CN115215764A - Preparation method of deuterated aromatic nitrile compound - Google Patents

Preparation method of deuterated aromatic nitrile compound Download PDF

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CN115215764A
CN115215764A CN202210812275.XA CN202210812275A CN115215764A CN 115215764 A CN115215764 A CN 115215764A CN 202210812275 A CN202210812275 A CN 202210812275A CN 115215764 A CN115215764 A CN 115215764A
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deuterated
aromatic nitrile
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sodium
nitrile compound
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摆建飞
吴涛
江之江
高章华
刘嫣然
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Ningbo Cuiying Chemical Technology Co ltd
Zhejiang University of Science and Technology ZUST
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

The invention discloses a preparation method of a deuterated aromatic nitrile compound, which is characterized in that the aromatic nitrile compound shown in formula (I) is used as a raw material, under the protection of inert atmosphere, the aromatic nitrile compound and an aliphatic alcohol compound generate aryl formimidate in situ in a catalytic system, then the aryl formimidate and a deuterated reagent generate hydrogen-deuterium exchange reaction, the aryl formimidate and the deuterated reagent are hydrolyzed in situ to obtain an aromatic nitrile ortho-position deuterated compound, and finally the product is separated and purified; the catalytic system comprises a metal catalyst, an auxiliary agent, an oxidant and a solvent. The method has the advantages of high operability and good deuteration effect.

