CN114085178A - Preparation method of 4-methyl-1-propyl-2-amino-1H-pyrrole-3-nitrile - Google Patents
Preparation method of 4-methyl-1-propyl-2-amino-1H-pyrrole-3-nitrile Download PDFInfo
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- CN114085178A CN114085178A CN202111637487.0A CN202111637487A CN114085178A CN 114085178 A CN114085178 A CN 114085178A CN 202111637487 A CN202111637487 A CN 202111637487A CN 114085178 A CN114085178 A CN 114085178A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- YXHGHIPMRPOBRH-UHFFFAOYSA-N 2-amino-4-methyl-1-propylpyrrole-3-carbonitrile Chemical compound CCCN1C=C(C)C(C#N)=C1N YXHGHIPMRPOBRH-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims abstract description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000003513 alkali Substances 0.000 claims abstract description 10
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims abstract description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 3
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000003814 drug Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 3
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical class C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 1
- RXMDFMQMRASWOG-UHFFFAOYSA-N 2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1h-pyrrolo[2,3-d]pyrimidin-4-one Chemical compound CCCN1C=C(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 RXMDFMQMRASWOG-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010057672 Male sexual dysfunction Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- -1 heterocyclic ketone Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 4-methyl-1-propyl-2-amino-1H-pyrrole-3-nitrile as an intermediate of Yokenafil, which comprises the following steps: the method comprises the following steps of condensing malononitrile and acetone under the action of alkali to obtain a compound shown in a formula (I), brominating the compound shown in the formula (I) to obtain a compound shown in a formula (II), and condensing the compound shown in the formula (II) and propylamine to form a target product shown in a formula (III). The invention provides a simple and convenient industrial production route for the intermediate of the Yokenafil, which reduces the cost, has the advantages of shorter reaction steps, simple and convenient reaction, avoids using tube products and can realize stable industrial production and preparation.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a Yokenafil intermediate 4-methyl-1-propyl-2-amino-1H-pyrrole-3-nitrile.
Background
Yonkenafil is a five-membered and six-membered heterocyclic ketone structural analogue of Cyclic Guanosine monophosphate (cGMP), and is a novel Phosphodiesterase (PDE) V inhibitor which is independently developed by national researchers and has independent intellectual property rights. Early pharmacodynamic test researches show that the compound has good selective inhibition effect on PDE V, and is obviously superior to the existing PDE V inhibitor medicines sildenafil and vardenafil in the market. Pharmacological experiments show that the Yokenafil has high tolerance dose in animal bodies, good safety, obviously lower toxic and side effects than the existing medicaments in the market, and is expected to become a new treatment medicament for male sexual dysfunction.
Currently, eukenafil has already applied for patent protection in China and the United states (Chinese application No. CN03142399. X; Chinese publication No. CN 1552714; U.S. application No. PCT/CN 2004/000487; U.S. publication No. WO2004/108726), and has also been reported as a new drug in China (eukenafil belongs to the 1.1 class of chemical drugs, namely, crude drugs and preparations thereof prepared by synthetic or semi-synthetic methods, and drugs which are not sold in the market at home and abroad). The research work of the drug effect, the pharmacology, the toxicology, the drug generation and the drug generation before clinic is finished, and the national drug approval center is going to perform technical evaluation on the clinical research of the variety.
Wherein 4-methyl-1-propyl-2-amino-1H-pyrrole-3-nitrile is used as an intermediate of Yokenafil, and the development of the synthesis process and the raw material cost thereof has very important significance.
In reference to the literature, only one patent CN112266349A reports the synthesis of 4-methyl-1-propyl-2-amino-1H-pyrrole-3-carbonitrile:
the epoxypropane and n-propylamine are substituted under the action of alkali, then the amino group is protected, the amino group is deprotected after the alcohol is oxidized into aldehyde, and finally the amino group and malononitrile are cyclized under the action of alkali to obtain the 4-methyl-1-propyl-2-amino-1H-pyrrole-3-nitrile.
The disadvantages of this route are: the hydrogen peroxide belongs to an easily explosive product, and the production amplification is dangerous; the reaction steps are long, the labor cost is high, and the industrial production is not facilitated.
The processes reported in the above documents require the use of tubular products, are dangerous to handle and have long steps, and therefore it is necessary to find a simple and low-cost route suitable for industrialization.
Disclosure of Invention
In order to solve the problems in the existing literature, a more efficient synthesis method is sought, the production cost is reduced, the synthesis steps of the compound are further researched, a low-cost route suitable for industrial production is found, and a new synthesis method is provided for pharmaceutical enterprises at home and abroad.
In order to overcome the defects in the prior art, the invention firstly provides a novel synthesis method.
