CN115477613B - Method for synthesizing 2-amino imidazoline compound - Google Patents

Method for synthesizing 2-amino imidazoline compound Download PDF

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CN115477613B
CN115477613B CN202211340313.2A CN202211340313A CN115477613B CN 115477613 B CN115477613 B CN 115477613B CN 202211340313 A CN202211340313 A CN 202211340313A CN 115477613 B CN115477613 B CN 115477613B
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CN115477613A (en
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黄治炎
王康
蔡佳栋
李胜
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Shaanxi Normal University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

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Abstract

The invention discloses a method for synthesizing 2-amino imidazoline compounds, which takes low-cost bromoacetate compounds and ethylene thiourea as raw materials, synthesizes thioether through substitution reaction, and then ammonolyzes thioether to prepare 2-amino imidazoline compounds or related drug molecules, and is accompanied with thioglycollate with odorless and additional value. The method has the advantages that: 1) The raw materials are cheap and easy to obtain, and the toxicity is low; 2) The obtained intermediate thioether is solid and is easy to purify and separate; 3) The product is solid, and is easy to separate from associated thioglycollic acid ester, and the two obtained products have high yield and purity. The method has the characteristics of simple process, mild reaction condition, low cost, environment friendliness, high yield and the like, and has good industrial application prospect.

Description

Method for synthesizing 2-amino imidazoline compound
Technical Field
The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of fine chemicals and medicine molecules containing 2-amino imidazoline structural units.
Background
The 2-amino imidazoline structural unit is widely used in medical intermediates and drug molecules, and belongs to an important organic compound. Such as clonidine hydrochloride, moxidecine hydrochloride (moxonidine), tizanidine skeletal muscle relaxant (tizanidine), indenazoline nasal vasoconstrictor (indanazoline), and novel targeted anticancer active molecules ONC201, ONC206 and ONC212 in clinical research stage all contain 2-amino imidazoline structural units. Among them, clonidine hydrochloride and tizanidine show a remarkable upward trend in recent years for domestic sales, and the 2021-year market scale is about 1.4 and 1.2 hundred million yuan, respectively. In addition, 2-aminoimidazolines are also important fine chemicals as an important class of guanidine-like organic compounds, such as for use as small molecule catalysts. Therefore, the research and development of a green, efficient, safe and simple synthesis process for preparing the compounds has good economic and social benefits.
As indicated above, 2-amino imidazolines mainly comprise two broad classes, one class being N-alkyl substituted, i.e., 2-alkylamine imidazolines; another class is the N-aryl substitution, namely 2-arylamine imidazolines. Six representative synthetic methods for such compounds are described below using clonidine preparation as an example.
(1) Missir was equal to 1993 and reported that 2, 6-dichloroaniline 1 was used as a raw material, formylated and chlorinated to give a dichloroimine intermediate 3, which was reacted with ethylenediamine in 1, 2-dichloroethane to give clonidine (patent RO 105262) in a unclear yield. In 2018, wang Gaohua et al (CN 107915679) improved the process with a total yield of 36% in three steps, and currently the method is used industrially to prepare clonidine. However, the method adopts sulfonyl chloride and sulfinyl chloride as raw materials, has strong corrosion to equipment and large wastewater amount. Along with the trend of environmental protection treatment and management and control, the production and environmental treatment cost is obviously improved.
(2) Mundla et al, 2000 reported that clonidine (Tetrahedron Letters,2000,41,6563-6566) was prepared from ethylene thiourea 4 as the starting material, which was reacted with methyl iodide and methyl chloroformate successively to give the key intermediate 6, which was reacted with 2, 6-dichloroaniline 1. The method is simple to operate, high in yield in each step, and easy to purify, and both compounds 5 and 6 are solids. However, methyl iodide and methyl chloroformate are both highly toxic chemicals, and the last ammonolysis step releases the highly toxic malodour gas methyl mercaptan, which prevents the route from being used for industrial production.
(3) Heinelt et al 2004 report that compound 1 was reacted with thiophosgene 7 to give isothiocyanate intermediate 8. The latter is reacted with ethylenediamine under the action of p-toluenesulfonyl chloride and sodium hydroxide to give clonidine in 60% yield (Tetrahedron, 2004,60,9883-9888). The method has short route, but has more impurities and low yield.