Description

Preparation method of deuterated aromatic nitrile compound
Technical Field
The invention relates to the technical field of synthesis of deuterated compounds, in particular to a preparation method of deuterated aromatic nitrile compounds.
Background
Deuterium is a stable form of nonradioactive isotope of hydrogen in nature, with carbon-deuterium bonds being more stable (6-9 times) than carbon-hydrogen bonds due to its greater atomic mass than hydrogen. In recent years, with the research on deuterated compounds, the research shows that after hydrogen in drug molecules is replaced by deuterium, metabolic sites can be sealed, and the generation of toxic metabolites can be reduced. In addition, deuteration can slow the rate of systemic clearance and thus prolong the half-life of the drug in vivo. Therefore, the aim of reducing the toxic and side effects of the drug can be achieved by reducing the single administration dosage without affecting the pharmacological activity of the drug. Due to the special pharmacokinetic properties of deuterated drugs, the research and development speed of deuterated drugs is accelerated in recent years, and the demand for various active compound deuteration strategies is increasing.
The cyano group has good biocompatibility and can often penetrate deep into the target protein to form hydrogen bond interaction with key amino acid residues of an active site; meanwhile, the cyano can also be used as a metabolic blocking site to inhibit small molecules from oxidative metabolism and improve the metabolic stability of the compound in vivo. As an important organic drug group, aromatic nitrile and its derivatives have wide application in the aspects of medicine and the like.
Figure BDA0003739688430000011
For example, verapamil is a calcium channel blocker and is used for treating diseases such as hypertension, angina, arrhythmia, cerebrovascular diseases and the like; febuxostat has obvious inhibiting effect on the XOR of the oxidized form and the reduced form, so that the effect of reducing uric acid is stronger and more durable, and the febuxostat can be used for treating chronic hyperuricemia caused by gout; etravirine is a new generation of non-nucleoside reverse transcriptase inhibitor, and can greatly reduce the morbidity and mortality of AIDS; perampanel is commonly used for the additive treatment of adults and children with partial epileptic seizures (with or without secondary generalized seizures) aged 12 years and older; 2- (4-substituted piperazine-1-yl) methylbenzonitrile serving as an antitumor drug has a stronger inhibition rate on tumor strains Skov3 (human ovarian cancer) than on other tumor strains; bicalutamide is used for the treatment of advanced prostate cancer.
At present, the research on deuteration on aromatic rings of aromatic nitrile derivatives is still in the initial stage. Because the carbon-nitrogen triple bond of the nitrile is a linear structure, and the catalyst is difficult to form a cyclic metal transition state with a nitrogen atom and an ortho-position hydrogen atom on an aromatic ring for catalytic reaction, the method has a great challenge for the aromatic nitrile compound ring whether in C-H activation or H/D exchange reaction. In addition, cyano is a reactive functional group in organic synthesis, can be converted into other functional groups or heterocycles, and has low tolerance to reaction conditions.
At present, few reports are made on the preparation method of the deuterated aromatic nitrile derivative. In 2014, dieter Muri et al indirectly obtain a deuterated aromatic nitrile product through a deuterated amide compound by using an iridium metal complex. Deuterium is used as a deuterium source in the reaction, and the catalyst is complex in structure and expensive in price, so that the application range of the catalyst is greatly limited;
Figure BDA0003739688430000021
disclosure of Invention
The invention aims to provide a preparation method of a deuterated aromatic nitrile compound, which has the advantages of high operability and good deuterated effect.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a preparation method of deuterated aromatic nitrile compounds comprises the steps of taking aromatic nitrile compounds shown in formula (I) as raw materials, generating aryl methyl imidic ester in situ with aliphatic alcohol compounds in a catalytic system under the protection of inert atmosphere, then generating hydrogen-deuterium exchange reaction with deuterated reagents, then hydrolyzing in situ to obtain deuterated compounds at ortho positions of the aromatic nitrile, and finally separating and purifying products; the catalytic system comprises a metal catalyst, an auxiliary agent, an oxidant and a solvent;
Figure BDA0003739688430000022
