CN103172635A - Piperazine or piperidine compound as well as salts, intermediates, preparation method and application thereof - Google Patents

Piperazine or piperidine compound as well as salts, intermediates, preparation method and application thereof Download PDF

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CN103172635A
CN103172635A CN2011104332731A CN201110433273A CN103172635A CN 103172635 A CN103172635 A CN 103172635A CN 2011104332731 A CN2011104332731 A CN 2011104332731A CN 201110433273 A CN201110433273 A CN 201110433273A CN 103172635 A CN103172635 A CN 103172635A
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amino
tetrahydrochysene
pyrazinyl
compound
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CN103172635B (en
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孟祥国
蔡正艳
周伟澄
蒋婧章
朱怡君
葛渊源
严萍萍
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Abstract

The invention discloses a piperazine or piperidine compound or salts thereof. The invention also discloses a preparation method of formula I and the preparation method comprises the step of condensing formula II and R7H in a solvent at the temperature of 10-30 DEG C under the action of alkali. The invention also discloses a preparation method of the salts of the formula I, comprising the steps of when formula VII and formula IR3 =H, F or NO2, sequentially carrying out amino protection reaction on the formula II to obtain formula V, carrying out ester hydrolysis on the formula V to obtain formula VI, carrying out condensation reaction on the formula VI and the R7H to obtain formula VII and carrying out deprotection and salification on the formula VII, wherein when formula VIIR3=NO2 and the formula IR3=NH2, the method also comprises the step of nitro reduction after the step of condensation and before the step of deprotection and salification. The invention also discloses a preparation method of intermediates in the formula I compound. The invention also discloses the intermediates in the preparation method of the formula I. The piperazine or piperidine compound or the salts thereof, disclosed by the invention, provides a new direction for the research and the development of DPP-4 (Dipeptidyl Peptidase-4) inhibitors and has important significance on developing the DPP-4 inhibitors.

Description

Piperazine or piperidines, its salt, intermediate, preparation method and application
Technical field
The invention belongs to the pharmaceutical chemistry synthesis technical field, be specifically related to novel structure, have piperazine or piperidines, its intermediate, its pharmacologically acceptable salts, its preparation method and application thereof that potential DPP-4 suppresses activity.
Background technology
Diabetes are diseases of a class serious threat human health.According to the World Health Organization, approximately there are 1.8 hundred million diabetic subjects in the whole world, and wherein 90% is diabetes B, expects the year two thousand thirty this numeral also with double.The treatment of diabetes B is take the small molecules oral medicine as main at present, sulfonylurea, meglitinide, biguanides and thiazolidinediones are the medicines commonly used of diabetes B, but these ofhypoglycemic medicines of life-time service can cause the patient that the untoward reactions such as hypoglycemia, body weight increase, Instreptozotocin Induced damage occur.The deficiency of traditional orally-taken blood sugar reducing medicine can be effectively avoided in the discovery of DPP-4 inhibitor, and DPP-4 is generally considered the novel targets of most promising treatment diabetes B.
DPP-4 also claims CD26, separated in rat liver first in 1966 and obtain, its protein three-dimensional structure was determined in 2003, DPP-4 is the high specific serine protease that exists with dimeric forms, and its natural substrate is glucagon-like-peptide-1 (GLP-1) and glucose pancreotropic hormone polypeptide (GIP).GLP-1 have dependence on the glucose insulin secretion accelerating, suppress glucagon secretion, promote beta Cell of islet regeneration and repair and delay after the meal the function such as stomach emptying, GIP has the insulin secretion accelerating function equally.DPP-4 can make it inactivation by interior GLP-1 and the GIP of fast degradation body.The DPP-4 inhibitor reduces the catalytic activity of enzyme by competitive binding DPP-4 active site, thereby the amount that increases the interior GLP-1 of body and GIP reaches the effect that promotes insulin secretion.The DPP-4 inhibitor can be stablized control blood sugar, improves the β cell function, and can not cause the increase of weight in patients, and can avoid risk of hypoglycemia, has significant advantage aspect drug safety, is the very promising medicine of a class.
after the crystalline structure report of DPP-4 in 2003, many new texture types in recent years, potent, the DPP-4 inhibitor that selectivity is high goes on the market in succession, sitagliptin phosphate (sitagliptin phosphate as Merck ﹠ Co., Inc.'s research and development, go on the market in the U.S. in October, 2006), vildagliptin (the vildagliptin of Novartis Co.,Ltd's research and development, obtain EU Committee approval in September, 2007) and the BMS-477118 (saxagliptin that develops cooperatively of Bristol-Myers Squibb Co. and Astrazeneca AB, in August, 2009 drugs approved by FDA listing), the SYR-322 of Wu Tian company (alogliptin benzoate, go on the market in Japan in April, 2010) and the Linagliptin (BI-1356 of Boehringer Ingeheim company, in May, 2011 U.S.'s listing).
At present, the DPP-4 inhibitor that contains Aminocycloalkane or piperazine fragment becomes a new direction of ofhypoglycemic medicine exploitation.Therefore, the compound of research structure novelty, piperidines or piperazine fragment is significant to developing potential DPP-4 inhibitor.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of piperazine or piperidines, its salt, intermediate, preparation method and application.Piperazine of the present invention or piperidines and salt thereof provide a new direction for the research and development of DPP-4 inhibitor, and is significant to developing potential DPP-4 inhibitor.
The invention provides a kind of suc as formula the piperazine shown in I or piperidines or its salt,
Figure BSA00000641198400021
Formula I
Wherein, X is C or N;
R 1And R 5Be H, F or NO independently 2(preferred R 1And R 5One of them is H or F, and another is H, F or NO 2);
R 2And R 4Be H or F independently;
R 3Be H, F, NO 2Or NH 2
R 6Be H or NH 2
R 7It is 5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino, pyridine-2-amino, pyridine-2-methylamino-, 6-fluorine pyridine-3-is amino, 1-oxo pyridine-2-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-.
Described salt preferably salt hydrochlorate, hydrobromate, vitriol, nitrate or phosphoric acid salt, more preferably hydrochloride.
Described formula I compound is preferred
X=N, R 1=R 4=R 6=H, R 2=R 3=R 5=F and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl (I-2), 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl (I-1), 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyls (I-3), 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl (I-4), three the ring [3,3,1,1 3,7] decane amino (I-5), 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino (I-6), 1-(three rings [3,3,1,1 3,7] decyl) ethylamino (I-7), 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, pyridine-2-amino (I-8), pyridine-2-methylamino-, amino (I-9), 1-oxo pyridine-2-is amino for 6-fluorine pyridine-3-, 2-cyanopyrrole base (I-11) or 1-(1-ethyl-2-pyrryl) methylamino-(I-10);
Or X=N, R 2=R 3=R 6=H, R 1=NO 2, R 4=R 5=F and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl (I-13), 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl (I-12), 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyls (I-14), 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl (I-15), three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino (I-16), 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino, pyridine-2-amino, pyridine-2-methylamino-, 6-fluorine pyridine-3-is amino, 1-oxo pyridine-2-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-;
Or X=C, R 1=R 2=F, R 3=NO 2, R 4=R 5=H, R 6=NH 2And R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl (I-18), 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl (I-17), 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyls (I-19), 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl (I-20), three the ring [3,3,1,1 3,7] decane amino (I-21), 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino (I-22), 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino (I-23), pyridine-2-amino, pyridine-2-methylamino-(I-24), 6-fluorine pyridine-3-are amino, 1-oxo pyridine-2-amino (I-25), 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-;
Or X=C, R 1=R 2=F, R 3=NH 2, R 4=R 5=H, R 6=NH 2And R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl (I-26), 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyls (I-27), 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl (I-28), three the ring [3,3,1,1 3,7] decane amino (I-29), 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino (I-30), 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino (I-31), pyridine-2-amino (I-34), pyridine-2-methylamino-(I-32), 6-fluorine pyridine-3-are amino, 1-oxo pyridine-2-amino (I-33), 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-.
Described formula I compound more preferably
X=N, R 1=R 4=R 6=H, R 2=R 3=R 5=F and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, pyridine-2-is amino, 6-fluorine pyridine-3-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-;
Or X=N, R 2=R 3=R 6=H, R 1=NO 2, R 4=R 5=F and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl or 1-(three rings [3,3,1,1 3,7] decyl) ethylamino;
Or X=C, R 1=R 2=F, R 3=NO 2, R 4=R 5=H, R 6=NH 2And R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, pyridine-2-methylamino-or 1-oxo pyridine-2-amino;
Or X=C, R 1=R 2=F, R 3=NH 2, R 4=R 5=H, R 6=NH 2And R 7=3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, three rings [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, pyridine-2-is amino, pyridine-2-methylamino-or 1-oxo pyridine-2-amino.
