CN116789556A - Preparation method of cyclopropoxy ethylamine - Google Patents

Preparation method of cyclopropoxy ethylamine Download PDF

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Publication number
CN116789556A
CN116789556A CN202310607590.3A CN202310607590A CN116789556A CN 116789556 A CN116789556 A CN 116789556A CN 202310607590 A CN202310607590 A CN 202310607590A CN 116789556 A CN116789556 A CN 116789556A
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cyclopropoxy
compound
ethylamine
steps
following
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徐红岩
袁伟芳
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Kanghua Shanghai New Drug R & D Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a preparation method of cyclopropoxy ethylamine. The preparation method mainly solves the technical problems that the prior preparation method is difficult to amplify and uses expensive metal reagents or dangerous reagents, and comprises the following steps: 1: the cyclopropyl alcohol reacts with acrylic ester to obtain a compound I (3-cyclopropoxy propionate), and (2) the compound I (3-cyclopropoxy propionate) is hydrolyzed to obtain a compound II (3-cyclopropoxy propionic acid); (3) Reacting the compound II (3-cyclopropoxy propionic acid) with diphenyl azide phosphate and heating and rearranging to obtain a compound III (Boc-protected cyclopropoxy ethylamine); (4) The compound III (Boc protected cyclopropoxy ethylamine) is subjected to acid deprotection to obtain a product IV (cyclopropoxy ethylamine). The beneficial effects of the invention are as follows: the cyclopropoxy ethylamine is synthesized based on commercial cyclopropane, dangerous reagents are not needed, the reaction process is easy for mass production, the whole reaction route has high overall yield, the product purity is high, the cost is relatively lower, and the three wastes are less.

Description

Preparation method of cyclopropoxy ethylamine
Technical Field
The invention relates to a preparation method of cyclopropoxy ethylamine.
Background
Cyclopropyl has been developed for the treatment of respiratory diseases, psychotic disorders, endocrine and metabolic diseases, infectious diseases, neurological diseases, cardiovascular and cerebrovascular diseases and tumor drugs such as ciprofloxacin, milnacipran, saxagliptin, nevirapine, prasugrel and the like, all of which have been marketed as cyclopropyl structures. Develop a novel cyclopropyl structural intermediate, which has important significance for drug development.
There are few published synthetic literature reports of cyclopropyloxyethylamine, which can be synthesized mainly by the following several strategies from chemical structural analysis.
Method 1: constructing cyclopropyl. Patent documents US2010/249088 (ASTELLAS PHARMA INC application) and tetrahedra (Tetrahedron, 1971, 27, 1799-1806) report the synthesis of target cyclopropyloxyethylamine by cyclopropylations of 2-chloroethylvinylethers (Simmons-Smith Cyclopropanation), wherein the Simmons-Smith cyclopropyl reaction yields are low, between 13-46%, and require the use of highly dangerous diethyl zinc, which is flammable, air and sensitive, not easy to use on a large scale. The synthetic route is as follows:
。
method 2: cyclopropyl alcohol alkylation. Journal of pharmaceutical chemistry [ Journal of Medicinal Chemistry, 2021, vol.64, # 24, p.18102-18113 ] and patent WO2019/126094 (briston-myersquibb CO 2019 application) report that cyclopropylalcohol and bromoacetic acid are used to build cyclopropyloxy groups, a reaction requiring sodium hydride and subsequent reactions requiring borane reduction and sodium azide and palladium on charcoal reduction to introduce amino groups. The reagent in the reaction process is inflammable and explosive, and is not easy to produce in large scale. The synthetic route is as follows:
。
method 3: cyclopropyl bromoalkylation. The construction of cyclopropyloxy groups by cyclopropyl bromides with primary alcohols has been reported in patent US 2016/168890 (MERCK KGAA 2016 application) and journal of pharmaceutical chemistry [ Journal of medicinal chemistry, 2001, vol.44, # 18, p.2966-2975 ], which likewise requires the use of sodium hydride, a strong base, but hardly any other base. The synthetic route is as follows:
the above methods are not easy to scale up due to the limitations of reagents. The simple and rapid route is developed to synthesize the cyclopropoxy ethylamine, so that the method meets the requirements of drug production and has great economic benefit and social significance.
