CN103804378A - Preparation method for 5,11-dihydro-6H-bispyridino-[3,2-b:2',3'-e][1,4]diazepines - Google Patents

Abstract

The invention discloses a preparation method for 5,11-dihydro-6H-bispyridino-[3,2-b:2',3'-e][1,4]diazepines. The method comprises a step of subjecting a compound represented by a formula III and monosubstituted amine to a coupling reaction under the catalysis of a metal catalyst so as to produce a compound represented by a general formula IV and a step of subjecting the compound represented by the general formula IV to an intramolecular cyclization reaction to produce a compound represented by a general formula I. Concrete reaction route is described in the specification. According to the invention, copper/iron metal catalysis is creatively employed for preparation of a target object, construction of a carbon-nitrogen bond by using copper/iron metal catalysis under mild conditions is realized, and technical biases are overcome; as a copper/iron metal is used as a catalyst, the advantages of convenient storage, a cheap price, wide sources, easy recovery and the like are obtained, the usage amount of monosubstituted amine is reduced, post-treatment is simplified, cost is saved, and the method is more applicable to industrial large-scale production and has a better industrial practical value.

Description

One is prepared the method for the two pyridos of 5,11-dihydro-6H-[3,2-b:2 ', 3 '-e] [Isosorbide-5-Nitrae] diazepine compound

Technical field

The present invention relates to one and prepare the method for the two pyridos of 5,11-dihydro-6H-[3,2-b:2 ', 3 '-e] [Isosorbide-5-Nitrae] diazepine compound, belong to technical field of medicine synthesis.

Background technology

Acquired immune deficiency syndrome (AIDS), it is acquired immune deficiency syndrome (AIDS), English name Acquired Immune Deficiency Syndrome, (AIDS), the mankind because infect human immunodeficiency virus (Human Immunodeficiency Virus, HIV) after, cause immune deficiency, concurrent a series of opportunistic infection and tumour, severe patient can cause dead syndrome.Nineteen eighty-three, the mankind find HIV first.At present, acquired immune deficiency syndrome (AIDS) becomes a kind of controlled chronic disease from a kind of fatal disease, has become the public health problem of serious threat people of the world health.

The two pyridos of 5,11-dihydro-6H-[3,2-b:2 ', 3 '-e] [Isosorbide-5-Nitrae] diazepine compound is the sweet class reverse transcriptase inhibitors of non-core of a kind of HIV-1 of Boehringer Ingelheim exploitation, and its chemical structure of general formula is as follows:

r is wherein H, C₁～C₆alkyl or C₃~ C₆cycloalkyl.

Nevirapine (Nevirapine, commodity are called Viramune) wherein, chemical name is 11-cyclopropyl-5,11-dihydro-4-methyl-6H bis-pyridos [3,2-b:2 ', 3 '-e] [Isosorbide-5-Nitrae] diazepine, its chemical structure is as follows:boehringer is gone on the market by U.S. FDA approval in September, 1996, now in multinational listing.Nevirapine can near the combination catalytic site of enzyme, directly acts on reversed transcriptive enzyme, suppresses its activity, suppresses HIV and copies, clinical in suppressing the being transmitted from a mother to her unborn child of acquired immune deficiency syndrome (AIDS).One of 1999 studies confirm that, prevention newborn infant, from parent vertical infection hiv virus (HIV), the older AIDS-treating medicine zidovudine (Zidovudine) of nevirapine is more effective.Recent research result shows that the drug effect of nevirapine is almost the twice of zidovudine.Nowadays,, in the formula of the drug cocktail therapy (treatment) to AIDS patient, nevirapine is indispensable medicament simply, has every year the huge market requirement.