The present invention also provides the preparation method of a kind of piperazine or piperidines (formula I), and it comprises the following steps: in solvent, under the effect of alkali, with formula II compound and R 7H carries out condensation reaction, and temperature of reaction is 10 ℃～30 ℃, gets final product;
Figure BSA00000641198400041
Formula II formula I
Wherein, X is N;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F, NO 2Or NH 2
R 6Be H or NH 2
Y is Cl;
R 7It is 5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino, pyridine-2-amino, pyridine-2-methylamino-, 6-fluorine pyridine-3-is amino, 1-oxo pyridine-2-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-.
Described R 1Preferred H or NO 2, R 2Preferred H or F, R 3Preferred H or F, R 4Preferred H or F, R 5Preferred F, R 6Preferred H, R 7Preferred 5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, pyridine-2-is amino, 6-fluorine pyridine-3-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-.
Described formula II compound is preferred
X=N, R 1=R 4=R 6=H, R 2=R 3=R 5=F and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino, pyridine-2-amino, pyridine-2-methylamino-, 6-fluorine pyridine-3-is amino, 1-oxo pyridine-2-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-;
Or X=N, R 2=R 3=R 6=H, R 1=NO 2, R 4=R 5=F and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino, pyridine-2-amino, pyridine-2-methylamino-, 6-fluorine pyridine-3-is amino, 1-oxo pyridine-2-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-.
Described formula II compound more preferably
X=N, R 1=R 4=R 6=H, R 2=R 3=R 5=F and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, pyridine-2-is amino, 6-fluorine pyridine-3-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-;
Or X=N, R 2=R 3=R 6=H, R 1=NO 2, R 4=R 5=F and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl or 1-(three rings [3,3,1,1 3,7] decyl) ethylamino.
Described condensation reaction can be the condensation reaction of this area routine.The present invention is following reaction conditions particularly preferably:
Described condensation reaction preferably includes the following step: with solution and the R of formula II compound 7H, alkali mix, and carry out condensation reaction, and temperature of reaction is 10 ℃～30 ℃, gets final product.One or more in the preferred methylene dichloride of described solvent, tetrahydrofuran (THF) and acetonitrile, more preferably methylene dichloride; The preferred 10-50mL/g formula of the consumption of described solvent II compound, more preferably 20-40mL/g formula II compound.The preferred pyridine of described alkali, triethylamine or 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene (being called for short DBU), more preferably triethylamine or DBU; The mol ratio preferred 1.0～3.0: 1 of described alkali and formula II compound, more preferably 1.2: 1.Described formula II compound and R 7The mol ratio of H preferred 1: 1～2, more preferably 1: 1.Preferred 15 ℃～25 ℃ of the temperature of reaction of described condensation reaction.The extent of reaction of described condensation reaction can be monitored by HPLC or TLC, when generally disappearing with formula II compound as reaction end, preferred 18h～25h, more preferably 15h～25h.The post-treating method of described condensation reaction preferably includes the following step: reaction system mixed with saturated sodium bicarbonate aqueous solution, uses dichloromethane extraction, and the organic phase anhydrous sodium sulfate drying, suction filtration, concentrated, through column chromatography purification, get final product; Described column chromatography eluent used is sherwood oil: ethyl acetate=1: 1; The method of described column chromatography can be selected according to the method for the column chromatography of this area routine.
Described formula I compound also can react with acid, makes the salt of above-mentioned formula I compound.Described acid can be the acid of this area routine, preferred hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid or phosphoric acid, more preferably hydrochloric acid.
Described formula II compound can be made by following method: in solvent, under the effect of alkali, formula III compound and acylating reagent are carried out acylation reaction, temperature of reaction is-20 ℃～10 ℃, gets final product;
Figure BSA00000641198400061
Formula III formula II
Wherein, X is N;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F, NO 2Or NH 2
R 6Be H or NH 2
Y is Cl.
Described R 1Preferred H or NO 2, R 2Preferred H or F, R 3Preferred H or F, R 4Preferred H or F, R 5Preferred F, R 6Preferred H.The preferred R of described formula III compound 1=R 4=R 6=H and R 2=R 3=R 5=F; Or R 2=R 3=R 6=H, R 1=NO 2And R 4=R 5=F.
Described acylation reaction can be the acylation reaction of this area routine.The present invention is preferably as follows reaction conditions:
Described acylation reaction preferably includes the following step: under-20 ℃～10 ℃, with the solution of acylating reagent, mix with the solution of alkali and formula III compound, carry out acylation reaction and get final product.Described acylation reaction more preferably comprises the following steps; Under-5 ℃～0 ℃, the solution of alkali and formula III compound is added dropwise in the solution of acylating reagent, carries out acylation reaction and get final product.
One or more in the preferred methylene dichloride of described solvent, tetrahydrofuran (THF) and acetonitrile, more preferably methylene dichloride; The preferred 10-50mL/g formula III of the consumption of described solvent compound, more preferably 20mL/g formula III compound.The preferred pyridine of described alkali or triethylamine, more preferably pyridine; The mol ratio of described alkali and formula III compound preferred 1～3: 1, more preferably 1.2: 1.The preferred phosgene of described acylating reagent or triphosgene (being called for short BTC), more preferably triphosgene; The mol ratio of described acylating reagent and formula III compound preferred 0.3～3: 1, more preferably 0.4: 1.Preferred-10 ℃～0 ℃ of the temperature of reaction of described acylation reaction, more preferably-5 ℃～0 ℃.The reaction process of described acylation reaction can be monitored by TLC, when generally disappearing with the formula III compound as the terminal point of reaction, preferably 0.5h～3h, more preferably 1h.
The present invention also provides the preparation method of the salt of a kind of piperazine or piperidines, and it comprises the following steps:
R in formula VII and formula I compound 3=H, F or NO 2The time, formula H compound is carried out amido protecting react to get formula V compound, above-mentioned formula V compound is carried out ester hydrolysis reaction get formula VI compound, with above-mentioned formula VI compound and R 7H carries out condensation reaction and gets formula VII compound, and above-mentioned formula VII compound is carried out the salt that deprotection, salt-forming reaction get formula I compound, gets final product;
Figure BSA00000641198400071
R in formula VII compound 3=NO 2And the R in formula I compound 3=NH 2The time, after described condensation reaction, also comprise before deprotection, salt-forming reaction nitro-reduction reaction the R3 in formula VII compound being reduced to amino;
Wherein, X=C;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 6Be NH 2
Y is OC 2H 5
R 7It is 5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino, pyridine-2-amino, pyridine-2-methylamino-, 6-fluorine pyridine-3-is amino, 1-oxo pyridine-2-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-.
Described R 1Preferred F, R 2Preferred F, R 3Preferred NO 2, R 4Preferred H, R 5Preferred H, R 7Preferred 5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, pyridine-2-methylamino-or 1-oxo pyridine-2-amino.
The preferred R of described formula II compound 1=R 2=F, R 3=NO 2, R 4=R 5=H and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino, pyridine-2-amino, pyridine-2-methylamino-, 6-fluorine pyridine-3-is amino, 1-oxo pyridine-2-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-;
Described formula II compound is R more preferably 1=R 2=F, R 3=NO 2, R 4=R 5=H and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino, pyridine-2-methylamino-, 1-oxo pyridine-2-is amino.
Described formula II compound can be made by the method for above-mentioned preparation formula II compound.
Described amido protecting reaction, ester hydrolysis reaction, condensation reaction and deprotection, salt-forming reaction can be amido protecting reaction, ester hydrolysis reaction, condensation reaction and deprotection, the salt-forming reaction of this area routine.The present invention is following reaction conditions particularly preferably:
Described amido protecting reaction preferably includes the following step: in solvent, under the effect of alkali, formula II compound and amido protecting agent are carried out the amido protecting reaction, temperature of reaction is 10 ℃～30 ℃, gets final product.The reaction of described amido protecting more preferably comprises the following steps: the solution of formula II compound to carry out amido protecting with amido protecting agent and to react with after alkali mixes, and temperature of reaction is 10 ℃～30 ℃, gets final product.
