155270-99-8

Usage

Uses

Used in Pharmaceutical Industry:
Istradefylline is used as an adenosine receptor 2A (A2A) antagonist for the treatment of Parkinson's disease. It inhibits catalepsy induced by haloperidol and alleviates postural defects in a dose-dependent manner without inducing dyskinesias or hyperactivity. It also decreases bradykinesias induced by L-DOPA and improves attentional and working memory deficits in PD models.
Used in Parkinson's Disease Treatment:
Istradefylline is used as an adjunctive treatment for Parkinson's disease to extend on-time in patients experiencing motor fluctuations. It has demonstrated activity alone and in combination with levo-dopa in preclinical animal models of PD.
Brand Name:
Nouriast

Originator

Kyowa Hakko Kirin (Japan)

Biochem/physiol Actions

Istradefylline (KW-6002) is a potent and selective adenosine A2A receptor selective antagonist which has been investigated for use in Parkinson′s Disease.

Synthesis

Numerous synthetic approaches to istradefylline have been developed, with a large majority of these methods employing 5,6-amino-1,3-diethyluracil 97 as a key intermediate. Despite the commercial availability of 96, most reported routes to istradefylline rely on sourcing of this intermediate via a wellestablished four-step synthesis from N,N-diethylurea (94) and cyanoacetic acid (95). Specifically, 6-amino-1,3-diethyluracil (96) can be formed by sequential treatment of 94 and 95 with Ac2O and NaOH. Nitrosation of 96 with NaNO2/AcOH/H2O, followed by Na2S2O4/NH3-mediated nitroso reduction provided 5,6-amino- 1,3-diethyluracil (97). Even though other groups have recently reported modified scale routes to istradefylline, the route described herein will focus on the sequence outlined by Kyowa Hakko Kogyo research laboratories during their initial development of istradefylline. EDC-mediated amine coupling involving 97 and 3,4-dimethoxycinnamic acid (98) led to the corresponding amide intermediate. After aqueous workup, this crude amide intermediate underwent cyclization with aqueous sodium hydroxide to yield the desired purine dione 99 in 47% yield over 2 steps. Methylation of 99 with MeI/K2CO3 provided istradefylline (XII) in 68% yield.

in vitro

the affinity of kw-6002 for the a2ar is 70-fold greater than that for the a1 receptor. the binding affinities (ki) of kw-6002 for human a1 receptor and a2a receptor are >287 nm and 9.12 nm, respectively [1].

in vivo

in mptp neurotoxin model of pd in mice, kw-6002 significantly attenuated striatal dopamine depletion under various conditions. in addition, pretreatment with kw-6002 (3.3 mg/kg, i.p.) before a single dose of mptp attenuated the partial dopamine and dopac depletions 1 week later [2].

references

[1] park a, stacy m. istradefylline for the treatment of parkinson's disease. expert opin pharmacother. 2012 jan;13(1):111-4. [2] chen jf, xu k, petzer jp, staal r, xu yh, beilstein m, sonsalla pk, castagnoli k, castagnoli n jr, schwarzschild ma. neuroprotection by caffeine and a(2a) adenosine receptor inactivation in a model of parkinson's disease. j neurosci. 2001;21(10):rc143.

InChI:InChI=1/C20H24N4O4/c1-6-23-18-17(19(25)24(7-2)20(23)26)22(3)16(21-18)11-9-13-8-10-14(27-4)15(12-13)28-5/h8-12H,6-7H2,1-5H3/b11-9+

Synthetic route

8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione (155270-98-7) + methyl iodide (74-88-4) → istradefylline (155270-99-8)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 5h;	99%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h;	95%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere;	95%

1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione (31617-39-7) + 3,4-dimethoxystyrene (6380-23-0) → istradefylline (155270-99-8)

Conditions	Yield
Stage #1: 1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione With pyridine; palladium diacetate; copper(II) acetate monohydrate; copper(l) chloride In N,N-dimethyl acetamide at 20℃; for 0.0833333h; Heck reaction; Inert atmosphere; Stage #2: 3,4-dimethoxystyrene In N,N-dimethyl acetamide at 120℃; for 20h; Heck reaction; Inert atmosphere;	95%