In prior art, there is multiple synthetic method about compound of Formula I and Boehringer, but the last two steps reaction is all formula III compound and cyclopropylamine condensation under High Temperature High Pressure strong alkaline condition in most of synthetic method, then obtain end product at highly basic, high temperature ShiShimonoseki ring, concrete reaction scheme is as follows:

The reaction of ullmann reaction, Ubbelohde, Goldberger reaction are all the reactions that builds carbon-nitrogen bond under classical employing copper catalysis, but the participation of the temperature of reaction that these reactions conventionally need to be higher (general temperature of reaction is all higher than 150 ℃), highly basic, nucleophilic reagent is greatly excessive, and needs a large amount of copper powder effects.High like this temperature of reaction has been brought a lot of difficulties to production operation, and makes safety operation be difficult to control, and causes the significant wastage of nucleophilic reagent.As: in the disclosed preparation method of U.S. Pat 5366972, the reaction needed of formula III compound and cyclopropylamine is carried out at the temperature of 150 ℃ in airtight stainless steel autoclave; In the disclosed preparation method of U.S. Pat 5569760, formula III compound need to carry out with reacting also of cyclopropylamine under the high temperature of 135 ~ 145 ℃ and in airtight stainless steel autoclave.It in these methods, is the volatilization of avoiding cyclopropylamine, in itself and formula II compound condensation process, need in autoclave, carry out, and temperature of reaction is all at 140 ℃, not only makes the energy consumption of production process high, and there is certain danger, be not suitable for industrialized production.

Research is afterwards found to utilize cuprous salt to build carbon-nitrogen bond, for example: in Chinese patent ZL200810107893.4, disclosed formula III compound reacts with cyclopropylamine and adopts cuprous halide as catalyzer, although the method by cuprous salt catalysis can make reaction conditions gentleness, but because cuprous salt is unstable, this makes troubles just to the storage of raw material, to the adverse influence of bringing of reaction, be not suitable for industrialized production yet.

Summary of the invention

The problems referred to above that exist for prior art, the object of this invention is to provide a kind of with low cost, environmental friendliness, reaction conditions gentleness, simple to operate, the preparation 5 that is applicable to suitability for industrialized production, the two pyridos of 11-dihydro-6H-[3,2-b:2 ', 3 '-e] method of [Isosorbide-5-Nitrae] diazepine compound.

For achieving the above object, the technical solution used in the present invention is as follows:

One is prepared the method for the two pyridos of 5,11-dihydro-6H-[3,2-b:2 ', 3 '-e] [Isosorbide-5-Nitrae] diazepine compound, comprises following reaction:

A) chloro-formula III compound: 2-N-(the chloro-4-methyl-3-of 2-pyridyl)-Niacinamide and monosubstituted amine: R-NH2 are carried out to linked reaction under the catalysis of metal catalyst, generate general formula I V compound;

B) general formula I V compound carries out intramolecular cyclization reaction and generates compound of Formula I, that is: 5, the two pyridos of 11-dihydro-6H-[3,2-b:2 ', 3 '-e] [Isosorbide-5-Nitrae] diazepine compound;

Concrete reaction scheme is as follows:

As a kind of preferred version, the R in formula is H, C₁～C₆alkyl or C₃~ C₆cycloalkyl.

As a kind of preferred version, described metal catalyst is copper powder or iron powder.

As a kind of preferred version, the operation of described linked reaction is as follows: under inert atmosphere, add organic solvent and formula III compound, monosubstituted amine, alkali and metal catalyst, stirring reaction at normal pressure ,-10～50 ℃.

As further preferred version, the mol ratio of described metal catalyst and formula III compound is 0.1:1 ~ 1:1; The mol ratio of described monosubstituted amine and formula III compound is 1:1 ~ 3:1.

As further preferred version, described inert atmosphere is argon atmospher or nitrogen atmosphere.

As further preferred version, described organic solvent is selected from benzene, toluene, ethylbenzene, dimethylbenzene, methylene dichloride, chloroform, ethylene dichloride, tetrahydrofuran (THF), ether, 2-methyltetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, N, dinethylformamide, N,N-dimethylacetamide, acetonitrile or esters solvent; To be selected from toluene, dimethylbenzene, methylene dichloride, tetrahydrofuran (THF), dioxane, DMF, acetonitrile, ethyl acetate, butylacetate, isopropyl acetate or propyl acetate as best.

As further preferred version, described alkali is organic bases or mineral alkali, and described mineral alkali is selected from sodium carbonate, salt of wormwood, saleratus, sodium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide or calcium oxide; Described organic bases is selected from triethylamine, pyridine, quinoline or diisopropyl ethyl amine; To be selected from sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide or triethylamine as best.

