CN111978320B - Synthesis method of 1H-pyrrolo [3, 2-c ] pyridine-6-alcohol - Google Patents
Synthesis method of 1H-pyrrolo [3, 2-c ] pyridine-6-alcohol Download PDFInfo
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- CN111978320B CN111978320B CN202010965253.8A CN202010965253A CN111978320B CN 111978320 B CN111978320 B CN 111978320B CN 202010965253 A CN202010965253 A CN 202010965253A CN 111978320 B CN111978320 B CN 111978320B
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Abstract
The invention provides a synthesis method of 1H-pyrrolo [3, 2-c ] pyridine-6-alcohol, which relates to the technical field of chemical intermediate synthesis, and is characterized in that 6-chloro-5-azaindole is used as a raw material, alkali is added to bind acid, and the raw material reacts with benzyl alcohol to generate 6- (benzyloxy) -1H-pyrrolo [3, 2-c ] pyridine, and the 1H-pyrrolo [3, 2-c ] pyridine-6-alcohol is obtained after hydrogenation debenzylation of 6- (benzyloxy) -1H-pyrrolo [3, 2-c ] pyridine; the problem of converting chlorine on 6-chloro-5-azaindole into hydroxyl is effectively solved, and the 1H-pyrrole [3, 2-c ] pyridine-6-ol product is successfully prepared; the method has the advantages of short route, commercially available raw material reagents, no use of dangerous and toxic chemical reagents, mild reaction conditions, simple operation and easy scale-up production.
Description
Technical Field
The invention relates to the technical field of chemical intermediate synthesis, in particular to a synthetic method of 1H-pyrrole [3, 2-c ] pyridine-6-alcohol.
Background
1H-pyrrolo [3, 2-c ] pyridin-6-ol is one of pyrrolo [3, 2-c ] pyridine compounds, is an important intermediate of renin inhibitors, and can control hypertension and reduce the risk of cardiovascular diseases when acting on a human body; pyrrolo [3, 2-c ] pyridine compounds are also applied to the preparation of medicaments for diseases such as immune system diseases, psoriasis, rheumatoid arthritis, tumors and the like in the pharmaceutical industry. In the prior art, no literature data is reported on the synthesis of 1H-pyrrolo [3, 2-c ] pyridine-6-ol.
For the hydrolysis of halogen at the 2-position of the pyridine ring, two general approaches, basic hydrolysis or acid hydrolysis, are used:
wherein, the group R generally refers to all atoms or atomic groups that can accept an additional electron to form a stable structure, and examples include, but are not limited to, hydrogen atoms, halogen atoms, methyl groups, ethyl groups, amine groups, carboxyl groups, hydroxyl groups, ester groups, and the like.
When alkaline hydrolysis is carried out, the alkali can be selected from sodium hydroxide, potassium hydroxide, etc., tetrahydrofuran or water is used as solvent, and saponification hydrolysis is carried out to obtain the product. When acidic hydrolysis is used, the acid may be hydrochloric acid, sulfuric acid, etc. When 6-chloro-5-azaindole is used as a raw material to synthesize 1H-pyrrolo [3, 2-c ] pyridin-6-ol by the above-mentioned acid or base hydrolysis method, no target product is produced when the 6-chloro-5-azaindole is directly subjected to basic hydrolysis or acidolysis.
Disclosure of Invention
The invention aims to provide a method for synthesizing 1H-pyrrole [3, 2-c ] pyridine-6-alcohol by taking 6-chloro-5-azaindole as a raw material, which has the advantages of only two-step reaction, mild reaction condition, higher yield and batch production.
In order to achieve the above purpose, the invention provides the following technical scheme: the synthetic route of 1H-pyrrolo [3, 2-c ] pyridin-6-ol is as follows:
the method comprises the steps of taking a compound 1 as a raw material, adding an alkali-bound acid, reacting with benzyl alcohol to generate a compound 2, and hydrogenating and debenzylating the compound 2 to obtain a compound 3.
Specifically, the compound 1 is reacted in an alkaline (I) solution of a first organic solvent in which benzyl alcohol is dissolved, reflux reaction is carried out for 10-20 h under the condition that the temperature of the reaction solution is kept at 80-120 ℃, the reaction solution is cooled to room temperature, filtering is carried out, and filtrate is taken and dried in a spinning mode to obtain a compound 2; and (3) mixing the compound 2 and palladium hydroxide or palladium-carbon in an alkaline (II) solution of a second organic solvent for reaction, mixing and reacting for 10-24 hours in a hydrogen environment at room temperature by using the palladium hydroxide or the palladium-carbon as a catalyst, filtering the reaction solution, and taking the filtrate for spin drying to obtain a compound 3.