In the reaction of described amido protecting, one or more in described solvent ethyl acetate, methylene dichloride and tetrahydrofuran (THF), more preferably methylene dichloride, the preferred 10mL/g formula of the consumption of described solvent II compound.One or more in the preferred pyridine of described alkali, diisopropylethylamine and triethylamine, more preferably triethylamine; The mol ratio preferred 1～2: 1 of described alkali and formula II compound, more preferably 1.2: 1.The preferred chloroformic acid benzyl ester of described amido protecting agent or tert-Butyl dicarbonate, more preferably tert-Butyl dicarbonate; The mol ratio preferred 1～2: 1 of described amido protecting agent and formula II compound, more preferably 1.2: 1.Preferred 15 ℃～25 ℃ of the temperature of reaction of described amido protecting reaction.The reaction process of described amido protecting reaction can be monitored by TLC or HPLC, when generally disappearing with formula II compound as the terminal point of reaction, preferably 1h～5h, more preferably 3h.The post-treating method of described amido protecting reaction preferably includes the following step: remove solvent under reduced pressure, through column chromatography purification, get final product; The preferred sherwood oil of eluent that described column chromatography is used: ethyl acetate=2: 1.
Described ester hydrolysis reaction preferably includes the following step: in solvent, under the effect of alkali, after formula V compound is carried out ester hydrolysis reaction, be acidified to pH=3～4 through acid, temperature of reaction is 10 ℃～30 ℃, gets final product.Described ester hydrolysis reaction more preferably comprises the following steps: the solution of formula V compound is mixed with alkali, after carrying out ester hydrolysis reaction, is acidified to pH=3～4 through acid, and temperature of reaction is 10 ℃～30 ℃, gets final product.
In described ester hydrolysis reaction, one or more in described solvent preferably water, acetonitrile, ethanol and tetrahydrofuran (THF), more preferably tetrahydrofuran (THF): water=1: 1 (V/V); The preferred 20mL/g formula of the consumption of described solvent V compound.One or more in the preferred sodium hydroxide of described alkali, sodium carbonate and potassium hydroxide, more preferably sodium hydroxide; The mol ratio preferred 1～10: 1 of described alkali and formula V compound, more preferably 3: 1.One or more in described sour preferably sulfuric acid, hydrochloric acid and phosphoric acid, more preferably hydrochloric acid; Described acid preferably participates in reaction with the form of the aqueous solution; Preferred 1～the 12mol/L of the concentration of described aqueous acid, more preferably 6mol/L.Preferred 10 ℃～30 ℃ of the temperature of reaction of described ester hydrolysis reaction.The reaction process of described ester hydrolysis reaction can be monitored by TLC or HPLC, when generally disappearing with formula V compound as the terminal point of reaction, preferably 0.5h～5h, more preferably 2h.The post-treating method of described ester hydrolysis reaction preferably includes the following step: with the reaction system dichloromethane extraction, and the organic phase anhydrous sodium sulfate drying, suction filtration, concentrated, get final product.
Described condensation reaction preferably includes the following step: in solvent, under the effect of condensation reagent, with formula VI compound and R 7H carries out condensation reaction, and temperature of reaction is 0 ℃～50 ℃, gets final product.Described condensation reaction more preferably comprises the following steps: formula VI compound and R 7The solution of H mixes with condensation reagent, carries out condensation reaction, and temperature of reaction is 10 ℃～40 ℃, gets final product.Described condensation reaction most preferably comprises the following steps: formula VI compound and R 7The solution of H mixes with condensation reagent, reacts 1～24h under 10 ℃～30 ℃, gets final product.
In described condensation reaction, one or more in the preferred methylene dichloride of described solvent, ethyl acetate, tetrahydrofuran (THF) and DMF, more preferably DMF; The preferred 10mL/g formula of the consumption of described solvent VI compound.the preferred 2-of described condensation reagent (7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (being called for short HATU), benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (being called for short HBTU), I-hydroxybenzotriazole (being called for short HOBt)/1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (being called for short EDCHCl), dicyclohexylcarbodiimide (being called for short DCC), block one or more in special condensing agent (being called for short BOP-reagent) and 1H-benzotriazole-1-base oxygen tripyrrole alkyl hexafluorophosphate (being called for short PyBOP), preferred HATU and/or HOBt/EDCHCl, the mol ratio preferred 1～2: 1 of described condensation reagent and formula VI compound, more preferably 1.14: 1.Preferred 10 ℃～30 ℃ of the temperature of reaction of described condensation reaction.The reaction process of described condensation reaction can be monitored by TLC or HPLC, when generally disappearing with formula VI compound as the terminal point of reaction, preferably 10h～25h, more preferably 12h～20h.The post-treating method of described condensation reaction preferably includes the following step: reaction system is mixed with water and organic solvent, and organic phase washes with water 3 times successively, and saturated aqueous sodium carbonate is washed 3 times, the organic phase anhydrous sodium sulfate drying, and suction filtration, concentrated, get final product; Described organic solvent ethyl acetate or methylene dichloride; After described washing, saturated aqueous sodium carbonate wash before also available saturated sodium-chloride water solution wash; Preferred 1: 1 of the volume ratio of described water and ethyl acetate; Preferred 1: 1 of the volume ratio of the solvent in described water and condensation reaction.
Described deprotection, salt-forming reaction preferably include the following step: at the C of acid 1～C 4Alcoholic solution in, formula VII compound is carried out deprotection, salt-forming reaction, temperature of reaction is 10 ℃～30 ℃, gets final product.
In described deprotection, salt-forming reaction, the preferred hydrochloric acid of described acid; Described C 1～C 4Pure particular methanol and/or ethanol, more preferably methyl alcohol; The C of described acid 1～C 4The preferred 2mol/L～10mol/L of concentration of alcoholic solution, more preferably 2mol/L～3mol/L; The C of described acid 1～C 4The preferred 10mL/g formula of alcoholic solution consumption VII compound.Preferred 15 ℃～25 ℃ of the temperature of reaction of described deprotection, salt-forming reaction.The reaction process of described deprotection, salt-forming reaction can be monitored by HPLC or TLC, when generally disappearing with formula VII compound as the terminal point of reaction, preferably 1h～5h, more preferably 1h～2h.The post-treating method of described deprotection, salt-forming reaction preferably includes the following step: remove solvent under reduced pressure, carry out recrystallization with the mixing solutions of methyl alcohol and Virahol or methyl alcohol and ether, suction filtration gets final product.
Described nitro-reduction reaction can be the nitro-reduction reaction of this area routine.The present invention is following condition particularly preferably:
Described nitro-reduction reaction preferably includes the following step: in solvent, under the effect of catalyzer, with formula VII compound with go back original reagent and carry out nitro-reduction reaction, get final product.Described nitro-reduction reaction more preferably comprises the following steps: solution and the catalyst mix with formula VII compound, then carries out nitro-reduction reaction with the reduction reagent mix, gets final product.
In described nitro-reduction reaction, described solvent preferred alcohol and/or methyl alcohol, more preferably methyl alcohol; The preferred 10mL/g formula of the consumption of described solvent VII compound.The preferred palladium carbon of described catalyzer (Pd/C); Palladium preferred mass mark in described palladium carbon is 10%; The mass ratio preferred 1～3: 10 of described catalyzer and formula VII compound, more preferably 1: 10.Described original reagent preferable formic acid ammonium or the hydrogen gone back; Described mol ratio preferred 1～10: 1 of going back original reagent and formula VII compound, more preferably 3: 1.When going back original reagent and be ammonium formiate, preferred 20 ℃～70 ℃ of the temperature of reaction of described nitro-reduction reaction, more preferably 55 ℃～65 ℃; When going back original reagent and be hydrogen, preferred 20 ℃～80 ℃ of the temperature of reaction of described nitro-reduction reaction, more preferably 70 ℃ (outer temperature).The reaction process of described nitro-reduction reaction can be monitored by TLC or HPLC, when generally disappearing with formula VII compound as the terminal point of reaction, preferably 2h～40h, more preferably 3h～30h.The post-treating method of described nitro-reduction reaction preferably includes the following step: removes solvent under reduced pressure, is dissolved in ethyl acetate, wash 3 times, and the organic phase anhydrous sodium sulfate drying, suction filtration, concentrated, get final product.
The salt of described formula I compound can further make formula I compound with alkali reaction.Described alkali can be the alkali of this area routine.The condition of described reaction can be selected by the reaction conditions of the acid-base neutralisation of this area routine.
Described formula II compound can be made by following method: in solvent, formula IV compound and reductive agent are carried out reduction reaction, temperature of reaction is 0 ℃～50 ℃, gets final product;
Figure BSA00000641198400111
Formula IV formula II
Wherein, X is C;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
R 6Be NH 2
Y is OC 2H 5
Described R 1Preferred F, R 2Preferred F, R 3Preferred NO 2, R 4Preferred H, R 5Preferred H.The preferred R of described formula IV compound 1=R 2=F, R 3=NO 2And R 4=R 5=H.