Compared with prior art, beneficial effect of the present invention is: the present invention creatively adopts the catalysis of copper/ferrous metal to prepare 5, the two pyridos [3 of 11-dihydro-6H-, 2-b:2 ', 3 '-e] [1,4] diazepine compound, has realized and under mild conditions, has adopted the catalysis of copper/ferrous metal to build carbon-nitrogen bond, has overcome the technology prejudice that reaction that employing copper/ferrous metal catalysis builds carbon-nitrogen bond must be carried out under High Temperature High Pressure; Especially, adopt copper/ferrous metal also to there are convenient storage, low price, wide material sources, be easy to the advantages such as recovery as catalyzer, not only reduce the consumption of monosubstituted amine, simplify aftertreatment, save cost, and increased the security of technique, and be more suitable in industrialized production, therefore there is extremely strong industrial utility value.

Embodiment

Below in conjunction with embodiment to the present invention do further in detail, intactly explanation.

Described formula III compound can obtain according to disclosed method preparation in prior art, and the embodiment of the present invention is to obtain according to disclosed method preparation in U.S. Pat 5366972.

Embodiment 1

By the chloro-N-of formula III compound 2-(the chloro-4-methyl-3-of 2-pyridyl)-Niacinamide (28.2g, 0.1mol), cyclopropylamine (15.0mL, 0.21mol), sodium carbonate (11.66g, 0.11mol) with fresh copper powder (0.28g, 0.04mol) add in 280mL methylene dichloride, under argon atmospher, in stirring at room temperature reaction 8 hours; Reaction finishes, and filters, and concentrated filtrate, obtains brown solid 30.0g, is formula IVa compound, is directly used in the next step.

Sodium hydride (11g, 0.46mol) and 100mL diethylene glycol dimethyl ether are added in reaction flask, be heated to 120 ℃, add the crude product of above-mentioned formula IVa compound, insulation reaction 1 hour; Remove diethylene glycol dimethyl ether under reduced pressure, under room temperature, add 200mL water, be stirred to after the whole dissolvings of solid, then add 100mL hexanaphthene, stir lower dropping Glacial acetic acid and regulate pH value to 7～8, separate out solid, suction filtration, filter cake washes with water rear dry, obtains solid 22.7g, be nevirapine (molar yield is 85%), HPLC purity >=98%.

Embodiment 2

Reaction formula is with embodiment 1.

By the chloro-N-of formula III compound 2-(the chloro-4-methyl-3-of 2-pyridyl)-Niacinamide (28.2g, 0.1mol), cyclopropylamine (15.0mL, 0.21mol), triethylamine (16.7mL, 0.12mol) with fresh copper powder (0.28g, 0.04mol) add in 280mL ethyl acetate, under argon atmospher, in stirring at room temperature reaction 8 hours; Reaction finishes, and filters, and concentrated filtrate, obtains brown solid 29.5g, is formula IVa compound, is directly used in the next step.

Sodium hydride (11g, 0.46mol) and 100mL diethylene glycol dimethyl ether are added in reaction flask, be heated to 120 ℃, add the crude product of above-mentioned formula IVa compound, insulation reaction 1 hour; Remove diethylene glycol dimethyl ether under reduced pressure, under room temperature, add 200mL water, be stirred to after the whole dissolvings of solid, then add 100mL hexanaphthene, stir lower dropping Glacial acetic acid and regulate pH value to 7～8, separate out solid, suction filtration, filter cake washes with water rear dry, obtains solid 22.4g, be nevirapine (molar yield is 84%), HPLC purity >=98%.

Embodiment 3

Reaction formula is with embodiment 1.

By the chloro-N-of formula III compound 2-(the chloro-4-methyl-3-of 2-pyridyl)-Niacinamide (28.2g, 0.1mol), cyclopropylamine (15.0mL, 0.21mol), sodium carbonate (11.66g, 0.11mol) with fresh iron powder (0.30g, 0.05mol) add in 280mL methylene dichloride, under argon atmospher, in stirring at room temperature reaction 8 hours; Reaction finishes, and filters, and concentrated filtrate, obtains brown solid 20.0g, is formula IVa compound, is directly used in the next step.