Wherein the first organic solvent is tetrahydrofuran, dioxane, toluene, dimethyl sulfoxide or N, N-dimethylformamide, and is preferably dioxane or N, N-dimethylformamide; the base (I) is sodium hydrogen, potassium tert-butoxide, sodium tert-butoxide or lithium diisopropylamide, preferably sodium hydrogen or potassium tert-butoxide; the second organic solvent is methanol, ethanol, ethyl acetate or tetrahydrofuran, preferably ethanol; the base (II) is triethylamine, DBU or TEDA, preferably TEDA.
According to the technical scheme, the synthesis method of the 1H-pyrrole [3, 2-c ] pyridine-6-alcohol provided by the technical scheme of the invention has the following beneficial effects:
the invention provides a new synthetic route for preparing 1H-pyrrole [3, 2-c ] pyridine-6-alcohol, which takes 6-chloro-5-azaindole as a raw material, adds alkali to bind acid, and reacts with benzyl alcohol to generate 6- (benzyloxy) -1H-pyrrolo [3, 2-c ] pyridine, and the 1H-pyrrole [3, 2-c ] pyridine-6-alcohol is obtained after hydrogenation and debenzylation of 6- (benzyloxy) -1H-pyrrolo [3, 2-c ] pyridine; the problem of converting chlorine on 6-chloro-5-azaindole into hydroxyl is effectively solved, and the 1H-pyrrole [3, 2-c ] pyridine-6-ol product is successfully prepared; the method has the advantages of short route, commercially available raw material reagents, no use of dangerous and toxic chemical reagents, mild reaction conditions, simple operation, high yield and easy scale-up production.
In the process of obtaining the 1H-pyrrolo [3, 2-c ] pyridine-6-alcohol by hydrogenating and debenzylating 6- (benzyloxy) -1H-pyrrolo [3, 2-c ] pyridine, the invention creatively adds the base (II), and the addition of the base (II) effectively inhibits the generation of over-reduction by-product 2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridine-6-alcohol.
It should be understood that all combinations of the foregoing concepts and additional concepts described in greater detail below can be considered as part of the inventive subject matter of this disclosure unless such concepts are mutually inconsistent.
The foregoing and other aspects, embodiments and features of the present teachings can be more fully understood from the following description taken in conjunction with the accompanying drawings. Additional aspects of the present invention, such as features and/or advantages of exemplary embodiments, will be apparent from the description which follows, or may be learned by practice of specific embodiments in accordance with the teachings of the present invention.
Drawings
The drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. Embodiments of various aspects of the present invention will now be described, by way of example, with reference to the accompanying drawings, in which:
FIG. 1 shows the nuclear magnetic hydrogen spectrum of the compound 1H-pyrrolo [3, 2-c ] pyridin-6-ol.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the drawings of the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention. Unless defined otherwise, technical or scientific terms used herein shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs.
The use of "first," "second," and similar terms in the description and claims of the present application do not denote any order, quantity, or importance, but rather the terms are used to distinguish one element from another. Similarly, the singular forms "a," "an," or "the" do not denote a limitation of quantity, but rather denote the presence of at least one, unless the context clearly dictates otherwise. The terms "comprises," "comprising," or the like, mean that the elements or items listed before "comprises" or "comprising" encompass the features, integers, steps, operations, elements, and/or components listed after "comprising" or "comprising," and do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
The chemical reagents adopted in the embodiment of the invention are all commercially available chemical reagents, the room temperature is 15-30 ℃, TEDA is triethylene diamine, and DBU is 1, 8-diazabicycloundec-7-ene.
The invention provides a synthetic method for preparing a compound 1H-pyrrole [3, 2-c ] pyridine-6-alcohol, which solves the technical problem that no target product is generated when 6-chloro-5-azaindole adopts a 2-halogen alkaline hydrolysis or acidolysis method on a pyridine ring in the prior art, and explores a synthetic route aiming at the problem as follows:
the synthetic route takes 6-chloro-5-azaindole (compound 1) as a raw material, alkali and acid are added to react with benzyl alcohol to generate 6- (benzyloxy) -1H-pyrrolo [3, 2-c ] pyridine (compound 2), and the 1H-pyrrolo [3, 2-c ] pyridine (compound 3) is obtained after hydrogenation debenzylation of the 6- (benzyloxy) -1H-pyrrolo [3, 2-c ] pyridine.