C20H26N4O5 → istradefylline (155270-99-8)

Conditions	Yield
With sodium methylate In 1,4-dioxane at 90 - 95℃; for 3h; Reagent/catalyst; Temperature;	94%

methyl 2‐cyano‐2‐[(2E)‐3‐(3,4‐dimethoxyphenyl)‐N‐methylprop‐2‐enamido]acetate → istradefylline (155270-99-8)

Conditions	Yield
With N,N'-diethylurea In 1,4-dioxane at 90 - 95℃; for 4h;	92.5%

1,3-diethyl-7,8-dimethyl-1H-purine-2,6-(3H,7H)-dione + 3,4-dimethoxy-benzaldehyde (120-14-9) → istradefylline (155270-99-8)

Conditions	Yield
With acetic anhydride; acetic acid at 110℃; for 10h;	92%

N,N'-diethylurea (623-76-7) + (E)-3,4-dimethoxycinnamic chloride (39856-08-1, 141236-46-6) + ethyl 2-methylaminocyanoacetate → istradefylline (155270-99-8)

Conditions	Yield
Stage #1: N,N'-diethylurea; ethyl 2-methylaminocyanoacetate In 1,4-dioxane at 95 - 100℃; for 5h; Stage #2: With potassium hydroxide at 10 - 95℃; for 3h; Stage #3: (E)-3,4-dimethoxycinnamic chloride With triethylamine In 1,4-dioxane at 10 - 45℃; for 5h; Temperature;	90.9%

carbonic acid dimethyl ester (616-38-6) + 8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione (155270-98-7) → istradefylline (155270-99-8)

Conditions	Yield
With potassium tert-butylate In N,N-dimethyl-formamide at 135℃; for 6h; Reagent/catalyst; Temperature; Molecular sieve;	86%
With potassium tert-butylate In N,N-dimethyl-formamide at 135℃; for 6h; Reagent/catalyst; Temperature; Molecular sieve;	86%

dimethyl sulfate (77-78-1) + 8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione (155270-98-7) → istradefylline (155270-99-8)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; Darkness;	71.8%

carbonic acid dimethyl ester (616-38-6) + (E)-N-(6-amino-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-(3,4-dimethoxyphenyl)propenamide (187393-68-6) → istradefylline (155270-99-8)

Conditions	Yield
Stage #1: (E)-N-(6-amino-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-(3,4-dimethoxyphenyl)propenamide With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 0.5h; Stage #2: carbonic acid dimethyl ester In N,N-dimethyl-formamide at 120 - 140℃; for 2h; Temperature;	52.4%

5,6-diamino-1,3-diethyluracil (52998-22-8) → istradefylline (155270-99-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 65 percent / pyridine / CH2Cl2 / 16 h / 20 °C 2: 92 percent / 1,1,1,3,3,3-hyxamethyldisilazane; (NH4)2SO4 / 4 h / 170 - 180 °C 3: 95 percent / potassium carbonate / dimethylformamide / 0.5 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: EDAC / dioxane; H2O 1.2: 35 percent / aq. NaOH / Heating 2.1: K2CO3 / dimethylformamide View Scheme
Multi-step reaction with 2 steps 1: 1) 1-<3-(dimethylamino)propyl>-3-ethylcarbodiimide hydrochloride, 2) 1N NaOH / 1) dioxane, H2O, 2) dioxane, H2O, reflux 2: K2CO3 / dimethylformamide / 50 °C View Scheme