The invention provides a novel preparation method for 4-methyl-1-propyl-2-amino-1H-pyrrole-3-nitrile, has the advantages of short steps, no use of dangerous reagents, mild conditions, simple operation and capability of realizing stable industrial production and preparation.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a process for the preparation of 4-methyl-1-propyl-2-amino-1H-pyrrole-3-carbonitrile comprising:
carrying out condensation reaction on malononitrile and acetone under the action of alkali to obtain a compound shown in a formula (I);
brominating a compound of formula (I) to obtain a compound of formula (II);
condensing the compound of the formula (II) and propylamine, and then closing a ring to obtain a target product, namely a compound of a formula (III);
wherein the structural formulas of the compounds of the formulas (I) to (III) are as follows:
in some embodiments, the preparation method specifically comprises the following steps:
step 1), carrying out condensation reaction on raw material malononitrile and acetone in a reaction solvent under the action of inorganic base to obtain a compound shown in a formula (I);
step 2), reacting the compound of formula (I) with N-bromosuccinimide to obtain a compound of formula (II);
and 3) condensing the compound shown in the formula (II) with propylamine and performing ring closing reaction to obtain the compound shown in the formula (III).
In some embodiments, in step 1), the alkali is an inorganic alkali, preferably aluminum oxide.
In some embodiments, in step 1), the reaction solvent is one or more of chloroform, dichloromethane and dichloroethane, and chloroform is preferred.
In some embodiments, in step 1), the reaction temperature is 20 to 25 ℃ and the reaction time is 1 to 2 hours.
In some embodiments, in step 2), the reaction temperature is 60-70 ℃ and the reaction time is 10-15 h.
In some embodiments, in step 2), a catalyst, benzoyl peroxide, is also added during the reaction.
In some embodiments, in step 3), the reaction solvent is one or more of ethanol, methanol and ethyl acetate; ethanol is preferred.
In some embodiments, in step 3), the reaction temperature is 20-30 ℃ and the reaction time is 6-8 h.
Has the advantages that:
the preparation method of the Yokenafil intermediate 4-methyl-1-propyl-2-amino-1H-pyrrole-3-nitrile provided by the invention has the advantages of short steps, simple and convenient reaction operation, mild conditions and contribution to industrial production.
The method is characterized by comprising the following steps: cheap raw materials, simple and convenient reaction operation and mild conditions. Firstly, a new synthesis method is provided, malononitrile and acetone are subjected to three steps of condensation, bromination and condensation with propylamine to carry out cyclization reaction to obtain a target compound, the steps are shorter than those of a route reported in a literature, and raw materials are cheap and easy to obtain; secondly, hydrogen peroxide which is an easily explosive product is avoided, and the reaction condition is mild; the method not only reduces the cost, but also simplifies the operation, avoids the resource waste and greatly reduces the three wastes, thereby having important significance for researching and developing the preparation method of the Yokenafil intermediate and amplifying the production.
Detailed Description
The present invention will be further described with reference to the following examples.
In this application, abbreviation reference table
| NBS | N-bromosuccinimide |
| EA | Ethyl acetate |
| HCl | Hydrogen chloride |
| 1H-NMR | Hydrogen spectrum of nuclear magnetic resonance |
| LC | Liquid phase analysis method |
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The test materials and reagents used in the following examples are commercially available without specific reference.
The compound is a Yokenafil intermediate 4-methyl-1-propyl-2-amino-1H-pyrrole-3-nitrile, and the chemical structural formula is as follows:
the preparation method comprises the following steps: the method comprises the following steps of condensing malononitrile and acetone under the action of alkali to obtain a compound shown in a formula (I), brominating the compound shown in the formula (I) to obtain a compound shown in a formula (II), condensing the compound shown in the formula (II) and propylamine, and then performing ring closure to obtain a target product shown in the formula (III).
The synthetic route is as follows:
the first embodiment is as follows:
malononitrile (11.67g,0.177mol), acetone (13mL,0.177mol) and chloroform (100mL) were added to the reaction flask, and alumina (35g) was added slowly. After the dropwise addition, the reaction is carried out for 1h at the temperature of 20-25 ℃. After completion of the reaction, filtration, extraction with chloroform (2 × 50mL) and concentration gave 17g of the compound of formula (i) (yield 100%).
Example two:
the intermediate compound of formula (I) (30g,0.28mol), NBS (65g,0.37mol), benzoyl peroxide (0.6g,2.48mmol) and chloroform (90mL) were added to a reaction flask, and the mixture was heated to 60-70 ℃ for reflux reaction for 15 hours. After the reaction, the reaction mixture was cooled, filtered, washed with chloroform, and the filtrate was concentrated and then distilled to obtain 36.6g of the compound of the formula (II) (yield 70%).