The specific reaction steps comprise that 6-chloro-5-azaindole reacts in an alkaline (I) solution of a first organic solvent in which benzyl alcohol is dissolved, the temperature of the reaction solution is kept at 80-120 ℃, reflux reaction is carried out for 10-20 hours, the reaction solution is cooled to room temperature, filtration is carried out, and filtrate is taken and dried in a spinning mode to obtain 6- (benzyloxy) -1H-pyrrolo [3, 2-c ] pyridine; mixing 6- (benzyloxy) -1H-pyrrolo [3, 2-c ] pyridine and palladium hydroxide or palladium carbon in an alkaline (II) solution of a second organic solvent for reaction, taking the palladium hydroxide or the palladium carbon as a catalyst, mixing and reacting for 10-24H under the conditions of hydrogen environment and room temperature, filtering the reaction solution, taking the filtrate, and spin-drying to obtain the 1H-pyrrolo [3, 2-c ] pyridine-6-ol. Wherein the first organic solvent is tetrahydrofuran, dioxane, toluene, dimethyl sulfoxide or N, N-dimethylformamide, the base (I) is sodium hydrogen, potassium tert-butoxide, sodium tert-butoxide or lithium diisopropylamide, the second organic solvent is methanol, ethanol, ethyl acetate or tetrahydrofuran, and the base (II) is triethylamine, DBU or TEDA.
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. In the invention, potassium tert-butoxide is used as the base (I) for synthesizing the compound 2, and triethylene diamine is used as the base (II) for synthesizing the compound 3. Because the base (I) and the base (II) mainly provide OH in the reaction-Therefore, similar technical effects can be achieved by replacing the alkali in example 1 with the above types of alkali, and thus, the description is omitted.
Example 1
1) Benzyl alcohol (15.95g, 147.5mmol, 1.5eq) was dissolved in 150ml anhydrous dioxane, compound 1(15g, 98.3mmol, 1.0eq) and potassium tert-butoxide (1.68g, 15.0mmol, 0.15eq) were added, the mixed reaction solution was warmed to 100 ℃, reflux reaction was carried out for 16h, the reaction solution was cooled to room temperature, filtration was carried out, the filtrate was taken and spin-dried to give compound 2(19g, 84.7mmol), and the product yield was 86.18%.
2) Compound 2(19g, 84.7mmol, 1.0eq) was dissolved in 200ml of methanol, triethylenediamine (0.48g, 4.2mmol, 0.05eq) and 10% palladium on carbon (1.8g) were added, hydrogen was introduced, reaction was carried out at room temperature for 16 hours, the palladium on carbon was removed by filtration from the reaction solution, and the filtrate was dried by spin-drying to give compound 3(10.45g, 84.7mmol) with a product yield of 91.95%.
The nuclear magnetic hydrogen spectrum of the compound 3 is shown in figure 1,1H-NMR(600MHz，DMSO)δ11.05(s，1H)，10.58(s，1H)，7.81(s，1H)，7.08(dd，J＝3.3，2.1Hz，1H)，6.26–6.15(m，1H)，6.00(s，1H)。
examples 2-5 differ from example 1 in the equivalent ratio of reactants, reaction temperature and reflux reaction time for the synthesis of compound 2, and the reaction conditions of the preamble are unchanged, and the specific reaction conditions are shown in table 1 below.
Among them, examples 2 and 3 are different from example 1 in that potassium tert-butoxide is different in equivalent when compound 2 is synthesized from compound 1. The yield of compound 2 is not greatly affected by further increasing the equivalent of potassium tert-butoxide relative to preferred example 1. The potassium tert-butoxide is used as a catalyst and only needs to be added in a catalytic amount, and the equivalent ratio of the potassium tert-butoxide to the compound is preferably 0.15. Examples 4 and 5 are different from example 1 in the amount of benzyl alcohol equivalent when compound 2 is synthesized from compound 1. When the equivalent ratio of the benzyl alcohol to the compound 1 is increased from 1 to 1.5, the yield of the compound 2 is obviously increased; but as the equivalent ratio of benzyl alcohol to compound 1 continued to rise from 1.5 to 3, the yield of compound 2 increased slightly. In general, the ratio of the equivalent of benzyl alcohol to 1 of the compound is preferably 1.5.
TABLE 1 reaction conditions and product yields for the preparation of Compound 2
Examples 6 to 9 are different from example 1 in the equivalent ratio of reactants, the mass ratio of catalyst, the reaction time of the synthesized compound 3, and the reaction conditions of the preamble, which are shown in table 1 below.