6-amino-1,3-diethyl-5-nitroso-1H,3H-pyrimidine-2,4-dione (89073-60-9) → istradefylline (155270-99-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 80 percent / NH3; sodium dithionite / H2O / 60 °C 2: 65 percent / pyridine / CH2Cl2 / 16 h / 20 °C 3: 92 percent / 1,1,1,3,3,3-hyxamethyldisilazane; (NH4)2SO4 / 4 h / 170 - 180 °C 4: 95 percent / potassium carbonate / dimethylformamide / 0.5 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: ammonium hydroxide; sodium dithionite / water / 0.5 h 2.1: pyridine / dichloromethane / 24 h / 20 °C 3.1: acetonitrile / Microwave irradiation 3.2: 5 h / 160 °C / Microwave irradiation 4.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: palladium 10% on activated carbon; hydrogen / methanol / 15 °C / 3750.38 - 4500.45 Torr 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 10 - 35 °C 3: sodium hydroxide / propan-1-ol / 5 h / Reflux 4: potassium carbonate / N,N-dimethyl-formamide / 3 h / 50 - 60 °C 5: acetic acid; acetic anhydride / 10 h / 110 °C View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / water / 30 - 50 °C 1.2: 1 h / 20 °C 2.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 1.5 h / 25 °C 2.2: 1 h / 20 °C 3.1: sodium hydroxide / water; 1,4-dioxane / 2 h / 60 °C 4.1: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Darkness View Scheme

6-amino-1,3-diethyluracil (41740-15-2) → istradefylline (155270-99-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 74 percent / acetic acid; NaNO2 / H2O / 0.25 h / 50 - 60 °C 2: 80 percent / NH3; sodium dithionite / H2O / 60 °C 3: 65 percent / pyridine / CH2Cl2 / 16 h / 20 °C 4: 92 percent / 1,1,1,3,3,3-hyxamethyldisilazane; (NH4)2SO4 / 4 h / 170 - 180 °C 5: 95 percent / potassium carbonate / dimethylformamide / 0.5 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium nitrite / acetic acid / 0.25 h / 50 - 60 °C 2.1: ammonium hydroxide; sodium dithionite / water / 0.5 h 3.1: pyridine / dichloromethane / 24 h / 20 °C 4.1: acetonitrile / Microwave irradiation 4.2: 5 h / 160 °C / Microwave irradiation 5.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C View Scheme

(E)-N-(6-amino-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-(3,4-dimethoxyphenyl)propenamide (187393-68-6) → istradefylline (155270-99-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 92 percent / 1,1,1,3,3,3-hyxamethyldisilazane; (NH4)2SO4 / 4 h / 170 - 180 °C 2: 95 percent / potassium carbonate / dimethylformamide / 0.5 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: acetonitrile / Microwave irradiation 1.2: 5 h / 160 °C / Microwave irradiation 2.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C View Scheme

3,4-dimethoxy-trans-cinnamic acid (14737-89-4) → istradefylline (155270-99-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: EDAC / dioxane; H2O 1.2: 35 percent / aq. NaOH / Heating 2.1: K2CO3 / dimethylformamide View Scheme
Multi-step reaction with 2 steps 1: 1) 1-<3-(dimethylamino)propyl>-3-ethylcarbodiimide hydrochloride, 2) 1N NaOH / 1) dioxane, H2O, 2) dioxane, H2O, reflux 2: K2CO3 / dimethylformamide / 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: thionyl chloride / toluene / 16 h / 75 °C 2.1: pyridine / dichloromethane / 24 h / 20 °C 3.1: acetonitrile / Microwave irradiation 3.2: 5 h / 160 °C / Microwave irradiation 4.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C View Scheme

N,N-diethylurea (634-95-7) → istradefylline (155270-99-8)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: acetic acid / 2 h / 80 °C 2.1: sodium nitrite / acetic acid / 0.25 h / 50 - 60 °C 3.1: ammonium hydroxide; sodium dithionite / water / 0.5 h 4.1: pyridine / dichloromethane / 24 h / 20 °C 5.1: acetonitrile / Microwave irradiation 5.2: 5 h / 160 °C / Microwave irradiation 6.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C View Scheme