(4) Chern et al 2005 reported that 2-imidazolidone 9 reacted with either phosphine oxide 10 or chlorophosphate to give 2-chloroimidazoline 11, which was reacted with alkylamine to produce 2-alkylamine imidazoline (SYNTHETIC COMMUNICATIONS,2005,35,2633-2639). Based on this, yang Yingying et al 2021 used this strategy to synthesize clonidine (CN 112341431), but no yield data was seen. And the phosphorus oxychloride has extremely strong corrosiveness and tear resistance, so that the phosphorus oxychloride not only seriously harms the health of first-line personnel, but also corrodes equipment and brings a large amount of waste water and waste gas.
(5) Farajollah et al 2011 reported that thiourea 12 was obtained by reacting compound 1 with ammonium thiocyanate. The amidinesulfonic acid 13 was obtained in 77% yield by oxidation of thiourea 12 with sodium molybdate and hydrogen peroxide, the latter being reacted with ethylenediamine in isopropanol to give clonidine in 91% yield in the final step (Chinese Journal of Chemistry,2011,29,1055-1058). The method relates to an oxidation process, and no report of industrial application is currently seen.
(6) The route proposed by Farajollah above was modified in 2012 by Bandgar et al. Thiourea 12 was reacted with methyl iodide to give 14, and compound 14 was reacted with ethylenediamine to prepare clonidine (IN 2010MU 02956). IN 2013, bandgar further replaced methyl iodide with dimethyl sulfate, the process was optimized and the final step produced clonidine IN 96% (IN 2011MU 03307). The method avoids oxidation with hydrogen peroxide, and improves safety. However, methyl iodide and dimethyl sulfate are toxic and use in large quantities presents a great risk to the health of production line personnel. Meanwhile, methyl mercaptan and ammonia gas are released, so that the method is not suitable for industrial synthesis.
The latter five routes each have advantages and disadvantages compared to the industrial synthesis described in scheme 1. By way of systematic comparison, we consider that the synthesis of 2-aminoimidazolines starting from inexpensive thioethylenes (scheme 2) has room for improvement and optimization. The invention is therefore improved on this basis.
Disclosure of Invention
The invention aims to provide a method for synthesizing 2-amino imidazoline compounds, which has the advantages of simple process, low price, environment friendliness, mild conditions and good yield.
Aiming at the purposes, the technical scheme adopted by the invention comprises the following steps:
1. reacting ethylene thiourea 4 with bromoacetate compound 15 in a solvent to prepare compound 16;
Wherein R 1 represents a C 1～C7 alkyl group or a benzyl group, preferably any one of ethyl, isopropyl, n-butyl, tert-butyl and benzyl;
2. The 2-amino imidazoline compound is prepared by adopting a compound 16 according to any one of the following two methods:
The method comprises the following steps: an alkylamine or arylamine 17 is adopted to ammonolyze the compound 16 to obtain a 2-amino imidazoline compound 18, and a thioglycollate compound 19 with additional value is associated;
Wherein R 2 represents a C 1～C7 alkyl group (specifically, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.), a para-or meta-C 1～C4 alkyl-substituted aryl group, a para-or meta-C 1～C3 alkoxy-substituted aryl group, etc.;
the second method is as follows: reacting the compound 16 with methyl chloroformate or di-tert-butyl dicarbonate to obtain an acylate 20, ammonolyzing the acylate 20 by adopting an arylamine 21 to obtain a 2-amino imidazoline compound 23, and concomitantly carrying out a thioglycolate compound 19 with additional value;
Wherein R 3 represents methyl or tert-butyl, and R 4 represents aryl or substituted aryl.
In the above step 1, the molar ratio of the ethylene thiourea 4 to the bromoacetate compound 15 is preferably 1:1.1 to 1.3, and the solvent is preferably any one of methanol, ethanol and isopropanol.
In the first method of the above step 2, the molar ratio of the compound 16 to the alkylamine or the aromatic amine 17 is preferably 1:1.0 to 1.3.
In the second method of the above step 2, the molar ratio of the compound 16 to methyl chloroformate or di-tert-butyl dicarbonate is preferably 1:1.0 to 1.3, preferably the molar ratio of compound 20 to aromatic amine 21 is 1:1.0 to 1.3.