Described reduction reaction can be the reduction reaction of this area routine.The present invention is following reaction conditions particularly preferably:
Described reduction reaction preferably includes the following step: under 0 ℃～50 ℃, the solution of formula IV compound is mixed with reductive agent, carry out reduction reaction, get final product.
The preferred methylene dichloride of described solvent, chloroform, tetracol phenixin, 1, one or more in 2-ethylene dichloride and acetonitrile, more preferably 1,2-ethylene dichloride and/or acetonitrile; Preferred 5～20mL/g the formula of the consumption of described solvent IV compound, more preferably 8mL/g formula IV compound.The preferred sodium borohydride of described reductive agent, sodium cyanoborohydride or sodium triacetoxy borohydride, more preferably sodium triacetoxy borohydride or sodium borohydride; The mol ratio preferred 1～5: 1 of described reductive agent and formula IV compound, more preferably 3: 1.Preferred 10 ℃～20 ℃ of the temperature of reaction of described reduction reaction.The reaction process of described reduction reaction can be monitored by HPLC or TLC, when generally disappearing with formula IV compound as the terminal point of reaction, preferably 12h～16h, more preferably 14h.The post-treating method of described reduction reaction preferably includes the following step: with reaction system and combined, stir, isolate water, it is mixed with methylene dichloride, and the pH value of system is adjusted to 8～9 with alkali, isolate organic phase, with the saturated sodium-chloride water solution washing, and use anhydrous sodium sulfate drying, suction filtration, concentrated, get final product; The concentration of described aqueous hydrochloric acid is 2mol/L.The volume ratio of the solvent in described hydrochloric acid and reduction reaction preferred 1～3: 1, more preferably 1: 1; The volume ratio of described methylene dichloride and hydrochloric acid preferred 1～3: 1, more preferably 1: 1; The mineral alkalis such as the preferred anhydrous sodium carbonate of described alkali or Anhydrous potassium carbonate, more preferably anhydrous sodium carbonate.
Described formula IV compound can be made by following method: in solvent, formula IX compound and ammonium acetate are carried out the alkene aminating reaction, get final product;
Figure BSA00000641198400121
Wherein, R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
Described R 1Preferred F, R 2Preferred F, R 3Preferred NO 2, R 4Preferred H, R 5Preferred H.The preferred R of described formula IX compound 1=R 2=F, R 3=NO 2And R 4=R 5=H.
Described alkene aminating reaction can be the alkene aminating reaction of this area routine, and the present invention is following reaction conditions particularly preferably:
Described alkene aminating reaction preferably includes the following step: the solution of formula IX compound is mixed with ammonium acetate, carry out the alkene aminating reaction, get final product.
One or more in the preferred Virahol of described solvent, ethanol and methyl alcohol, more preferably methyl alcohol; The preferred 10mL/g formula of the consumption of described solvent IX compound.The mol ratio preferred 1～5: 1 of described ammonium acetate and formula IX compound, more preferably 3: 1.Preferred 20 ℃～80 ℃ of the temperature of reaction of described alkene aminating reaction, more preferably 50 ℃～70 ℃.The reaction process of described alkene aminating reaction can be monitored by TLC or HPLC, when generally disappearing with formula IX compound as the terminal point of reaction, preferred 3h.The post-treating method of described alkene aminating reaction preferably includes the following step: remove solvent under reduced pressure, add acetic acid ethyl dissolution, and wash organic phase 3 times with saturated aqueous sodium carbonate successively, saturated sodium-chloride water solution is washed organic phase 1 time, merge organic phase, use anhydrous sodium sulfate drying, suction filtration, concentrated, get final product.
Described formula IX compound can be made by following method: under protection of inert gas, in solvent, under the effect of alkali, formula XII compound and 4-ethoxycarbonyl piperidines-3-keto hydrochloride are carried out nucleophilic substitution reaction, temperature of reaction is-20 ℃～30 ℃, gets final product;
Figure BSA00000641198400122
Wherein, R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
Described R 1Preferred F, R 2Preferred F, R 3Preferred NO 2, R 4Preferred H, R 5Preferred H.The preferred R of described formula XII compound 1=R 2=F, R 3=NO 2And R 4=R 5=H.
Described nucleophilic substitution reaction can be the nucleophilic substitution reaction of this area routine.The present invention is following reaction conditions particularly preferably:
Described nucleophilic substitution reaction preferably includes the following step: under protection of inert gas, the solution of 4-ethoxycarbonyl piperidines-3-keto hydrochloride with after alkali mixes, is carried out nucleophilic substitution reaction with formula XII compound, temperature of reaction is-20 ℃～30 ℃, gets final product.Described nucleophilic substitution reaction more preferably comprises the following steps: under protection of inert gas; at-15 ℃～-5 ℃, with solution and the alkali mixing 10min～20min of 4-ethoxycarbonyl piperidines-3-keto hydrochloride, at-10 ℃～0 ℃; dropping formula XII compound carries out nucleophilic substitution reaction, gets final product.
One or more in alcohol, DMF, dimethyl sulfoxide (DMSO) and the N-Methyl pyrrolidone of the preferred toluene of described solvent, methylene dichloride, chloroform, tetrahydrofuran (THF), ethyl acetate, acetone, 1～4 carbon, more preferably N-Methyl pyrrolidone; The preferred 8mL/g formula of the consumption of described solvent XII compound.The preferred triethylamine of described alkali, pyridine, diisopropylethylamine or DBU, more preferably diisopropylethylamine; The mol ratio preferred 1～5: 1 of described alkali and formula XII compound, more preferably 2.1: 1.The mol ratio preferred 1: 1～3 of described formula XII compound and 4-ethoxycarbonyl piperidines-3-keto hydrochloride, more preferably 1: 1.1.Described rare gas element preferred nitrogen.Preferred-10 ℃～25 ℃ of the temperature of reaction of described nucleophilic substitution reaction.The reaction process of described nucleophilic substitution reaction can be monitored by HPLC or TLC, when generally disappearing with formula XII compound as the terminal point of reaction, preferred 4h～6h.The post-treating method of described nucleophilic substitution reaction preferably includes the following step: reaction system is mixed with frozen water, and suction filtration, filter cake water and sherwood oil are successively washed, and oven dry gets final product; Preferred 50 ℃～65 ℃ of the temperature of described oven dry.
The present invention also provides the preparation method of the intermediate II of a kind of piperazine or piperidines or its salt, and it is made by following either method,
Method one: in solvent, under the effect of alkali, formula III compound and acylating reagent are carried out acylation reaction, temperature of reaction is-20 ℃～10 ℃, gets final product;
Figure BSA00000641198400131
Formula III formula II
Wherein, X is N;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F, NO 2Or NH 2
R 6Be H or NH 2
Y is Cl;
Method two: in solvent, formula IV compound and reductive agent are carried out reduction reaction, temperature of reaction is 0 ℃～50 ℃, gets final product;
Formula IV formula II
Wherein, X is C;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
R 6Be NH 2
Y is OC 2H 5
Its each reaction conditions is all as the reaction conditions in the preparation method of above-mentioned formula II compound.
The present invention also provides suc as formula the piperazine shown in II, formula IX, formula IV, formula V, formula VI or formula VII or the intermediate of piperidines or its salt,
Figure BSA00000641198400142
Formula II
Wherein, Y is Cl or OC 2H 5
X is C or N;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F, NO 2Or NH 2
R 6Be H or NH 2
Figure BSA00000641198400143
Formula IX
Wherein, R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
Figure BSA00000641198400151
Formula IV
Wherein, R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
Formula V
Wherein, R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
Figure BSA00000641198400153
Formula VI
Wherein, R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
Figure BSA00000641198400154
Formula VII
Wherein, R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
R 7It is 5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino, pyridine-2-amino, pyridine-2-methylamino-, 6-fluorine pyridine-3-is amino, 1-oxo pyridine-2-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-.