(E)-3,4-dimethoxycinnamic chloride (39856-08-1, 141236-46-6) → istradefylline (155270-99-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: pyridine / dichloromethane / 24 h / 20 °C 2.1: acetonitrile / Microwave irradiation 2.2: 5 h / 160 °C / Microwave irradiation 3.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: pyridine / 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran / 20 °C / Large scale 2: sodium hydroxide / isopropyl alcohol; water / 75 - 80 °C 3: potassium carbonate / N,N-dimethyl-formamide / 10 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 5 h / 5 - 35 °C 2: N,N'-diethylurea / 1,4-dioxane / 4 h / 90 - 95 °C View Scheme

5,6-diamino-1,3-diethylpyrimidine-2,4-(1H,3H)-dione hydrochloride → istradefylline (155270-99-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 10 - 35 °C 2: sodium hydroxide / propan-1-ol / 5 h / Reflux 3: potassium carbonate / N,N-dimethyl-formamide / 3 h / 50 - 60 °C 4: acetic acid; acetic anhydride / 10 h / 110 °C View Scheme

N-(6-amino-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)acetamide → istradefylline (155270-99-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / propan-1-ol / 5 h / Reflux 2: potassium carbonate / N,N-dimethyl-formamide / 3 h / 50 - 60 °C 3: acetic acid; acetic anhydride / 10 h / 110 °C View Scheme

3,4-dimethoxystyrene (6380-23-0) + 1,3-diethyl-8-iodo-7-methylpurine-2,6-dione → istradefylline (155270-99-8)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; palladium dichloride In N,N-dimethyl-formamide at 100℃; for 12h; Inert atmosphere;	58.87 g
With N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; palladium dichloride In N,N-dimethyl-formamide at 100℃; for 12h; Inert atmosphere;	58.87 g

N,N'-diethylurea (623-76-7) → istradefylline (155270-99-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1,4-dioxane / 4 h / 100 - 105 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 4 h / 10 - 55 °C 3: sodium methylate / 1,4-dioxane / 3 h / 90 - 95 °C View Scheme

5,6-diamino-1,3-diethyluracil (52998-22-8) + (E)-3,4-dimethoxycinnamic chloride (39856-08-1, 141236-46-6) → istradefylline (155270-99-8)

Conditions	Yield
With sodium carbonate In ethanol at 60℃; for 3.5h;

istradefylline (155270-99-8) → (1α,2α,3β,4β)-1,3-bis[1,3-diethyl-7-methyl-3,7-dihydropurine-2,6-dion-8-yl]-2,4-bis(3,4-dimethoxyphenyl)cyclobutane

Conditions	Yield
With aluminum (III) chloride In chloroform at 30 - 40℃; for 10h; UV-irradiation; Inert atmosphere;	87.2%
for 1.66667h; Irradiation;	12 mg

1,5-dibromo-pentane (111-24-0) + istradefylline (155270-99-8) → (E)-7,7'-(pentane-1,5-diyl)bis(8-((E)-3,4-dimethoxystyryl)-1,3-diethyl-1H-purine-2,6(3H,7H)-dione)

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In acetone at 20℃;	69.2%

1,4-dibromo-butane (110-52-1) + istradefylline (155270-99-8) → (E)-7-(5-bromobutyl)-8-(3,4-dimethoxystyryl)-1,3-diethyl-1H-purine-2,6( 3H,7H)-dione

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In acetone at 20℃;	59.9%

istradefylline (155270-99-8) → (Z)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine

Conditions	Yield
In acetone Irradiation;	16%

Upstream product

• 120-14-9 3,4-dimethoxy-benzaldehyde 
• 1785764-26-2 5,6-diamino-1,3-diethylpyrimidine-2,4-(1H,3H)-dione hydrochloride 
• 52998-22-8 5,6-diamino-1,3-diethyluracil 
• 39856-08-1 (E)-3,4-dimethoxycinnamic chloride 
• 623-76-7 N,N'-diethylurea 
• 616-38-6 carbonic acid dimethyl ester 
• 187393-68-6 (E)-N-(6-amino-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-(3,4-dimethoxyphenyl)propenamide 
• 6380-23-0 3,4-dimethoxystyrene 
• 77-78-1 dimethyl sulfate 
• 155270-98-7 8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione 
• 634-95-7 N,N-diethylurea 
• 31617-39-7 1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione 
• 14737-89-4 3,4-dimethoxy-trans-cinnamic acid 
• 41740-15-2 6-amino-1,3-diethyluracil 