TABLE 2 reaction conditions and product yields for the preparation of Compound 3
Example 6 differs from example 1 only in that during the synthesis of compound 3 from compound 2, no base triethylenediamine was added, and other reaction conditions were unchanged, the yield was 0 and only the by-product 2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-ol was excessively reduced.
Example 7, example 8 and example 9 differ from example 1 in that the amount of triethylenediamine equivalent is different when compound 3 is synthesized from compound 2. When the equivalent ratio of the compound 2 to the triethylene diamine is increased from 0.1 to 1, the yield of the compound 2 is not influenced; therefore, the equivalent ratio of triethylenediamine to compound 2 is preferably 0.1.
The embodiments show that the synthetic route for preparing 1H-pyrrolo [3, 2-c ] pyridine-6-ol provided by the invention can really and effectively solve the problem that the existing alkali or acid hydrolysis technology cannot obtain 1H-pyrrolo [3, 2-c ] pyridine-6-ol from 6-chloro-5-azaindole, and the synthetic route is high in product yield, less in by-product and suitable for industrial mass production.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, the protection scope of the present invention should be determined by the appended claims.
Claims (7)
1. A synthetic method of 1H-pyrrole [3, 2-c ] pyridine-6-alcohol is characterized in that the synthetic route is as follows:
the method comprises the steps of taking a compound 1 as a raw material, adding an alkali-bound acid, reacting with benzyl alcohol to generate a compound 2, and hydrogenating and debenzylating the compound 2 to obtain a compound 3;
specifically, the method comprises the following steps:
reacting the compound 1 in an alkaline (I) solution of a first organic solvent in which benzyl alcohol is dissolved, performing reflux reaction for 10-20 hours at the temperature of 80-120 ℃, cooling the reaction solution to room temperature, filtering, and spin-drying the filtrate to obtain a compound 2; the base (I) is sodium hydrogen, potassium tert-butoxide, sodium tert-butoxide or lithium diisopropylamide;
under the conditions of hydrogen environment and room temperature, mixing and reacting the compound 2 and palladium hydroxide or palladium carbon in an alkaline (II) solution of a second organic solvent for 10-24 hours, wherein the palladium hydroxide or palladium carbon is used as a catalyst, filtering a reaction solution, and spin-drying a filtrate to obtain a compound 3; the alkali (II) is triethylamine, DBU or TEDA.
2. The method of synthesizing 1H-pyrrolo [3, 2-c ] pyridin-6-ol of claim 1 wherein the first organic solvent is tetrahydrofuran, dioxane, toluene, dimethyl sulfoxide, or N, N-dimethylformamide.
3. The method of synthesizing 1H-pyrrolo [3, 2-c ] pyridin-6-ol of claim 1 wherein the second organic solvent is methanol, ethanol, ethyl acetate, or tetrahydrofuran.
4. The method for synthesizing 1H-pyrrolo [3, 2-c ] pyridin-6-ol according to claim 2, wherein the compound 1 is reacted with an alkaline solution (I) of a first organic solvent in which benzyl alcohol is dissolved at a temperature of 90 to 110 ℃ for 12 to 16 hours under reflux, and the first organic solvent is dioxane or N, N-dimethylformamide.
5. The process for the synthesis of 1H-pyrrolo [3, 2-c ] pyridin-6-ol according to claim 1 wherein the base (i) is sodium hydrogen or potassium tert-butoxide.
6. The process for the synthesis of 1H-pyrrolo [3, 2-c ] pyridin-6-ol according to claim 1 wherein the base (ii) is TEDA.
7. The method of synthesizing 1H-pyrrolo [3, 2-c ] pyridin-6-ol of claim 3 wherein the second organic solvent is ethanol.
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| CN102036666A (en) * | 2008-03-20 | 2011-04-27 | 森林实验室控股有限公司 | Novel piperazine derivatives as inhibitors of stearoyl-coA desaturase |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102036666A (en) * | 2008-03-20 | 2011-04-27 | 森林实验室控股有限公司 | Novel piperazine derivatives as inhibitors of stearoyl-coA desaturase |
Non-Patent Citations (2)
| Title |
|---|
| Azaindole derivatives. 57. Dehydrogenation of substituted 5- and 7-azaindolines activated by manganese dioxide;Azimov, V. A.等;《Khimiya Geterotsiklicheskikh Soedinenii》;19791231(第3期);第375页 * |
| Development of peptidomimetic boronates as proteasome inhibitors;Micale, Nicola等;《European Journal of Medicinal Chemistry》;20131231;第64卷;第24页Scheme 1 * |
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