In the above step 2, the solvent used for ammonolysis is preferably any one of tetrahydrofuran, ethylene glycol dimethyl ether, dioxane, acetonitrile, 1, 2-dichloroethane, acetic acid, and the like.
The beneficial effects of the invention are as follows:
1. The invention firstly replaces methyl iodide with bromoacetate compounds such as tert-butyl bromoacetate or benzyl bromoacetate with equivalent price to prepare the compound 16, and the compound 16 is solid and is simple to prepare; then adopting alkylamine or aromatic amine with higher activity and other ammonolysis compounds 16, or adopting methyl chloroformate or di-tert-butyl dicarbonate acylated compounds 16, then ammonolyzing acylate with aromatic amine with lower activity to obtain the target product 2-amino imidazoline compound with high yield, and simultaneously, accompanying thioglycollic acid tert-butyl ester or benzyl ester with additional value and the like, wherein the latter has no peculiar smell. The method can obtain various aryl substituted 2-amino imidazoline drug molecules with high yield, avoids the use of high-toxicity methyl iodide, avoids the generation of methyl mercaptan in the route, and solves the problem of link pollution of toxic and unpleasant gases. Therefore, the invention obviously improves the safety of the route and has the characteristics of green and environment-friendly.
2. The invention realizes the two-step synthesis of 2-amino imidazoline fine chemicals or drug molecules, and has the advantages of short reaction steps, mild conditions and high yield compared with the existing industrial synthesis method.
Detailed Description
The present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited to these examples.
Example 1
1. Into a 1L single-necked flask, 20g (0.196 mol) of ethylene thiourea 4 and 300mL of absolute ethanol were added, followed by 46g (0.235 mol) of tert-butyl bromoacetate 15-1, and the mixture was reacted at room temperature for 20 hours. After the reaction, the solvent ethanol was removed under reduced pressure to obtain a colorless viscous liquid, which was diluted with a small amount of methylene chloride, and petroleum ether was added thereto and stirred to obtain 56g of tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 as a white solid in 94% yield.
2. In a 250mL single flask were added 20g (67.3 mmol) of tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) glycolate hydrobromide 16-1, 100mL of tetrahydrofuran, and 9.0g (74.0 mmol) of 2-methylbenzylamine 17-1, followed by reaction at 80℃for 20 hours. After the reaction is finished, the solvent tetrahydrofuran is directly filtered, the filter cake is washed by methylene chloride, then the filter cake is transferred to a beaker, methylene chloride and 0.5mol/L sodium hydroxide aqueous solution are added for stirring extraction, an organic phase is separated, the aqueous phase is extracted for 3 times by methylene chloride, the combined organic phases are dried by anhydrous sodium sulfate, the solvent is removed after filtration, and the 11g N- (2-methylbenzyl) -4, 5-dihydro-1-hydrogen-imidazole-2-ammonia 18-1 is obtained after drying, wherein the yield is 86 percent and the purity is more than 99 percent. The filtrate was concentrated, and the residue was purified by distillation under reduced pressure (100 Pa,30 ℃ C.) to give 6g of t-butyl thioglycolate 19-1 in 61% yield.
Example 2
Step 1 of this embodiment is the same as step 1 of embodiment 1. In step 2 of this example, 20g (67.3 mmol) of tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) glycolate hydrobromide 16-1 and 100mL of tetrahydrofuran were added to a 250mL single-necked flask, and 10.6g (74 mmol) of 2, 4-difluorobenzylamine 17-2 were further added to react at 80℃for 20 hours. After the reaction, the solvent tetrahydrofuran is directly removed under reduced pressure, then the residual liquid is stirred and diluted with dichloromethane and 1mol/L of dilute hydrochloric acid, an organic phase is separated, the pH of an aqueous phase is adjusted to 11, the aqueous phase is continuously extracted for 3 times by dichloromethane, the combined organic phases are dried by anhydrous sodium sulfate, the solvent is removed after filtration, and 10g N- (2, 4-difluorobenzyl) -4, 5-dihydro-1-hydrogen-imidazole-2-ammonia 18-2 is obtained after drying, the yield is 71 percent, and the purity is more than 99 percent. The filtrate was concentrated, and the residue was purified by distillation under reduced pressure (100 Pa,30 ℃ C.) to give 6g of t-butyl thioglycolate 19-1 in 61% yield.