Downstream Products

• 155272-03-0 (E)-8-(3,4-Dihydroxystyryl)-1,3-diethyl-7-methylxanthine 
• 606080-73-3 (Z)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine 

Relevant academic research and scientific papers

Synthetic method of istradefylline

The invention discloses a synthetic method of istradefylline, and belongs to the technical field of medicines. The synthesis method of the istradefylline mainly comprises the steps of acylation, ringclosing, methylation and the like. The method is high in yield, simple in step and single in solvent, wherein reaction selectivity can be effectively promoted and side reactions are reduced; after ring closing is finished, dimethyl sulfate is dropwise added for a methylation reaction by means of the alkalinity of dimethyl sulfate. The method can be more thorough and cleaner than a dimethyl carbonate reaction in the prior art. The whole process can be carried out in one reaction kettle, wherein the solvent only relates to ethanol and subsequently refined methanol and can be recycled, so that the synthesis method has advantages of high reaction selectivity and yield.

Environment-friendly preparation method of istradefylline

The invention provides an environment-friendly preparation method of istradefylline. 2-methyl aminocyanoacetate is taken as an initial raw material and is firstly subjected to an amidation reaction and then cyclized or firstly cyclized and then subjected to the amidation reaction, 1,3-diethyl-5-(N-methyl-N-(E)-3,4-dimethoxy phenylpropylene acryl)amino-6-aminouracil is prepared and then cyclized inthe presence of alkali, and istradefylline is prepared. According to the method, raw materials are cheap and easy to obtain, the step is simple and safe, and the method is green, environmentally friendly and low in cost; the prepared product has a shallow color and luster and is high in purity and yield.

Istradefylline preparation method

The invention provides an istradefylline preparation method. 1,3-diethyl-5,6-diaminouracil used as a starting material undergoes an acylation reaction, a ring formation reaction and a methylation reaction to prepare istradefylline. The ring formation reaction and the methylation reaction are carried out simultaneously, an istradefylline intermediate (E)-1,3-diethyl-6-amino-5-(3,4-dimethoxyphenylacryloyl)aminouracil is reacted by adding a methylating agent in an alkaline environment, and the obtained solution is filtered and crystallized to obtain the istradefylline. The ring formation and themethylation are simultaneously carried out, and the methylation is immediately carried out after the completion of the ring formation to promote the forward proceeding, so the yield of the product isincreased, large amounts of organic solvents are saved, and the generation amount of an organic waste liquid is reduced; and the method has the advantages of simplicity in operation, and high reactionconversion rate, and allows the purity of the product to be higher than 99%.

Istradefylline raw material drug and preparation method thereof

The invention relates to an istradefylline raw material drug and a preparation method thereof. Specifically, the invention relates to an istradefylline raw material drug. A compound shown in formula III is not higher than 0.5% and is a medicine preparation consisting of the istradefylline raw material drug and a pharmacologically acceptable carrier and/ or diluent. The raw material drug and the preparation thereof have better safety, effectiveness and stability. The formula III is shown in the description.

For treating Parkinson drug Iraq curved tea alkali preparation method of crystal form II (by machine translation)

The invention discloses a method for treating Parkinson's drug Iraq curved tea preparation method of alkali crystalline form II, Iraq and curved theophylline with the mixed solvent after mixing, heating to 70 - 90 °C dissolved, then rapidly cooling to 0 - 5 °C, crystallization, to obtain the treatment of Parkinson's drug Iraq curved tea alkali crystalline form II; the invention for the treatment of Parkinson's drug Iraq curved tea alkali crystalline form II, its stability and the prior of the Iraqi curved tea alkali crystalline form II considerable, but yield and purity higher, greatly improves the quality of the product, and can improve its bioavailability, conducive to its pharmaceutical processing and in the use of the drug combination in, at the same time can provide qualitative and quantitative information, to further study the solid curative effect of the medicament has important significance. (by machine translation)