In formula II compound, when X=N, described R 1Preferred H or NO 2, R 2Preferred H or F, R 3Preferred H or F, R 4Preferred H or F, R 5Preferred F, R 6Preferred H, the preferred Cl of Y.When X=C, described R 1Preferred F, R 2Preferred F, R 3Preferred NO 2, R 4Preferred H, R 5Preferred H, R 6Preferred NH 2, the preferred OC of Y 2H 5
The preferred X=N of described formula II compound, R 1=R 4=R 6=H, R 2=R 3=R 5=F and Y=Cl;
Or X=N, R 2=R 3=R 6=H, R 1=NO 2, R 4=R 5=F and Y=Cl;
Or X=C, R 1=R 2=F, R 3=NO 2, R 4=R 5=H and Y=OC 2H 5
In formula IX compound, described R 1Preferred F, R 2Preferred F, R 3Preferred NO 2, R 4Preferred H, R 5Preferred H.The preferred R of described formula IX compound 1=F, R 2=F, R 3=NO 2, R 4=H and R 5=H.
In formula IV compound, described R 1Preferred F, R 2Preferred F, R 3Preferred NO 2, R 4Preferred H, R 5Preferred H.The preferred R of described formula IV compound 1=F, R 2=F, R 3=NO 2, R 4=H and R 5=H.
In formula V compound, described R 1Preferred F, R 2Preferred F, R 3Preferred NO 2, R 4Preferred H, R 5Preferred H.The preferred R of described formula V compound 1=F, R 2=F, R 3=NO 2, R 4=H and R 5=H.
In formula VI compound, described R 1Preferred F, R 2Preferred F, R 3Preferred NO 2, R 4Preferred H, R 5Preferred H.The preferred R of described formula VI compound 1=F, R 2=F, R 3=NO 2, R 4=H and R 5=H.
In formula VII compound, described R 1Preferred F, R 2Preferred F, R 3Preferred NO 2, R 4Preferred H, R 5Preferred H, R 7Preferred 5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, pyridine-2-methylamino-or 1-oxo pyridine-2-amino.
The preferred R of described formula VII compound 1=F, R 2=F, R 3=NO 2, R 4=H, R 5=H and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino, pyridine-2-amino, pyridine-2-methylamino-, 6-fluorine pyridine-3-is amino, 1-oxo pyridine-2-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-;
Described formula VII compound is R more preferably 1=F, R 2=F, R 3=NO 2, R 4=H, R 5=H and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, pyridine-2-methylamino-or 1-oxo pyridine-2-amino.
The present invention also provides above-mentioned piperazine or amino piperidine compounds, its pharmacy acceptable salt, optical isomer or polymorphic form for the preparation of the application in the medicine that treats and/or prevents diabetes, hyperglycemia and insulin resistance.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, but arbitrary combination namely get the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material be commercially available getting all.
Positive progressive effect of the present invention is: piperazine of the present invention or piperidines and salt thereof provide a new direction for the research and development of DPP-4 inhibitor, and is significant to developing potential DPP-4 inhibitor.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example according to ordinary method and condition, or is selected according to catalogue.
In following examples, undefined abbreviation has its generally accepted implication, and unless stated otherwise, all room temperatures all refer to 20 ℃～30 ℃ of temperature.Table 1, table 2, table 3 and table 4 are respectively the physicochemical data of Compound I-1～I-11, the physicochemical data of Compound I-12～I-16, the physicochemical data of Compound I-17～I-25 and the physicochemical data of Compound I-26～I-34.
Embodiment of the method 1
Synthesizing of 1-chloroformyl-4-(2,4,5-trifluorophenyl) piperazine (II)
Triphosgene (254mg, 0.9mmol) is dissolved in the 10ml methylene dichloride, and cryosel is bathed cooling, make interior temperature drop to-5 ℃～0 ℃, slowly drip pyridine (219mg, 2.8mmol) and 1-(2,4,5-trifluorophenyl) dichloromethane solution of piperazine (500mg, 2.3mmol), temperature control is below 0 ℃, 10min adds, and maintains under 0 ℃ to react 1h the completely dissolve of TLC raw material, because the acyl chlorides activity is higher, not easily separated II drops into next step reaction with the form of crude product.
Embodiment of the method 2
Synthesizing of 1-chloroformyl-4-(2,4,5-trifluorophenyl) piperazine (II)
Pass into excessive phosgene in the 10ml methylene dichloride, cryosel is bathed cooling, makes interior temperature drop to-5 ℃～0 ℃, slowly drip triethylamine (282mg, 2.8mmol) and 1-(2,4, the 5-trifluorophenyl) piperazine (500mg, 2.3mmol) dichloromethane solution, temperature control is below 0 ℃, 10min adds, maintain under 0 ℃ and react 1h, the completely dissolve of TLC raw material, because the acyl chlorides activity is higher, not easily separated II drops into next step reaction with the form of crude product.
Embodiment of the method 3
Synthesizing of (4-(2,4,5-trifluorophenyl)-1-piperazinyl) (3-trifluoromethyl-5,6-dihydro-[1,2,4] triazoles [4,3-a]-7 (8H)-pyrazinyl) ketone (I-1)
Add 3-(trifluoromethyl)-5,6,7 in above-mentioned reaction solution, 8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazine (444mg, 2.3mmol) and triethylamine (273mg, 2.7mmol) rises to room temperature with temperature of reaction, stirs 20h.Add saturated sodium bicarbonate solution 20ml termination reaction, dichloromethane extraction (20ml * 2) merges organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated, column chromatography (sherwood oil: ethyl acetate=1: 1) get white powder solid 575mg, two step yields 57.2%.
I-2～I-10 is identical with the I-1 synthetic method; I-11 is by acylate and prolineamide generation condensation reaction, with diacetyl oxide, dehydration of amide is made at last; I-6 and I-7 use DBU as alkali when condensation reaction; I-10 is oily matter, and itself and hydrochloric acid salify are easy to preserve.
Embodiment of the method 4
Synthesizing of (4-(2,3-, two fluoro-6-nitrophenyls)-1-piperazinyl) (3-trifluoromethyl-5,6-dihydro-[1,2,4] triazoles [4,3-a]-7 (8H)-pyrazinyl) ketone (I-12)
Piperazine anhydrous (0.535g, 6.2mmol) is dissolved in 10ml toluene, agitation and dropping 2,3,4-trifluoronitrobenzene (1.000g, 5.6mmol), stirring at room 1h.Add the 15ml 2mol/L HCl aqueous solution, stir 30min, water is washed 3 times with toluene, tell water, add appropriate methylene dichloride, stir, anhydrous sodium carbonate is transferred pH8-9, tell dichloromethane layer, wash 1 time, the organic phase anhydrous sodium sulfate drying, concentrated to get orange-yellow oily thing 1-(2 at suction filtration, 3-two fluoro-6-nitrophenyls) piperazine crude product 1.013g, crude product yield 73.8%.
With two (trichloromethyl) carbonic ethers (being called for short BTC) (495mg, 1.7mmol) be dissolved in the 10ml methylene dichloride, cryosel is bathed cooling, makes interior temperature drop to-5 ℃～0 ℃, slowly drip pyridine (725mg, 9.2mmol) and the mixed solution of 1-(2,3-, two fluoro-6-nitrophenyls) piperazine crude product (1.013g, 4.2mmol), temperature control is below 0 ℃, 10min adds, and maintains under 0 ℃ to react 1h, directly carries out next step reaction.
Add 3-(trifluoromethyl)-5,6,7 in above-mentioned reaction solution, 8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazine (800mg, 4.2mmol) and triethylamine (842mg, 8.4mmol) rises to room temperature with temperature of reaction system, stirs 20h.Add saturated sodium bicarbonate solution 20ml termination reaction, dichloromethane extraction (20ml * 2) merges organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated, column chromatography (sherwood oil: ethyl acetate=3: 2) get yellow solid 1.254g, three step yields 48.1%.
I-13～I-16 is identical with the synthetic method of I-12.
Embodiment of the method 5
Synthesizing of (4-(2,3-, two fluoro-6-nitrophenyls)-1-piperazinyl) (3-trifluoromethyl-5,6-dihydro-[1,2,4] triazoles [4,3-a]-7 (8H)-pyrazinyl) ketone (I-12)
Piperazine anhydrous (0.535g, 6.2mmol) is dissolved in the 10ml DMF, agitation and dropping 2,3,4-trifluoronitrobenzene (1.000g, 5.6mmol) and triethylamine (0.566g, 5.6mmol), stirring at room 1h.Add the 15ml 2mol/L HCl aqueous solution, stir 30min, water is washed 3 times with ethyl acetate, tell water, add appropriate methylene dichloride, stir, anhydrous sodium carbonate is transferred pH8-9, tell dichloromethane layer, washing organic phase 3 times, the organic phase anhydrous sodium sulfate drying, concentrates and to get orange-yellow oily thing 1-(2 suction filtration, 3-two fluoro-6-nitrophenyls) piperazine crude product 1.213g, crude product yield 89.2%.