Example 3
In step 2 of this example, 2, 4-difluorobenzylamine 17-2 of example 2 was replaced with equimolar 4-trifluoromethylbenzylamine 17-3, and the other steps were the same as in example 2 to give 12.5g N- (4-trifluoromethylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-amine 18-3 in 77% yield and >99% purity. The filtrate was concentrated, and the residue was purified by distillation under reduced pressure (100 Pa,30 ℃ C.) to give 6g of t-butyl thioglycolate 19-1 in 61% yield.
Example 4
Step 1 of this embodiment is the same as step 1 of embodiment 1. In step 2 of this example, 2.52g (8.48 mmol) of tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) glycolate hydrobromide 16-1 and 20mL of tetrahydrofuran were added to a 100mL single-necked flask, and 1.00g (9.33 mmol) of p-toluidine 17-4 was further added thereto to react at 80℃for 20 hours. After the reaction, the solvent tetrahydrofuran was directly removed under reduced pressure, and then the residual solution was diluted with dichloromethane and 1mol/L of diluted hydrochloric acid with stirring, an organic phase was separated, the pH of the aqueous phase was adjusted to 11, extraction with dichloromethane was continued for 3 times, the organic phases were dried over anhydrous sodium sulfate, and the solvent was removed after filtration. The crude product is washed by diethyl ether and dried to obtain 1.00g N- (p-tolyl) -4, 5-dihydro-1H-imidazole-2-ammonia 18-4, the yield is 70%, and the purity is more than 99%. The diethyl ether filtrate was concentrated, and the residue was purified by distillation under reduced pressure (100 Pa,30 ℃ C.) to give 0.76g of t-butyl thioglycolate 19-1 in 55% yield.
Example 5
Step 1 of this embodiment is the same as step 1 of embodiment 1. In step 2 of this example, 20g (67.3 mmol) of tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) glycolate hydrobromide 16-1, 100mL of methylene chloride, 15.7g (154.8 mmol) of triethylamine, 8.3g (87.5 mmol) of methyl chloroformate were added to a 250mL single flask, and the mixture was reacted at room temperature for 6 hours. After the completion of the reaction, the organic phase was washed with water, the solvent was removed under reduced pressure, and dried to obtain 14.7g of tert-butyl 2- (4, 5-dihydro-1-formate-imidazole) mercaptoacetate 20-1 in a yield of 84%. In a 100mL single flask, 2.33g (8.48 mmol) of tert-butyl 2- (4, 5-dihydro-1-formate-imidazole) mercaptoacetate (20-1), 15mL of methanol and 1.5mL of acetic acid were added, and 1.0g (9.33 mmol) of p-toluidine (21-1) was added to the flask, followed by reaction at 80℃for 20 hours. After the reaction, the solvents methanol and acetic acid were directly removed under reduced pressure. The residue was then diluted with dichloromethane and water with stirring, the organic phase was separated, the aqueous phase was adjusted to pH 11, extraction with dichloromethane was continued 3 times, the combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed after filtration. The crude product is washed by diethyl ether and dried to obtain 1.15g N- (p-tolyl) -4, 5-dihydro-1H-imidazole-2-ammonia 22-1, the yield is 78%, and the purity is more than 99%. The diethyl ether filtrate was concentrated, and the residue was concentrated by distillation under reduced pressure (100 Pa,30 ℃ C.) to give 0.76g of t-butyl thioglycolate 19-1 in 55% yield.
Example 6
In step2 of this example, 2.03g (7.38 mmol) of tert-butyl 2- (4, 5-dihydro-1-formate-imidazole) glycolate, 15mL of methanol and 1.5mL of acetic acid were placed in a 100mL single-necked flask, and 1.00g (8.12 mmol) of p-methoxyaniline 21-2 was added thereto to react at 80℃for 20 hours. The other steps were carried out in the same manner as in example 5 to obtain 1.13g N- (p-methoxyphenyl) -4, 5-dihydro-1H-imidazole-2-ammonia 22-2 in a yield of 80% and a purity of >99%. The diethyl ether filtrate was concentrated and the residue was purified by distillation under reduced pressure (100 Pa,30 ℃ C.) to give 0.70g of t-butyl thioglycolate 19-1 in 58% yield.