the invention uses cheap metal as catalyst, uses one-pot two-step method, and has simple operation and high exchange degree of hydrogen and deuterium without separating intermediate. The method has the characteristics of good operability and stability, high catalytic efficiency, high economic benefit, simple and convenient operation, easy separation of products and the like.
Preferably, the deuterated reagent is one of deuterium oxide, deuterated methanol and deuterated benzene. More preferably heavy water.
Preferably, the inert gas atmosphere is a gas atmosphere composed of nitrogen or argon.
Preferably, the metal catalyst is selected from one of decacarbonyl manganese, pentacarbonyl manganese bromide, manganese acetate, cobalt hydroxide, ferric oxide and ferroferric oxide. When manganese pentacarbonyl bromide is selected, the highest deuteration degree can reach 98%.
Preferably, the auxiliary agent is one of sodium acetate, potassium acetate, sodium oxalate, sodium carbonate and potassium carbonate. When sodium acetate is selected, the highest deuteration degree can reach 95%. The addition of the auxiliary agent can effectively promote the exchange rate of hydrogen and deuterium in the reaction process and improve the reaction deuteration degree.
Preferably, the solvent is one of N-methylpyrrolidone, tetrahydrofuran, dioxane, cyclohexane and cyclopentyl methyl ether. N-methyl pyrrolidone is preferred, and when the solvent is selected, the highest deuteration degree of the product can reach 95%.
Preferably, the oxidizing agent is one of sodium hypochlorite, hydrogen peroxide, peracetic acid, sodium dichromate, sodium perborate, potassium perborate, and methyl hypochlorite. When sodium hypochlorite is selected, the highest deuteration degree can reach 95%. The addition of the oxidizing agent can promote the in-situ generation of the aryl formimidate by the nitrile compound and the alcohol.
Preferably, the aliphatic alcohol compound is one of methanol, ethanol, isopropanol, tert-butanol and benzyl alcohol. When ethanol is selected, the highest deuteration degree can reach 98 percent.
Preferably, the molar ratio of the materials is aromatic nitrile compounds: fatty alcohol compounds: oxidizing agent: a deuterated reagent: metal catalyst: auxiliary agent: solvent =1:1.1:1:10-500:0.05-0.20:1:20-500.
Preferably, R is 1 Is one or more of alkyl, alkoxy, vinyl, aromatic substituent, nitro, amino, trifluoromethyl, halogen, pyridine, thiophene and furan; the R is 2 Is one or more of benzyl, methyl, ethyl, isopropyl, tertiary butyl, alkoxy, allyl and tertiary butyl. The alkyl group can be selected from saturated hydrocarbon with 1-6 carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, etc. The aromatic substituent may be phenyl, naphthalene, etc.
The invention has the beneficial effects that: the method utilizes the transition metal to activate the aromatic nitrile compound, realizes the deuteration reaction of the aromatic nitrile compound by forming the intermediate of aryl formimidate and taking the deuteration reagent as a deuterium source, realizes the synthesis of a deuteration product, and has the advantages of high operability, convenient operation and low cost.
The method is completed by adopting a technical route under the conventional laboratory conditions, the solvent is not required to be replaced midway in the one-pot reaction, and the method has the advantages of high reaction operability, good deuteration effect, good selectivity and wide application range.
The process method has good universality, can be used for preparing various deuterated aromatic nitrile compounds, and is also suitable for various aromatic nitrile medicaments.
Detailed Description
The technical solution of the present invention will be further specifically described below by way of specific examples.
In the present invention, the raw materials and equipment used are commercially available or commonly used in the art, unless otherwise specified. The methods in the following examples are conventional in the art unless otherwise specified.
General description of the embodiments
A preparation method of deuterated aromatic nitrile compounds comprises the steps of taking aromatic nitrile compounds shown in formula (I) as raw materials, under the protection of inert atmosphere, firstly generating aryl formimidate in situ with aliphatic alcohol compounds in a catalytic system, then generating hydrogen-deuterium exchange reaction with deuterated reagents, then performing in situ hydrolysis to obtain aromatic nitrile ortho-position deuterated compounds, and finally separating and purifying products; the catalytic system comprises a metal catalyst, an auxiliary agent, an oxidant and a solvent;
Figure BDA0003739688430000041