Example three:
a reaction flask was charged with compound of formula (II) (13.1g,62mmol), n-propylamine (5.5g,93mmol), ethanol (1)00mL) at 20-30 ℃ for 6h, after the LC controlled reaction is completed, decompressing and draining the ethanol, adding 200mL of water and 200mL of ethyl acetate, separating out an organic phase, draining to obtain a crude product, adding HCl/EA (hydrochloric acid)/EA (acetic acid) into the crude product to form a salt, separating out a product, filtering, and dissociating to obtain 10.4g of a compound (III) (the yield is 90%).1H NMR(400MHz,DMSO)δ0.801-0.838(m,3H),1.534-1.589(m,2H),1.916-1.919(s,3H),3.553-3.589(m,2H),5.626(s,2H),5.955-5.958(s,1H)。
The above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention and these are intended to be within the scope of the invention.
Claims (9)
1. A method for preparing 4-methyl-1-propyl-2-amino-1H-pyrrole-3-carbonitrile, comprising:
carrying out condensation reaction on malononitrile and acetone under the action of alkali to obtain a compound shown in a formula (I);
brominating a compound of formula (I) to obtain a compound of formula (II);
condensing the compound of the formula (II) and propylamine, and then closing a ring to obtain a target product, namely a compound of a formula (III);
wherein the structural formulas of the compounds of the formulas (I) to (III) are as follows:
2. the method of claim 1, comprising the steps of:
step 1), carrying out condensation reaction on raw material malononitrile and acetone in a reaction solvent under the action of inorganic base to obtain a compound shown in a formula (I);
step 2), reacting the compound of the formula (I) with N-bromosuccinimide to obtain a compound of a formula (II);
and 3) condensing the compound shown in the formula (II) and propylamine, and carrying out ring closing reaction to obtain the compound shown in the formula (III).
3. The preparation method according to claim 2, wherein in the step 1), the alkali is an inorganic alkali, preferably aluminum oxide.
4. The preparation method according to claim 2, wherein in the step 1), the reaction solvent is one or more of chloroform, dichloromethane and dichloroethane.
5. The method according to claim 2, wherein the reaction temperature in step 1) is 20 to 25 ℃ and the reaction time is 1 to 2 hours.
6. The preparation method according to claim 2, wherein the reaction temperature in step 2) is 60-70 ℃ and the reaction time is 10-15 h.
7. The method according to claim 2, wherein in step 2), benzoyl peroxide is added as a catalyst during the reaction.
8. The preparation method according to claim 2, wherein in the step 3), the reaction solvent is one or more of ethanol, methanol and ethyl acetate.
9. The method according to claim 2, wherein the reaction temperature in step 3) is 20-30 ℃ and the reaction time is 6-8 hours.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002057267A1 (en) * | 2000-12-01 | 2002-07-25 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine a1, a2a, and a3 receptor and uses thereof |
| US20030073708A1 (en) * | 2000-12-01 | 2003-04-17 | Castelhano Arlindo L. | Compounds specific to adenosine A3 receptor and uses thereof |
| WO2003048120A2 (en) * | 2001-11-30 | 2003-06-12 | Osi Pharmaceuticals, Inc. | 2-aryl pyrrologpyrimidines for a1 and a3 receptors |
| US6878716B1 (en) * | 1998-06-02 | 2005-04-12 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 receptor and uses thereof |
| CN112266349A (en) * | 2020-11-17 | 2021-01-26 | 上海凌凯医药科技有限公司 | Method for preparing 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile |
-
2021
- 2021-12-29 CN CN202111637487.0A patent/CN114085178A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6878716B1 (en) * | 1998-06-02 | 2005-04-12 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 receptor and uses thereof |
| WO2002057267A1 (en) * | 2000-12-01 | 2002-07-25 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine a1, a2a, and a3 receptor and uses thereof |
| US20030073708A1 (en) * | 2000-12-01 | 2003-04-17 | Castelhano Arlindo L. | Compounds specific to adenosine A3 receptor and uses thereof |
| WO2003048120A2 (en) * | 2001-11-30 | 2003-06-12 | Osi Pharmaceuticals, Inc. | 2-aryl pyrrologpyrimidines for a1 and a3 receptors |
| CN112266349A (en) * | 2020-11-17 | 2021-01-26 | 上海凌凯医药科技有限公司 | Method for preparing 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile |
Non-Patent Citations (2)
| Title |
|---|
| SØREN LINDBÆK BROMAN ET AL.: "A Bis(heptafulvenyl)-dicyanoethylene Thermoswitch with Two Sites for Ring Closure", 《ORGANIC LETTERS》, vol. 14, no. 1, pages 318 - 321 * |
| YUHPYNG L. CHEN ET AL.: "Synthesis and Oral Efficacy of a 4-(Butylethylamino)pyrrolo[2, 3-d]pyrimidine:A Centrally Active Corticotropin-Releasing Factor 1 Receptor Antagonist", 《J. MED. CHEM.》, vol. 40, pages 1749 - 1754 * |
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