Example 7
In step 2 of this example, 1.54g (5.61 mmol) of tert-butyl 2- (4, 5-dihydro-1-formate-imidazole) mercaptoacetate 20-1, 15mL of methanol and 1.5mL of acetic acid were placed in a 100mL single flask, and 1.0g (6.17 mmol) of 2, 6-dichloroaniline 21-3 was further added thereto to react at 80℃for 20 hours. The other procedure was followed in the same manner as in example 5 to obtain 0.96g of 2, 6-dichloro-N- (2-imidazolin-2-yl) aniline 22-3 in a yield of 75% and a purity of >99%. The diethyl ether filtrate was concentrated and the residue was purified by distillation under reduced pressure (100 Pa,30 ℃ C.) to give 0.5g of t-butyl thioglycolate 19-1 in 54% yield.
Example 8
In step 2 of this example, 1.34g (4.90 mmol) of tert-butyl 2- (4, 5-dihydro-1-formate-imidazole) mercaptoacetate 20-1, 15mL of methanol and 1.5mL of acetic acid were placed in a 100mL single-necked flask, and 1.00g (5.39 mmol) of 4-amino-5-chloro-2, 1, 3-benzothiadiazole 21-4 was further added thereto to react at 80℃for 20 hours. The other procedure was followed in the same manner as in example 5 to give 0.97g of 5-chloro-4- (4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazol-4-amine 22-4 in a yield of 79% and a purity of >99%. The diethyl ether filtrate was concentrated and the residue was purified by distillation under reduced pressure (100 Pa,30 ℃ C.) to give 0.44g of t-butyl thioglycolate 19-1 in 55% yield.
Example 9
In step 2 of this example, 1.87g (6.83 mmol) of tert-butyl 2- (4, 5-dihydro-1-formate-imidazole) glycolate 20-1, 15mL of methanol and 1.5mL of acetic acid were placed in a 100mL single-necked flask, and 1.00g (7.51 mmol) of (4, 5-dihydro-1H-imidazol-2-yl) -4-indenamine 21-5 were further placed therein to react at 80℃for 20 hours. The other procedure was followed in the same manner as in example 5 to give 1.03g of (4, 5-dihydro-1H-imidazol-2-yl) -4-indene amine 22-5 in a yield of 75% and a purity of >99%. The diethyl ether filtrate was concentrated and the residue was purified by distillation under reduced pressure (100 Pa,30 ℃ C.) to give 0.61g of t-butyl thioglycolate 19-1 in 55% yield.
Example 10
Step 1 of this embodiment is the same as step 1 of embodiment 1. In step 2 of this example, 20g (67.3 mmol) of tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) glycolate hydrobromide 16-1, 100mL of tetrahydrofuran, and 100mL of water were added to a 250mL single-necked flask, and 17.6g (80.6 mmol) of di-tert-butyl dicarbonate was added to the flask in an ice-water bath, and the mixture was reacted at room temperature for 6 hours. After the reaction, inorganic salt is filtered off, tetrahydrofuran is removed under reduced pressure, the residual liquid is filtered to obtain a crude product, petroleum ether is added for recrystallization after water washing, and 17g of tert-butyl 2- (4, 5-dihydro-1-tert-butyl formate-imidazole) thioglycolate is obtained, and the yield is 81%. Then, the tert-butyl 2- (4, 5-dihydro-1-formate-imidazole) mercaptoacetate 20-1 in example 5 step 2 was replaced with an equimolar tert-butyl 2- (4, 5-dihydro-1-formate-imidazole) mercaptoacetate 20-2, and the other steps were the same as in example 5 step 2 to give N- (p-tolyl) -4, 5-dihydro-1H-imidazole-2-ammonia 22-1.
Example 11
In step 1 of this example, 5.0g (49 mmol) of ethylene thiourea 4 and 100mL of absolute ethanol were added to a 250mL single-necked flask, and 9.8g (59 mmol) of ethyl bromoacetate 15-2 were further added thereto to react at room temperature for 20 hours. After the reaction, the solvent ethanol is removed under reduced pressure, after the reaction is finished, the solvent ethanol is removed under reduced pressure to obtain colorless viscous liquid, a small amount of dichloromethane is added for dilution, petroleum ether is added for stirring, and 12g of ethyl 2- (4, 5-dihydro-1-hydrogen-imidazole) thioglycolate hydrobromide 16-2 is obtained, and the yield is 92%.