Sodium hydride (11g, 0.46mol) and 100mL diethylene glycol dimethyl ether are added in reaction flask, be heated to 120 ℃, add the crude product of above-mentioned formula IVa compound, insulation reaction 1 hour; Remove diethylene glycol dimethyl ether under reduced pressure, under room temperature, add 200mL water, be stirred to after the whole dissolvings of solid, then add 100mL hexanaphthene, stir lower dropping Glacial acetic acid and regulate pH value to 7～8, separate out solid, suction filtration, filter cake washes with water rear dry, obtains solid 12.0g, be nevirapine (molar yield is 45%), HPLC purity >=98%.

Embodiment 4

Reaction formula is with embodiment 1.

By the chloro-N-of formula III compound 2-(the chloro-4-methyl-3-of 2-pyridyl)-Niacinamide (28.2g, 0.1mol), cyclopropylamine (15.0mL, 0.21mol), sodium carbonate (11.66g, 0.11mol) with fresh copper powder (0.28g, 0.04mol) add in 280mL isopropyl acetate, under argon atmospher, in stirring at room temperature reaction 8 hours; Reaction finishes, and filters, and concentrated filtrate, obtains brown solid 30.0g, is formula IVa compound, is directly used in the next step.

Potassium tert.-butoxide (25g, 0.22mol) and 100mL diethylene glycol dimethyl ether are added in reaction flask, be heated to 120 ℃, add the crude product of above-mentioned formula IVa compound, insulation reaction 1 hour; Remove diethylene glycol dimethyl ether under reduced pressure, under room temperature, add 200mL water, be stirred to after the whole dissolvings of solid, then add 100mL hexanaphthene, stir lower dropping Glacial acetic acid and regulate pH value to 7～8, separate out solid, suction filtration, filter cake washes with water rear dry, obtains solid 22.9g, be nevirapine (molar yield is 86%), HPLC purity >=98%.

Embodiment 5

By the chloro-N-of formula III compound 2-(the chloro-4-methyl-3-of 2-pyridyl)-Niacinamide (28.2g, 0.1mol), ethamine (8.4mL, 0.13mol), potassium hydroxide (7.28g, 0.13mol) with fresh copper powder (0.28g, 0.04mol) add in 280mL toluene, under argon atmospher, stirring reaction 16 hours under ice bath; Reaction finishes, and filters, and concentrated filtrate, obtains brown solid 28.5g, is formula IVb compound, is directly used in the next step.

Sodium hydride (11g, 0.46mol) and 100mL diethylene glycol dimethyl ether are added in reaction flask, be heated to 120 ℃, add the crude product of above-mentioned formula IVb compound, insulation reaction 1 hour; Remove diethylene glycol dimethyl ether under reduced pressure, under room temperature, add 200mL water, be stirred to after the whole dissolvings of solid, add again 100mL hexanaphthene, stir lower dropping Glacial acetic acid and regulate pH value to 7～8, separate out solid, suction filtration, filter cake washes with water rear dry, obtains solid 21.1g, be formula V compound: 11-ethyl-5,11-dihydro-4-methyl-6H bis-pyridos [3,2-b:2 ', 3 '-e] [1,4] phenodiazine Zhuo (molar yield is 83%), HPLC purity >=98%.

Embodiment 6

Reaction scheme is with embodiment 5.

By the chloro-N-of formula III compound 2-(the chloro-4-methyl-3-of 2-pyridyl)-Niacinamide (28.2g, 0.1mol), ethamine (8.4mL, 0.13mol), sodium bicarbonate (15.9g, 0.15mol) with fresh copper powder (0.28g, 0.04mol) add 280mL N, in dinethylformamide, under argon atmospher, stirring reaction 16 hours under ice bath; Reaction finishes, and filters, and concentrated filtrate, obtains brown solid 29g, is formula IVb compound, is directly used in the next step.

Sodium hydride (11g, 0.46mol) and 100mL dimethylbenzene are added in reaction flask, be heated to 120 ℃, add the crude product of above-mentioned formula IVb compound, insulation reaction 1 hour; Remove dimethylbenzene under reduced pressure, under room temperature, add 200mL water, be stirred to after the whole dissolvings of solid, add again 100mL hexanaphthene, stir lower dropping Glacial acetic acid and regulate pH value to 7～8, separate out solid, suction filtration, filter cake washes with water rear dry, obtains solid 20.3g, be formula V compound: 11-ethyl-5,11-dihydro-4-methyl-6H bis-pyridos [3,2-b:2 ', 3 '-e] [1,4] phenodiazine Zhuo (molar yield is 80%), HPLC purity >=98%.