the deuterated reagent is one of heavy water, deuterated methanol and deuterated benzene; the inert atmosphere is a gas environment consisting of nitrogen or argon; the metal catalyst is selected from one of decacarbonyl manganese, pentacarbonyl manganese bromide, manganese acetate, cobalt hydroxide, ferric oxide and ferroferric oxide; the auxiliary agent is one of sodium acetate, potassium acetate, sodium oxalate, sodium carbonate and potassium carbonate; the solvent is one of N-methyl pyrrolidone, tetrahydrofuran, dioxane, cyclohexane and cyclopentyl methyl ether; the oxidant is one of sodium hypochlorite, hydrogen peroxide, peracetic acid, sodium dichromate, sodium perborate, potassium perborate and methyl hypochlorite; the aliphatic alcohol compound is one of methanol, ethanol, isopropanol, tert-butanol and benzyl alcohol.
The molar ratio of the materials is aromatic nitrile compounds: fatty alcohol compounds: oxidizing agent: a deuterated reagent: metal catalyst: auxiliary agent: solvent =1:1.1:1:10-500:0.05-0.20:1:20-500.
The R is 1 Is one or more of alkyl, alkoxy, vinyl, aromatic substituent, nitro, amino, trifluoromethyl, halogen, pyridine, thiophene and furan; said R is 2 Is one or more of benzyl, methyl, ethyl, isopropyl, tertiary butyl, alkoxy, allyl and tertiary butyl.
Example 1 synthesis of phthalonitrile ortho-deuterated product:
taking 15mL of dry sealed tube under nitrogen atmosphere, according toBenzonitrile (103mg, 1mmol) and sodium hypochlorite (150mg, 2mmol) were added in portions, ethanol (0.1 mL) was slowly added dropwise with stirring, and the reaction solution was reacted at room temperature for 24 hours (in situ preparation of arylformimidate). To the reaction mixture was then added carbonyl manganese bromide (27.5mg, 0.1mmol), sodium acetate (82mg, 1mmol), N-methylpyrrolidone: heavy water =0.5/0.5mL (v/v = 1/1), and reacted at 100 ℃ for 0.5 hour. After the reaction was completed, 5mL1N aq HCl was added, and the mixture was stirred at room temperature for about 1 hour (arylformimidate was hydrolyzed to obtain aromatic nitrile). Extraction was 2-3 times with 10mL ethyl acetate, the organic phase was dried and concentrated to give the crude product. And purifying the crude product by column chromatography to obtain a benzonitrile ortho-deuterated product. 1 H NMR(500MHz,Chloroform-d)δ7.62(m,1H),7.60-7.54(m,0.2H),7.49-7.47(m,2H)。
Under the same conditions, starting from the respective substituted aromatic nitrile derivatives, derivative 1 (deuterated aromatic nitrile derivative represented by formula II) was obtained under the conditions described above, the results of which are shown in the following table:
aromatic nitrile compound raw material Deuterated products Degree of deuteration (%) Yield (%)
Example 2 4-aminophenylacetonitrile 2-d 91 63
Example 3 4-fluorobenzonitrile 3-d 90 64
Example 4 3, 5-difluorobenzonitrile 4-d 89 69
Example 5 2-bromo-4-fluorobenzonitrile 5-d 93 76
Example 6 4-amino-2-methoxybenzonitrile 6-d 88 62
Example 7 4-phenoxybenzonitrile 7-d 87 65
Example 8 4-morpholinylbenzonitrile 8-d 92 74
Example 9 3-phenoxy-4-methoxybenzonitrile 9-d 89/94 78
Example 10 Febuxostat 10-d 90 66
。
4-aminobenzoyl cyanides (deuterated 4-aminophenylacetonitrile, 2-d)
1 H NMR(500MHz,Chloroform-d)δ6.94-6.92(m,0.18H,Labelled),6.57-6.55(m,2H),3.62(t,J＝1.0Hz,2H),3.16(brs,2H).
4-fluoronitrile (deuterated 4-fluorobenzonitrile, 3-d)
1 H NMR(500MHz,Chloroform-d)δ7.61-7.57(m,0.2H,Labelled),7.15-7.09(m,2H).
3,5-Diaminobenzonitrile (deuterated 3, 5-difluorobenzonitrile, 4-d)
1 H NMR (500MHz, chloroform-d) delta 6.83-6.73 (m, 0.22H, labelled), 5.44 (s, 1H), 4.35 (brs, 4H), 2- (bromomethyl) -4-fluorobenozonile (deuterated 2-bromo-4-fluorobenzonitrile, 5-d)
1 H NMR(500MHz,Chloroform-d)δ7.66-7.58(m,0.07H,Labelled),7.10(d,J＝16.5Hz,1H),7.08(m,1H),4.51(d,J＝1.1Hz,2H).
4-amino-2-methoxybenzonitril (deuterated 2-bromo-4-fluorobenzonitrile, 6-d)
1 H NMR(500MHz,Chloroform-d)δ7.42-7.40(m,0.13H,Labelled),6.42-6.37(m,2H),4.40(brs,2H),3.92(s,3H).
4-phenoxybenzonitile (deuterated 4-phenoxybenzonitrile, 7-d)
1 H NMR(500MHz,Chloroform-d)δ7.74-7.69(m,0.26H,Labelled),7.37-7.32(m,2H),7.18-7.13(m,2H),7.09(tt,J＝9.0,2.0Hz,1H),7.03-7.01(m,2H).
4-morpholino benzazole (deuterated 4-morpholinylbenzonitrile, 8-d)
1 H NMR(500MHz,Chloroform-d)δ7.13-7.07(m,0.16H,Labelled),6.87-6.80(m,2H),3.89-3.83(m,2H),3.19-3.13(m,2H).
3-benzyloxy-4-methoxybenzonitrile (deuterated 3-phenoxy-4-methoxybenzonitrile, 9-d)
1 H NMR(500MHz,Chloroform-d)δ7.45-7.43(m,0.06H,Labelled),7.40-7.37(m,4H),7.35-7.34(m,0.11H,Labelled),7.33-7.29(m,1H),7.26-7.24(m,1H),5.15(t,J＝1.0Hz,2H),3.87(s,3H).
2- (3-cyano-4-isobutoxyphenyl) -4-methidazole-5-carboxylic acid (deuterated febuxostat, 10-d)
1 H NMR(500MHz,Chloroform-d)δ8.26(d,J＝2.1Hz,1H),8.19-8.17(m,1H),7.22-7.20(m,0.1H,Labelled),3.96(d,J＝5.0Hz,2H),2.85-2.77(m,1H),2.68(s,2H),1.15(d,J＝7.2Hz,6H)。
The above-described embodiments are only preferred embodiments of the present invention, and are not intended to limit the present invention in any way, and other variations and modifications may be made without departing from the spirit of the invention as set forth in the claims.