Method of preparing istradefylline crystal form III by means of ball-milling method

The invention discloses a method of preparing an istradefylline crystal form III by means of a ball-milling method. The method comprises the following steps: putting istradefylline in a ball-milling tank; adding 100mg of istradefylline into 15-20 mu L tetrahydrofuran; and grinding the mixture at a grinding frequency of 5-10HZ for 60-100min to obtain the tetrahydrofuran crystal form III. The preparation method is novel in process, the reaction yield is improved, and the purity of the finally prepared istradefylline product reaches 99.6% through detection. The istradefylline prepared by the method is matched with a special solvent, and the grinding frequency and the grinding time as a raw material, so that the optical purity of the prepared istradefylline crystal form III is 99.9% or above,and the product quality is improved greatly.

Improved synthesis technology of istradefylline

The invention provides an improved synthesis technology of istradefylline. According to the technology, istradefylline is prepared from 1,3-diethyl-6-amino-5-nitrosouracil (SM-III) as a starting material through four steps.

New crystal form of istradefylline and preparation method thereof

The invention discloses a new crystal form of istradefylline and a preparation method thereof. The powder X-ray diffraction of the new crystal form of istradefylline has characteristic peaks where 2theta is equal to 10.4 +/-0.2 degrees, 11.2 +/-0.2 degrees, 15.8 +/-0.2 degrees, 24.6 +/-0.2 degrees, and 25.2 +/-0.2 degrees. The new crystal form of istradefylline is thermodynamically stable and has obviously improved solubility in water; the new crystal form of istradefylline, which is crystalline solid powder having a small particle size, is good in fluidity, so that the problem of non-uniform crystal condensation and dispersion in process operation of a preparation can be solved; the new crystal form of istradefylline is more suitable for storage and for use as a bulk pharmaceutical chemical; and a new way is provided for the preparation of istradefylline drugs.

A Iraq new synthetic method of curved theophylline (by machine translation)

The invention discloses a method for the synthesis of the Iraqi curved theophylline new method, the present invention provides a compound (E)- 8 - [(3, 4 - dimethoxyphenyl) vinyl] - 1, 3 - diethyl - 7 - methyl - 3, 7 - dihydro - 1H - purine - 2, 6 - dione (also known as the Iraqi curved theophylline) new methods of synthesis, has been good purity and high yield of iraqi tune theophylline, improves the Iraq curved theophylline drug production and safety in the use of, at the same time reducing the cost of industrial production. (by machine translation)

Novel preparation method for Istradefylline

The invention relates to a preparation method for Istradefylline represented by a formula (I) shown in the description. The method comprises the following steps: subjecting 6-amino-1,3-diethyl-5-nitroso-1H-pyrimid-2,4-dione represented by a formula (II) shown in the description, which serves as a raw material, to catalytic reduction and salt forming, so as to obtain 5,6-diamino-1,3-diethyl-1H-pyrimid-2,4-dione hydrochloride represented by a formula (III) shown in the description; then, carrying out acetylation on the compound (III), so as to obtain N-(6-amino-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimid-5-yl)acetamide represented by a formula (IV) shown in the description; carrying out further ring closing, so as to obtain 1,3-diethyl-8-methyl-1H-purin-2,6(3H,7H)-dione represented by a formula (V) shown in the description; and carrying out methylation on the compound (V) firstly, and then, subjecting the methylation product to a condensation reaction with veratraldehyde represented by a formula (VII) shown in the description, thereby obtaining the end product Istradefylline. According to the novel preparation method for the Istradefylline, provided by the invention, raw materials, which are readily available industrially and are low in price, are used, the production process is more environmentally friendly, and the obtained product Istradefylline is high in yield and purity, thereby having a relatively high practical value.