In step 2 of this example, the tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 of step 2 of example 1 was replaced with an equimolar ethyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-2, and the other steps were the same as step 2 of example 1 to give N- (2-methylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-1.
Example 12
In step 1 of this example, 5.0g (49 mmol) of ethylene thiourea 4 and 100mL of absolute ethanol were added to a 250mL single-necked flask, and 10.7g (59 mmol) of isopropyl bromoacetate was further added thereto for 15-3, followed by reaction at room temperature for 20 hours. After the reaction, the solvent ethanol is removed under reduced pressure to obtain colorless viscous liquid, a small amount of dichloromethane is added for dilution, petroleum ether is added for stirring, and 12.5g of isopropyl 2- (4, 5-dihydro-1-hydrogen-imidazole) thioglycolate hydrobromide 16-3 is obtained, and the yield is 90%.
In step 2 of this example, the tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 of step 2 of example 1 was replaced with an equimolar isopropyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-3, and the other steps were the same as step 2 of example 1 to give N- (2-methylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-1.
Example 13
In step 1 of this example, 5.0g (49 mmol) of ethylene thiourea 4 and 100mL of absolute ethanol were added to a 250mL single-necked flask, and 11.5g (59 mmol) of n-butyl bromoacetate 15-4 were further added thereto and reacted at room temperature for 20 hours. After the reaction, the solvent ethanol was removed under reduced pressure to obtain a colorless viscous liquid, which was diluted with a small amount of methylene chloride, and petroleum ether was added thereto and stirred to obtain 12.6g of n-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-4 in a yield of 87%.
In step 2 of this example, the tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 of step 2 of example 1 was replaced with an equimolar amount of N-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-4, and the other steps were the same as step 2 of example 1 to give N- (2-methylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-1.
Example 14
In step 1 of this example, 5.0g (49 mmol) of thiosemicarbazide 4 and 100mL of absolute ethyl alcohol were added to a 250mL single-necked flask, and then 11.5g (59 mmol) of isobutyl bromoacetate was added thereto for reaction at room temperature for 20 hours. After the reaction, the solvent ethanol was removed under reduced pressure to obtain a colorless viscous liquid, which was diluted with a small amount of methylene chloride, and petroleum ether was added thereto and stirred to obtain 13.2g of isobutyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-5 in a yield of 91%.
In step 2 of this example, isobutyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-5 was used in place of tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 in step 2 of example 1, and the other steps were the same as in step 2 of example 1 to give N- (2-methylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-1.
Example 15
In step 1 of this example, 5.0g (49 mmol) of thiosemicarbazide 4 and 100mL of absolute ethyl alcohol were added to a 250mL single-necked flask, and 13.5g (59 mmol) of benzyl bromoacetate 15-6 were further added thereto to react at room temperature for 20 hours. After the reaction, the solvent ethanol was removed under reduced pressure to give a white solid, which was washed with petroleum ether under stirring, and the filter cake was filtered and dried to give 15g of benzyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-6 in 92% yield.
In step 2 of this example, the tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 of step 2 of example 1 was replaced with an equimolar amount of benzyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-6, and the other steps were the same as in step 2 of example 1 to give N- (2-methylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-1.
Examples of application of synthesis of bioactive molecules
Application example 1
In a 250mL single port flask were added 10g (52.8 mmol) of N- (2-methylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-amine 18-1, 100mL of methanol, 5.7g (105.6 mmol) of sodium methoxide, and 13.63g (48.0 mmol) of 1-benzyl-3-methoxycarbonyl-4-piperidone hydrochloride, followed by reaction at 80℃for 20 hours. After the reaction was completed, methanol was distilled off under reduced pressure, and then the remaining solid was extracted with methylene chloride and water, and the organic phase was dried by distillation under reduced pressure to give 17.7g of pale yellow solid product ONC 201, yield 86%, purity >99%.
Application example 2
In a 250mL single port flask were added 10g (47.3 mmol) of N- (2, 4-difluorobenzyl) -4, 5-dihydro-1-hydro-imidazole-2-amine 18-2, 100mL of methanol, 5.12g (94.7 mmol) of sodium methoxide, and 12.2g (43.0 mmol) of 1-benzyl-3-methoxycarbonyl-4-piperidone hydrochloride, followed by reaction at 80℃for 20 hours. After the reaction was completed, methanol was distilled off under reduced pressure, and then the remaining solid was extracted with methylene chloride and water, and the organic phase was dried by distillation under reduced pressure to give 15.5g of pale yellow solid product ONC 206, yield 80% with purity >99%.