Excess phosgene is passed in the 10ml methylene dichloride, cryosel is bathed cooling, make interior temperature drop to-5 ℃～0 ℃, slowly drip pyridine (725mg, 9.2mmol) and 1-(2,3-two fluoro-6-nitrophenyls) piperazine crude product (1.213g, 5.0mmol) mixed solution, temperature control is below 0 ℃, 10min adds, maintain under 0 ℃ and react 1h, directly carry out next step reaction.
Add 3-(trifluoromethyl)-5,6,7 in above-mentioned reaction solution, 8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazine (800mg, 4.2mmol) and triethylamine (842mg, 8.4mmol) rises to room temperature with temperature of reaction system, stirs 20h.Add saturated sodium bicarbonate solution 20ml termination reaction, dichloromethane extraction (20ml * 2) merges organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated, column chromatography (sherwood oil: ethyl acetate=3: 2) get yellow solid 1.345g, three step yields 52.1%.
Embodiment of the method 6
Synthesizing of 1-(2,3-, two fluoro-4-nitrophenyls)-4-ethoxycarbonyl piperidines-3-ketone (IX)
4-ethoxycarbonyl piperidines-3-keto hydrochloride (50.000g, 0.24lmol) is dissolved in the 400ml N-Methyl pyrrolidone, and cryosel is bathed cooling; be cooled to-10 ℃; add diisopropylethylamine (59.300g, 0.460mol) under nitrogen protection, stir 15min; temperature control drips 2 at about-5 ℃; 3,4-trifluoronitrobenzene (38.800g, 0.219mol); add under rear 0 ℃ and react 2h, rise to room temperature and continue to stir 2h.Reaction solution is poured in the 2L frozen water, separated out the brown color solid, suction filtration, filter cake is washed with massive laundering, sherwood oil, the brown color solid 59.310g of oven dry, crude product yield 82.5%.m.p：117-120℃， 1H-NMR(CDCl 3)，δ(ppm)：7.88-7.83(m，1H，J＝9.6，7.6，2.2)，6.67-6.63(m，1H，J＝9.6，8.0，2.0)，4.26(q，2H，J＝6.8)，3.97(s，2H)，3.54(t，2H，J＝4.8)，2.51-2.49(m，2H)，1.33(t，3H，J＝6.8)。
Embodiment of the method 7
Synthesizing of 1-(2,3-, two fluoro-4-nitrophenyls)-4-ethoxycarbonyl piperidines-3-ketone (IX)
4-ethoxycarbonyl piperidines-3-keto hydrochloride (50.000g, 0.241mol) is dissolved in 400ml ethanol, and cryosel is bathed cooling; be cooled to-10 ℃; add triethylamine (51.060g, 0.460mol) under nitrogen protection, stir 15min; temperature control drips 2 at about-5 ℃; 3,4-trifluoronitrobenzene (38.800g, 0.219mol); add under rear 0 ℃ and react 2h, rise to room temperature and continue to stir 2h.Reaction solution is poured in the 2L frozen water, separated out the brown color solid, suction filtration, filter cake is washed with massive laundering, sherwood oil, the brown color solid 60.110g of oven dry, crude product yield 83.6%.
Embodiment of the method 8
1-(2,3-, two fluoro-4-nitrophenyls)-3-amino-4-ethoxycarbonyl-1,2,5,6-tetrahydropyridine (IV) synthetic
IX crude product (59.310g, 0.181mol) is dissolved in 600ml methyl alcohol, adds ammonium acetate (41.770g, 0.542mol) backflow 3h.Remove solvent under reduced pressure, add the 1L acetic acid ethyl dissolution, saturated sodium carbonate solution is washed organic phase (500ml * 3), saturated nacl aqueous solution 800ml washes 1 time, the organic phase anhydrous sodium sulfate drying, concentrated to get orange red solid crude product 60.400g at suction filtration, crude product yield approximately 100%.m.p：106-110℃， 1H-NMR(CDCl 3)，δ(ppm)：7.88-7.84(m，1H)，6.69-6.64(m，1H)，4.20(q，2H，J＝6.4)，3.99(s，2H)，3.57-3.54(t，2H，J＝5.6)，2.52(t，2H，J＝5.2)，1.37-1.28(m，3H)。
Embodiment of the method 9
Synthesizing of 1-(2,3-, two fluoro-4-nitrophenyls)-3-amino-4-ethoxycarbonyl piperidines (II)
500ml Glacial acetic acid ice-water bath is cooled to 10 ℃～20 ℃, adds sodium borohydride (20.9g, 0.550mol) in batches, and temperature control stirs 1h and prepares sodium triacetoxy borohydride at 10-20 ℃.Add above-mentioned IV crude product 60.400g and 1,2-ethylene dichloride 500ml, stirring at room 14h.Add 2mol/L HCl aqueous solution 400ml, stirring at room 1h, isolate water, add again the 500ml methylene dichloride and with the anhydrous sodium carbonate pH8-9 that alkalizes, isolate organic phase, saturated sodium-chloride water solution is washed organic phase, and uses anhydrous sodium sulfate drying, suction filtration, concentrated yellow solid 46.700g, the crude product yield 77.3% of getting.m.p：87-90℃。 1H-NMR(CDCl 3)，δ(ppm)：7.86-7.81(m，1H)，6.75-6.70(m，1H)，4.22(q，2H，J＝6.4)，3.70-3.52(m，2H)，3.52(m，1H)，3.19-2.98(m，2H)，2.71-2.66(m，1H)，2.23-1.94(m，2H)，1.31(t，3H，J＝6.4)。
Embodiment of the method 10
Synthesizing of 1-(2,3-, two fluoro-4-nitrophenyls)-3-amino-4-ethoxycarbonyl piperidines (II)
Above-mentioned IV crude product 60.400g is dissolved in the 500ml acetonitrile, adds sodium borohydride (20.9g, 0.550mol) in batches, and then temperature control is warming up to stirring at room 14h 0 ℃ of left and right after adding.Add 2mol/L HCl aqueous solution 400ml, stirring at room 1h, isolate water, add again the 500ml methylene dichloride and with the anhydrous sodium carbonate pH8-9 that alkalizes, isolate organic phase, saturated sodium-chloride water solution is washed organic phase, and uses anhydrous sodium sulfate drying, suction filtration, concentrated yellow solid 46.700g, the crude product yield 77.3% of getting.m.p：87-90℃。 1H-NMR(CDCl 3)，δ(ppm)：7.86-7.81(m，1H)，6.75-6.70(m，1H)，4.22(q，2H，J＝6.4)，3.70-3.52(m，2H)，3.52(m，1H)，3.19-2.98(m，2H)，2.71-2.66(m，1H)，2.23-1.94(m，2H)，1.31(t，3H，J＝6.4)。
Embodiment of the method 11
Synthesizing of 1-(2,3-, two fluoro-4-nitrophenyls)-3-t-butoxycarbonyl amino-4-ethoxycarbonyl piperidines (V)
Above-mentioned crude product II (46.700g, 0.142mol) is dissolved in the 500ml methylene dichloride, adds triethylamine (17.170g, 0.170mol), adds at last tert-Butyl dicarbonate (37.133g, 0.170mol), stirring at room 3h.Remove solvent under reduced pressure, column chromatography (sherwood oil: ethyl acetate=2: 1) get yellow solid 54.751g, nucleophilic substitution, alkene ammonification, reduction and four step of amido protecting total recovery 58.2%.m.p：126-129℃。 1H-NMR(CDCl 3)，δ(ppm)：7.87-7.83(m，1H)，6.76-6.71(m，1H)，5.26(s，1H)，4.30-4.19(m，3H)，3.67-3.47(m，2H)，3.26-3.15(m，2H)，2.85-2.81(m，1H)，2.20-1.96(m，2H)，1.58-1.44(m，9H)，1.33-1.29(m，3H)。
Embodiment of the method 12
Synthesizing of 1-(2,3-, two fluoro-4-nitrophenyls)-3-t-butoxycarbonyl amino-4-carboxylic acid piperidines (VI)
V (26.504g, 0.062mol) is dissolved in tetrahydrofuran (THF)/water 520ml (V/V=1: 1), add sodium hydrate solid (7.414g, 0.185mol), stirring at room 2h.6mol/L HCl acidified aqueous solution is to pH3-4, and dichloromethane extraction (100ml * 3) merges organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated faint yellow solid 24.200g, the yield 97.6% of getting.m.p：188-191℃。 1H-NMR(DMSO)，δ(ppm)：7.89-7.84(m，1H)，6.94-6.90(m，1H)，6.60-6.59(m，1H)，4.07(m，1H)，3.83-3.41(m，2H)，3.15-3.01(m，2H)，2.81-2.77(m，1H)，2.10-1.72(m，2H)，1.32(s，9H)。
Embodiment of the method 13
Synthesizing of (3-amino-1-(2,3-, two fluoro-4-nitrophenyls)-4-piperidyl) (3-trifluoromethyl-5,6-dihydro-[1,2,4] triazoles [4,3-a]-7 (8H)-pyrazinyl) ketone hydrochloride (I-17)
VI (2.0g, 5.0mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazine (0.912g, 4.7mmol) is dissolved in the anhydrous DMF of 20ml, add HOBt (0.770g, 5.7mmol) and EDCHCl (1.092g, 5.7mmol), stirring at room 20h.Add 20ml water and 20ml ethyl acetate after reaction, organic phase washing 3 times, saturated aqueous sodium carbonate is washed 3 times, the organic phase anhydrous sodium sulfate drying, suction filtration, concentrated yellow spumescence solid 2.967g, crude product yield＞100%, the re-crystallizing in ethyl acetate of getting, suction filtration, dry to get yellow solid 1.827g, recrystallization yield 63.6%. 1H-NMR(CDCl 3+D 2O)，δ(ppm)：7.89-7.84(m，1H)，6.77-6.73(m，1H)，5.29-5.00(m，2H)，4.57-4.11(m，5H)，3.68-3.65(m，2H)，3.22-3.03(m，3H)，2.43-1.81(m，2H)，1.37(s，9H)。
Yellow solid obtained above (1.000g, 1.7mmol) is dissolved in 10ml 2-3mol/L HCl/MeOH, and stirring at room 1h removes solvent under reduced pressure, and methanol/isopropanol recrystallization, suction filtration get yellow solid 0.503g, recrystallization yield 56.5%.