Disclosure of Invention
The invention aims to provide a preparation method of cyclopropoxy ethylamine, which mainly solves the technical problems that the existing synthesis method has dangerous reaction, uses dangerous reagent, cannot realize amplified production and the like.
The technical scheme of the invention is as follows: a preparation method of cyclopropoxy ethylamine comprising the following steps: (1) The Michael addition reaction (michael addition) of cyclopropyl alcohol with acrylate to form compound I (3-cyclopropoxy propionate); (2) Hydrolysis of Compound I (3-cyclopropoxy propionate)Producing compound II (3-cyclopropoxypropionic acid); (3) Compound II (3-cyclopropoxy propionic acid) reacted with diphenyl azide phosphate and subjected to Ke Disi rearrangement (Curtius rearrangement) to form compound III (Boc-protected cyclopropoxy ethylamine); (4) Finally, the compound III (Boc protected cyclopropyloxyethylamine) is subjected to acid t-butoxycarbonyl (Boc) removal protection to obtain a product IV (cyclopropyloxyethylamine). Wherein step 1 is synthesized with reference to the report of U.S. pharmaceutical chemistry (J.Med. Chem.2021,64 (13), 9057-9077). The reaction route is as follows:。
the method comprises the following steps:
(1) Stirring and reacting the cyclopropyl alcohol and acrylic ester in sodium hydroxide aqueous solution and DMSO at room temperature to obtain a compound I (3-cyclopropoxy propionate);
(2) Hydrolyzing the compound I (3-cyclopropoxy propionate) by using alkali metal hydroxide to obtain a compound II (3-cyclopropoxy propionic acid);
(3) Reacting the compound II (3-cyclopropoxy propionic acid) with diphenyl azide phosphate to produce an acyl azide compound, directly heating the acyl azide compound with tertiary butanol in toluene solution without purification, and carrying out Ke Disi rearrangement reaction (Curtius rearrangement) to obtain a compound III (Boc-protected cyclopropoxy ethylamine);
(4) The compound III (Boc protected cyclopropyloxyethylamine) is subjected to acid t-butoxycarbonyl (Boc) protection to obtain a product IV (cyclopropyloxyethylamine).
Further, in the step (1), the acrylic ester is one of methyl acrylate, ethyl acrylate or benzyl acrylate, preferably methyl acrylate or ethyl acrylate. The molar ratio of the cyclopropyl alcohol to the acrylic ester is 1:1.1-1.5, preferably 1:1.3;
further, in the step (2), the alkaline metal hydroxide is one of sodium hydroxide, potassium hydroxide or lithium hydroxide;
further, in the step (3), the heating temperature between the substrate and the tertiary butanol in the toluene solution is 100-120 ℃, and the weight ratio of the substrate to the toluene solution to the tertiary butanol is 1: 5-10: 3-5;
further, in said step (4), said acid is trifluoroacetic acid or a hydrogen chloride-organic solvent solution, preferably trifluoroacetic acid; the organic solvent is one of dichloromethane, ethyl acetate, dioxane or acetonitrile, preferably dichloromethane.
Drawings
FIG. 1 shows a nuclear magnetic pattern of compound I of the present invention.
FIG. 2 shows a nuclear magnetic pattern of compound III of the present invention.
FIG. 3 shows a nuclear magnetic pattern of compound IV of the invention.
The beneficial effects of the invention are as follows: the invention synthesizes cyclopropyloxy ethylamine based on commercial cyclopropyl alcohol, does not need to use dangerous metal reagents to construct cyclopropyl rings, and does not need dangerous reagents such as sodium hydrogen and the like to complete etherification reaction. The new method for synthesizing the cyclopropoxy ethylamine through the addition reaction and the Ke Disi rearrangement reaction is provided, dangerous reactions and dangerous reagents are not used, the reaction process is easy to translate to mass production, the whole reaction route has high overall yield, the product purity is high, the cost is relatively lower, and the three wastes are less.