Finally be necessary described herein: above embodiment is only for being described in more detail technical scheme of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.

Claims (10)

1. prepare the method for the two pyridos of 5,11-dihydro-6H-[3,2-b:2 ', 3 '-e] [Isosorbide-5-Nitrae] diazepine compound for one kind, it is characterized in that, comprise following reaction:

A) by chloro-formula III compound: 2-N-(the chloro-4-methyl-3-of 2-pyridyl)-Niacinamide and monosubstituted amine: R-NH₂under the catalysis of metal catalyst, carry out linked reaction, generate general formula I V compound;

B) general formula I V compound carries out intramolecular cyclization reaction and generates compound of Formula I, that is: 5, the two pyridos of 11-dihydro-6H-[3,2-b:2 ', 3 '-e] [Isosorbide-5-Nitrae] diazepine compound;

Concrete reaction scheme is as follows:

2. preparation 5 according to claim 1, the method for the two pyridos of 11-dihydro-6H-[3,2-b:2 ', 3 '-e] [Isosorbide-5-Nitrae] diazepine compound, is characterized in that: the R in formula is H, C₁～C₆alkyl or C₃~ C₆cycloalkyl.

3. preparation 5 according to claim 1, the method for the two pyridos of 11-dihydro-6H-[3,2-b:2 ', 3 '-e] [Isosorbide-5-Nitrae] diazepine compound, is characterized in that: described metal catalyst is copper powder or iron powder.

4. preparation 5 according to claim 1, the two pyridos [3 of 11-dihydro-6H-, 2-b:2 ', 3 '-e] [1,4] method of diazepine compound, is characterized in that, the operation of described linked reaction is as follows: under inert atmosphere, add organic solvent and formula III compound, monosubstituted amine, alkali and metal catalyst, stirring reaction at normal pressure ,-10～50 ℃.

5. preparation 5 according to claim 4, the method for the two pyridos of 11-dihydro-6H-[3,2-b:2 ', 3 '-e] [Isosorbide-5-Nitrae] diazepine compound, is characterized in that: the mol ratio of described metal catalyst and formula III compound is 0.1:1 ~ 1:1; The mol ratio of described monosubstituted amine and formula III compound is 1:1 ~ 3:1.

6. preparation 5 according to claim 4, the method for the two pyridos of 11-dihydro-6H-[3,2-b:2 ', 3 '-e] [Isosorbide-5-Nitrae] diazepine compound, is characterized in that: described inert atmosphere is argon atmospher or nitrogen atmosphere.

7. preparation 5 according to claim 4, the two pyridos [3 of 11-dihydro-6H-, 2-b:2 ', 3 '-e] [1,4] method of diazepine compound, it is characterized in that: described organic solvent is selected from benzene, toluene, ethylbenzene, dimethylbenzene, methylene dichloride, chloroform, ethylene dichloride, tetrahydrofuran (THF), ether, 2-methyltetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, N, dinethylformamide, N,N-dimethylacetamide, acetonitrile or esters solvent.

8. preparation 5 according to claim 7, the two pyridos [3 of 11-dihydro-6H-, 2-b:2 ', 3 '-e] [1,4] method of diazepine compound, it is characterized in that: described organic solvent is selected from toluene, dimethylbenzene, methylene dichloride, tetrahydrofuran (THF), dioxane, DMF, acetonitrile, ethyl acetate, butylacetate, isopropyl acetate or propyl acetate.

9. preparation 5 according to claim 4, the two pyridos [3 of 11-dihydro-6H-, 2-b:2 ', 3 '-e] [1,4] method of diazepine compound, it is characterized in that: described alkali is organic bases or mineral alkali, and described mineral alkali is selected from sodium carbonate, salt of wormwood, saleratus, sodium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide or calcium oxide; Described organic bases is selected from triethylamine, pyridine, quinoline or diisopropyl ethyl amine.

10. preparation 5 according to claim 9, the two pyridos of 11-dihydro-6H-[3,2-b:2 ', 3 '-e] [1,4] method of diazepine compound, is characterized in that: described alkali is selected from sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide or triethylamine.