene, chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, isopropyl acetate, 2- butanone,
Acetone, 1,2- dimethyl -2- imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N, N- dimethyl formyl
Amine, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyridine, methanol, ethyl alcohol, isopropanol, just
Butanol, ethylene glycol, the tert-butyl alcohol, tert-pentyl alcohol, polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether,
1,2- propylene glycol, diethoxymethane, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- methyltetrahydrofuran,
One of n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, chloroform, acetic acid, hydrochloric acid, trifluoroacetic acid or water are more
Kind；Preferably toluene, acetonitrile, methanol, ethyl alcohol, glycol dimethyl ether, N,N-dimethylformamide, N-Methyl pyrrolidone, four
One of hydrogen furans, 2- methyltetrahydrofuran, hydrochloric acid, trifluoroacetic acid or water are a variety of.
10. a kind of preparation method of 1,7- dimethyl xanthine according to claim 1, which is characterized in that step b
In, 0-150 DEG C, preferably 20-120 DEG C is selected from described in reaction temperature；Reaction time 0.5-36 hour, preferably 1-24 hour.
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| CN112979651A (en) * | 2021-04-09 | 2021-06-18 | 南京纽邦生物科技有限公司 | Preparation method of hypoxanthine |
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| CN1086818A (en) * | 1992-08-10 | 1994-05-18 | 贝林格尔·英格海姆公司 | The xanthine of asymmetric replacement |
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2019
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1086818A (en) * | 1992-08-10 | 1994-05-18 | 贝林格尔·英格海姆公司 | The xanthine of asymmetric replacement |
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| CHRISTA E. MULLER等: ""Imidazo[2,1-i]purin-5-ones and Related Tricyclic Water-Soluble Purine Derivatives: Potent A_(2A)- and A_3-Adenosine Receptor Antagonists"", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| FUJII T.等: "Purines. XLIX. Synthesis and proton nuclear magnetic resonance study of 3,7-dialkylxanthines and 1,3,7-trialkylxanthines", 《CHEMICAL AND PHARMACEUTICAL BULLETIN》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112979651A (en) * | 2021-04-09 | 2021-06-18 | 南京纽邦生物科技有限公司 | Preparation method of hypoxanthine |
| CN112979651B (en) * | 2021-04-09 | 2022-02-01 | 南京纽邦生物科技有限公司 | Preparation method of hypoxanthine |
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