Application example 3
In a 250mL single port flask were added 10g (41.3 mmol) of N- (4-trifluoromethylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-amine 18-3, 100mL of methanol, 4.46g (82.6 mmol) of sodium methoxide, and 10.7g (37.6 mmol) of 1-benzyl-3-methoxycarbonyl-4-piperidone hydrochloride, followed by reaction at 80℃for 20 hours. After the reaction was completed, methanol was distilled off under reduced pressure, and then the remaining solid was extracted with methylene chloride and water, and the organic phase was dried by distillation under reduced pressure to obtain 15.5g of pale yellow solid product ONC 212, yield 85% with purity >99%.

Claims (7)

1. The method for synthesizing the 2-amino imidazoline compound is characterized by comprising the following steps of:
(1) Reacting ethylene thiourea 4 with bromoacetate compound 15 in a solvent to prepare compound 16;
Wherein R 1 represents a C 1～C7 alkyl group or a benzyl group;
(2) The 2-amino imidazoline compound is prepared by adopting a compound 16 according to any one of the following two methods:
The method comprises the following steps: an alkylamine or arylamine 17 is adopted to ammonolyze the compound 16 to obtain a 2-amino imidazoline compound 18, and a thioglycollate compound 19 with additional value is associated;
Wherein R 2 represents any one of C 1～C7 alkyl, para-or meta-C 1～C4 alkyl-substituted aryl, para-or meta-C 1～C3 alkoxy-substituted aryl;
The second method is as follows: reacting the compound 16 with methyl chloroformate or di-tert-butyl dicarbonate to obtain an acylate 20, ammonolyzing the acylate 20 by adopting an arylamine 21 to obtain a 2-amino imidazoline compound 22, and concomitantly carrying out a thioglycolate compound 19 with additional value;
Wherein R 3 represents methyl or tert-butyl, and R 4 represents aryl or substituted aryl.
2. The method for synthesizing 2-amino imidazolines according to claim 1, wherein: in the step (1), the molar ratio of the ethylene thiourea 4 to the bromoacetate compound 15 is 1:1.1 to 1.3.
3. The method for synthesizing 2-amino imidazolines according to claim 1, wherein: in the step (1), R 1 represents any one of ethyl, isopropyl, n-butyl, tert-butyl and benzyl.
4. The method for synthesizing 2-amino imidazolines according to claim 1, wherein: in the step (1), the solvent is any one of methanol, ethanol and isopropanol.
5. The method for synthesizing 2-amino imidazolines according to claim 1, wherein: in the first method of the step (2), the molar ratio of the compound 16 to the alkylamine or the arylamine 17 is 1:1.0 to 1.3.
6. The method for synthesizing 2-amino imidazolines according to claim 1, wherein: in the second method of the step (2), the molar ratio of the compound 16 to the methyl chloroformate or the di-tert-butyl dicarbonate is 1:1.0 to 1.3, the molar ratio of the compound 20 to the aromatic amine 21 is 1:1.0 to 1.3.
7. The method for synthesizing 2-amino imidazolines according to claim 1, wherein: in the step (2), the solvent used for ammonolysis is any one of tetrahydrofuran, ethylene glycol dimethyl ether, dioxane, acetonitrile, 1, 2-dichloroethane and acetic acid.
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CN101687812A (en) * 2007-07-02 2010-03-31 弗·哈夫曼-拉罗切有限公司 The 2-imidazolinium compounds that trace amine associated receptors (TAAR) is had good affinity

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US2819965A (en) * 1956-02-23 1958-01-14 Eastman Kodak Co Carboxymethylmercapto compounds as stabilizers for photographic emulsions
CN1242004A (en) * 1996-11-25 2000-01-19 普罗克特和甘保尔公司 Process for making 2-amino-2-imidazoline, guanidine, and 2-amino-3,4,5,6-tetrahydropyrimidine derivatives
CN101687812A (en) * 2007-07-02 2010-03-31 弗·哈夫曼-拉罗切有限公司 The 2-imidazolinium compounds that trace amine associated receptors (TAAR) is had good affinity

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