Get the above-mentioned yellow solid sterling of 100mg, be placed in 5ml methylene dichloride and 5ml sodium hydroxide saturated aqueous solution, stirred 1 hour, isolate organic phase, dichloromethane extraction water twice merges organic phase, the anhydrous sodium sulfate drying organic phase, suction filtration, concentrated, the free alkali that obtains Compound I-1 is yellow oil 85mg, because this free alkali is oily matter, is unfavorable for preserving, therefore, I-17～I～34 compounds are all preserved with the form of its hydrochloride.
The synthetic method of I-18～I-24 is identical with I-17, and I-25 uses HATU to be condensing agent, and DIEA is alkali.
Embodiment of the method 14
Synthesizing of (3-amino-1-(4-amino-2,3-difluorophenyl)-4-piperidyl) (3-trifluoromethyl-5,6-dihydro-[1,2,4] triazoles [4,3-a]-7 (8H)-pyrazinyl) ketone hydrochloride (I-26)
VI (2.0g, 5.0mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazine (0.912g, 4.7mmol) is dissolved in the anhydrous DMF of 20ml, add HOBt (0.770g, 5.7mmol) and EDCHCL (1.092g, 5.7mmol), stirring at room 20h.Add 20ml water and 20ml ethyl acetate after reaction, organic phase washing 3 times, saturated aqueous sodium carbonate is washed 3 times, the organic phase anhydrous sodium sulfate drying, suction filtration, concentrated yellow spumescence solid 2.967g, crude product yield＞100%, the re-crystallizing in ethyl acetate of getting, suction filtration, dry to get yellow solid 1.827g, recrystallization yield 63.6%.
Above-mentioned yellow solid (1.827g, 3.2mmol) is dissolved in 20ml methyl alcohol, adds 10%Pd/C 182mg and ammonium formiate (0.605g, 9.6mmol), backflow 3h.Remove solvent under reduced pressure, be dissolved in the 20ml ethyl acetate, wash organic phase 3 times, the organic phase anhydrous sodium sulfate drying, suction filtration, the concentrated purple spumescence solid crude product 1.700g that to get directly carry out next step reaction.Purple spumescence solid crude product 1.700g is dissolved in 17ml 2-3mol/L HCl/MeOH, stirring at room 1h.The methanol/ether crystallization gets lavender solid 1.261g, two step yields 76.6%.
Compound I-27～I-32 synthetic method is the same.
Embodiment of the method 15
Synthesizing of 2-(3-amino-1-(2,3-, two fluoro-4-aminophenyls)-4-piperidine formyl is amino)-1-oxo pyridine hydrochloride (I-33)
VI (0.900g, 2.2mmol) be dissolved in the anhydrous N of 10ml, in dinethylformamide, add successively DIEA (1.419g, 11mmol), 1-oxo-PA hydrochloride (0.352g, 2.4mmol) and HATU (0.988g, 2.6mmol), first react 2h under 0 ℃, after rise to room temperature reaction 10h.Add entry and methylene dichloride, organic phase is washed, saturated sodium-chloride is washed, saturated sodium carbonate is washed, the organic phase anhydrous sodium sulfate drying, and suction filtration, the concentrated yellow solid crude product 1.311g that to get, re-crystallizing in ethyl acetate gets 0.798g, recrystallization yield 72.2%.Above-mentioned yellow solid (0.798g, 1.6mmol) is dissolved in 40ml methyl alcohol, adds 80mg10%Pd/C, pass into the hydrogen normal pressure hydrogenation, stir 6h.Suction filtration, remove solvent under reduced pressure and get grey crude product 0.786g, directly carry out the next step.Grey crude product 0.786g is dissolved in 7ml 2-3mol/L HCl/MeOH, stirs 1h, removes solvent under reduced pressure, and the methanol/ether recrystallization gets gray solid 0.413mg, two step yields 58.5%.
Embodiment of the method 16
Synthesizing of 2-(3-amino-1-(2,3-, two fluoro-4-aminophenyls)-4-piperidine formyl is amino) pyridine hydrochloride (I-34)
VI (2.000g, 5.0mmol) be dissolved in the anhydrous N of 20ml, in dinethylformamide, add successively DIEA (3.225g, 25mmol), 1-oxo-PA hydrochloride (0.803g, 5.5mmol) and HATU (2.280g, 6.0mmol), first react 2h under 0 ℃, after rise to room temperature reaction 10h.Add entry and methylene dichloride, organic phase is washed, saturated sodium-chloride is washed, saturated sodium carbonate is washed, the organic phase anhydrous sodium sulfate drying, and suction filtration, the concentrated yellow solid crude product 2.800g that to get, re-crystallizing in ethyl acetate gets 2.007g, recrystallization yield 81.6%.Above-mentioned yellow solid (0.500g, 1.0mmol) is dissolved in 20ml ethanol, adds 0.050g 10%Pd/C, pressurization (1MPa) hydrogenation, outer temperature (70 ℃) stirs 30h.Suction filtration, remove solvent under reduced pressure and get grey crude product 0.463g, directly carry out the next step.Grey crude product 0.463g is dissolved in 5ml 2-3mol/LHCl/MeOH, stirs 2h, removes solvent under reduced pressure, and the methanol/ether crystallization gets gray solid 0.297g, two step yields 69.7%.
Effect embodiment
Part piperazine or 3-amino piperidine compounds have carried out external DPP-4 enzyme inhibition test
DPP-4 enzyme activity determination method is the color development method take glycyl proline(Pro) p-Nitroaniline (Gly-Pro-p-nitroanilide) as substrate.DPP-4 catalytic substrate Gly-Pro-p-nitroanilide hydrolysis under alkaline condition, generate glycyl proline(Pro) and yellow p-Nitroaniline, p-Nitroaniline has the characteristic absorption peak at wavelength 405nm place, the absorption value size that records at the 405nm place by spectrophotometer or microplate reader is how many chromophoric group PNA growing amounts reflects the enzymic activity height, and reaction formula is as follows.
The required DPP-4 enzyme amount of Gly-Pro-p-nitroanilide of one minute hydrolysis 1 μ mol is defined as 1U, (substrate 0.4mM in DPP-4 enzyme activity determination system, DPP-4 is appropriate, damping fluid 50mM Tris-HCl, pH8.3) add the various inhibitor of different concns, 37 ℃ of reactions were measured 405nm place light absorption value by spectrophotometer or microplate reader after one hour, then were converted into the growing amount of p-nitroaniline according to the light absorption value that the Beer-Bouguer law records with the 405nm place.For certain inhibitor, the amount that suppresses 1U enzyme required inhibitor alive is defined as a unit suppresses active, estimate the activity of various inhibitor with this.