Claims (10)

1. A preparation method of a deuterated aromatic nitrile compound is characterized in that an aromatic nitrile compound shown in a formula (I) is used as a raw material, under the protection of inert atmosphere, the aromatic nitrile compound and an aliphatic alcohol compound generate aryl methyl imidic ester in situ in a catalytic system, then the aryl methyl imidic ester and a deuterated reagent generate hydrogen-deuterium exchange reaction, the aryl methyl imidic ester and the deuterated reagent are hydrolyzed in situ to obtain an aromatic nitrile ortho-position deuterated compound, and finally the product is separated and purified; the catalytic system comprises a metal catalyst, an auxiliary agent, an oxidant and a solvent;
Figure FDA0003739688420000011
2. the method of claim 1, wherein the deuterated reagent is one of deuterium oxide, deuterated methanol and deuterated benzene.
3. The method according to claim 1, wherein the inert gas atmosphere is a gas atmosphere composed of nitrogen or argon.
4. The preparation method according to claim 1, wherein the metal catalyst is selected from one of manganese decacarbonyl, manganese pentacarbonyl bromide, manganese acetate, cobalt hydroxide, ferric oxide and ferroferric oxide.
5. The preparation method according to claim 1, wherein the auxiliary agent is one of sodium acetate, potassium acetate, sodium oxalate, sodium carbonate and potassium carbonate.
6. The method according to claim 1, wherein the solvent is one of N-methylpyrrolidone, tetrahydrofuran, dioxane, cyclohexane, and cyclopentyl methyl ether.
7. The method of claim 1, wherein the oxidizing agent is one of sodium hypochlorite, hydrogen peroxide, peracetic acid, sodium dichromate, sodium perborate, potassium perborate, and methyl hypochlorite.
8. The method according to claim 1, wherein the aliphatic alcohol compound is one of methanol, ethanol, isopropanol, tert-butanol, and benzyl alcohol.
9. The method according to claim 1, wherein the molar ratio of the materials is aromatic nitrile compound: fatty alcohol compounds: oxidizing agent: a deuterated reagent: metal catalyst: auxiliary agent: solvent =1:1.1:1:10-500:0.05-0.20:1:20-500.
10. The method according to claim 1, wherein R is 1 Is one or more of alkyl, alkoxy, vinyl, aromatic substituent, nitro, amido, trifluoromethyl, halogen, pyridine, thiophene and furan; said R is 2 Is one or more of benzyl, methyl, ethyl, isopropyl, tertiary butyl, alkoxy, allyl and tertiary butyl.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0782252A (en) * 1993-06-30 1995-03-28 Fuji Photo Film Co Ltd Production of imidic acid ester compound and n-pyrazolylamidoxime compound
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0782252A (en) * 1993-06-30 1995-03-28 Fuji Photo Film Co Ltd Production of imidic acid ester compound and n-pyrazolylamidoxime compound
CN104529823A (en) * 2014-10-23 2015-04-22 江苏南方农药研究中心 Benzimidate compound preparation method
CN108675942A (en) * 2018-06-19 2018-10-19 杭州盛漫生物科技有限公司 A kind of preparation method of aromatic nitrile compounds
US20220024925A1 (en) * 2020-07-22 2022-01-27 Acurx Pharmaceuticals Llc Deuterium-Substituted 7-Substituted-2-(Benzylamino)-6-Ozopurine Compounds and Uses Thereof

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Title
SARA KOPF，ET AL.: "Manganese-catalyzed selective C–H activation and deuteration by means of a catalytic transient directing group strategy", 《CHEM. COMMUN.》 *
XIAOXU YANG，ET AL.: "Manganese-Catalyzed ortho-C-H Alkenylation of Aromatic N-H Imidates with Alkynes: Versatile Access to Mono-Alkenylated Aromatic Nitriles.", 《ADV. SYNTH. CATAL.》 *

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