The screening of inhibitor is to form the enzyme activity determination system with a certain amount of enzyme, the various inhibitor and the blank that add different amounts, shown by table 5 data, part of compounds in the present invention has certain DPP-4 and suppresses active, and DPP-4 inhibitor and the structure of modification of Future Development brand new played directive function.
The preliminary inhibition activity experiment of table 5. part of compounds (100 μ g/ml) to DPP-4
Compound Inhibiting rate (%)
I-17 38.0
I-18 23.8
I-19 94.7
I-20 50.3
I-22 14.7
I-24 98.7
I-29 11.9
Figure BSA00000641198400241
Figure BSA00000641198400251
Figure BSA00000641198400261
Figure BSA00000641198400271
Figure BSA00000641198400281
Figure BSA00000641198400301

Claims (15)

1. a piperazine or piperidines or its salt, it is characterized in that: its structure is suc as formula shown in I:
Figure FSA00000641198300011
Formula I
Wherein, X is C or N;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F, NO 2Or NH 2
R 6Be H or NH 2
R 7It is 5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino, pyridine-2-amino, pyridine-2-methylamino-, 6-fluorine pyridine-3-is amino, 1-oxo pyridine-2-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-.
2. piperazine as claimed in claim 1 or piperidines or its salt is characterized in that:
X=N, R 1=R 4=R 6=H, R 2=R 3=R 5=F and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, pyridine-2-is amino, 6-fluorine pyridine-3-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-;
Or X=N, R 2=R 3=R 6=H, R 1=NO 2, R 4=R 5=F and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl or 1-(three rings [3,3,1,1 3,7] decyl) ethylamino;
Or X=C, R 1=R 2=F, R 3=NO 2, R 4=R 5=H, R 6=NH 2And R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, pyridine-2-methylamino-or 1-oxo pyridine-2-amino;
Or X=C, R 1=R 2=F, R 3=NH 2, R 4=R 5=H, R 6=NH 2And R 7=3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, three rings [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, pyridine-2-is amino, pyridine-2-methylamino-or 1-oxo pyridine-2-amino.
3. piperazine as claimed in claim 1 or 2 or piperidines or its salt, it is characterized in that: described salt is hydrochloride, hydrobromate, vitriol, nitrate or phosphoric acid salt.
4. the preparation method of a piperazine or piperidines, is characterized in that comprising the following steps: in solvent, under the effect of alkali, with formula II compound and R 7H carries out condensation reaction, and temperature of reaction is 10 ℃～30 ℃, gets final product;
Figure FSA00000641198300021
Formula II formula I
Wherein, X is N;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F, NO 2Or NH 2
R 6Be H or NH 2
Y is Cl;
R 7It is 5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino, pyridine-2-amino, pyridine-2-methylamino-, 6-fluorine pyridine-3-is amino, 1-oxo pyridine-2-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-;
Described alkali is pyridine, triethylamine or 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene.
5. preparation method as claimed in claim 4, it is characterized in that: described formula II compound is made by following method: in solvent, under the effect of alkali, formula III compound and acylating reagent are carried out acylation reaction, temperature of reaction is-20 ℃～10 ℃, gets final product;
Formula III formula II
Wherein, X is N;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F, NO 2Or NH 2
R 6Be H or NH 2
Y is Cl.
6. preparation method as claimed in claim 5, it is characterized in that: described acylating reagent is phosgene or triphosgene.
7. preparation method as claimed in claim 5, it is characterized in that: described alkali is pyridine or triethylamine.
8. the preparation method of the salt of a piperazine or piperidines, is characterized in that comprising the following steps:
R in formula VII and formula I compound 3=H, F or NO 2The time, formula II compound is carried out amido protecting react to get formula V compound, above-mentioned formula V compound is carried out ester hydrolysis reaction get formula VI compound, with above-mentioned formula VI compound and R 7H carries out condensation reaction and gets formula VII compound, and above-mentioned formula VII compound is carried out the salt that deprotection, salt-forming reaction get formula I compound, gets final product;
Figure FSA00000641198300032
R in formula VII compound 3=NO 2And the R in formula I compound 3=NH 2The time, after described condensation reaction, also comprise nitro-reduction reaction before deprotection, salt-forming reaction, with the R in formula VII compound 3Be reduced to amino;
Wherein, X=C;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 6Be NH 2
Y is OC 2H 5
R 7It is 5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino, pyridine-2-amino, pyridine-2-methylamino-, 6-fluorine pyridine-3-is amino, 1-oxo pyridine-2-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-.
9. preparation method as claimed in claim 8, it is characterized in that: described formula II compound is made by following method: in solvent, formula IV compound and reductive agent are carried out reduction reaction, temperature of reaction is 0 ℃～50 ℃, gets final product;
Figure FSA00000641198300041
Formula IV formula II
Wherein, X is C;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
R 6Be NH 2
Y is OC 2H 5
10. preparation method as claimed in claim 9, it is characterized in that: described solvent is methylene dichloride, chloroform, tetracol phenixin, 1, one or more in 2-ethylene dichloride and acetonitrile.
11. preparation method as claimed in claim 9 is characterized in that: described reductive agent is sodium borohydride, sodium cyanoborohydride or sodium triacetoxy borohydride.
12. the preparation method of the intermediate II of a piperazine or piperidines or its salt is made by following either method:
Method one: in solvent, under the effect of alkali, formula III compound and acylating reagent are carried out acylation reaction, temperature of reaction is-20 ℃～10 ℃, gets final product;
Formula III formula II
Wherein, X is N;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F, NO 2Or NH 2
R 6Be H or NH 2
Y is Cl;
Method two: in solvent, formula IV compound and reductive agent are carried out reduction reaction, temperature of reaction is 0 ℃～50 ℃, gets final product;
Figure FSA00000641198300051
Formula IV formula II
Wherein, X is C;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
R 6Be NH 2
Y is OC 2H 5
Its each reaction conditions is as described in claim 5～7 and 9～11 any one.
13. suc as formula the piperazine shown in II, formula IX, formula IV, formula V, formula VI or formula VII or the intermediate of piperidines or its salt:
Figure FSA00000641198300052
Formula II
Wherein, Y is Cl or OC 2H 5
X is C or N;
R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F, NO 2Or NH 2
R 6Be H or NH 2
Figure FSA00000641198300061
Formula IX
Wherein, R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
Figure FSA00000641198300062
Formula IV
Wherein, R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
Figure FSA00000641198300063
Formula V
Wherein, R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
Figure FSA00000641198300064
Formula VI
Wherein, R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
Figure FSA00000641198300071
Formula VII
Wherein, R 1And R 5Be H, F or NO independently 2
R 2And R 4Be H or F independently;
R 3Be H, F or NO 2
R 7It is 5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 1-(three rings [3,3,1,1 3,7] decyl) ethylamino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-amino, pyridine-2-amino, pyridine-2-methylamino-, 6-fluorine pyridine-3-is amino, 1-oxo pyridine-2-is amino, 2-cyanopyrrole base or 1-(1-ethyl-2-pyrryl) methylamino-.
14. the intermediate of piperazine as claimed in claim 13 or piperidines or its salt is characterized in that:
Described formula II compound is X=N, R 1=R 4=R 6=H, R 2=R 3=R 5=F and Y=Cl;
Or X=N, R 2=R 3=R 6=H, R 1=NO 2, R 4=R 5=F and Y=Cl;
Or X=C, R 1=R 2=F, R 3=NO 2, R 4=R 5=H and Y=OC 2H 5
Described formula IX compound is R 1=F, R 2=F, R 3=NO 2, R 4=H and R 5=H;
Described formula IV compound is R 1=F, R 2=F, R 3=NO 2, R 4=H and R 5=H;
Described formula V compound is R 1=F, R 2=F, R 3=NO 2, R 4=H and R 5=H;
Described formula VI compound is R 1=F, R 2=F, R 3=NO 2, R 4=H and R 5=H;
Described formula VII compound is R 1=F, R 2=F, R 3=NO 2, R 4=H, R 5=H and R 7=5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, 3-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [4,3-a] pyrazinyl, 3-ethyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazole [4,3-a] pyrazinyl, three the ring [3,3,1,1 3,7] decane is amino, 3-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, 4-hydroxyl three rings [3,3,1,1 3,7] decane-1-is amino, pyridine-2-methylamino-or 1-oxo pyridine-2-amino.
15. piperazine as described in claim 1～3 any one or amino piperidine compounds, and its pharmacy acceptable salt is for the preparation of the application in the medicine that treats and/or prevents diabetes, hyperglycemia and insulin resistance.
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