Detailed Description
The invention is further illustrated below in conjunction with specific examples, which should not be construed as limiting the invention.
Example 1
(1): synthesis of Compound I (ethyl 3-cyclopropoxypropionate)
Into a 5L three-necked flask, 2L dimethyl sulfoxide, 235 g (4.1 mol) cyclopropyl alcohol and ethyl acrylate 610 g (6.1 mol) were successively added, followed by stirring, and 80mL of 5N aqueous sodium hydroxide solution (0.4 mol) was added under cooling in a normal temperature water bath. After the addition was completed, the reaction mixture was stirred at room temperature for 40 hours. The reaction solution was poured into 5L of water, stirred, and extracted with methylene chloride (3L. Times.3). The organic phases were combined, washed once with water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to give crude product (680 g, yield-100%), oil, and the next reaction. Separating with small amount of product column chromatography to obtain pure product, and nuclear magnetic resonance spectrum shown in figure 1, 1 H-NMR (400 MHz, DMSO-d6): δ 4.05 (q,J= 7.2 Hz, 2H), 3.70 (t,J= 6.4 Hz, 2H), 3.20 (m, 1H), 2.48 (t,J= 6.4 Hz, 2H), 1.16~1.21 (m, 4H), 0.49 (m, 2H), 0.38 (m, 2H)。
(2): synthesis of Compound II (3-cyclopropoxypropionic acid)
1L of tetrahydrofuran, compound I (ethyl 3-cyclopropoxypropionate, 680g, based on 4.1 mol) and an aqueous solution of lithium hydroxide [ prepared from 344g (8.2 mol) of lithium hydroxide and 1L of water ] were sequentially added to a 3L three-necked flask, and the mixture was stirred at room temperature to react for 10 hours. The organic solvent was removed by concentration under reduced pressure, the remaining aqueous phase was cooled, washed twice with ethyl acetate, acidified to ph=3 with 4N hydrochloric acid and extracted with dichloromethane (500 ml×5). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate and concentrated to give crude product (325 g, yield 61%) as an oil which was reacted directly in the next step.
(3): synthesis of Compound III (Boc protected Cyclopropyloxyethylamine)
Dichloromethane (3L), compound II (3-cyclopropoxypropionic acid, 325g, 2.5 mol) and triethylamine (505 g, 5 mol) were added in sequence to a 5L three-necked flask, cooled to 0 ℃ in an ice water bath, diphenyl azide phosphate (DPPA, 894 g, 3.25 mol) was added dropwise, the temperature was controlled to <10 ℃, and the reaction solution after addition was stirred overnight at room temperature. The reaction solution is washed by a potassium bisulfate aqueous solution (1L multiplied by 3) with the mass percent concentration of 5% and saturated brine (1L multiplied by 1) in sequence, dried by anhydrous sodium sulfate, concentrated to dryness, and then added with 1L of toluene and 300mL of tertiary butanol for reflux reaction for 10 hours at 100-120 ℃. The reaction solution is cooled and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by 100-200 mesh silica gel column chromatography (eluent ethyl acetate: petroleum ether volume ratio=1:10 to 1:5) to give compound III (Boc-protected cyclopropyloxyethylamine, 372 g, yield 74%) as a pale yellow oil. The nuclear magnetic resonance spectrum is shown in FIG. 2,1H-NMR (400 MHz, CDCl 3): delta 4.82 (bs, 1H), 3.56 (t, J=5.2 Hz, 2H), 3.25-3.30 (m, 3H), 1.45 (s, 9H), 0.57 (m, 2H), 0.48 (m, 2H).
(4): synthesis of product IV (cyclopropyloxyethylamine)
Dichloromethane (200 mL), compound III (Boc-protected cyclopropyloxyethylamine, 100 g,0.50 mol) and trifluoroacetic acid (50 mL) after cooling to 0 ℃ in an ice water bath were added sequentially to a 1L single-port flask and stirred for 4 hours. Concentrating to obtain the product IV (cyclopropyloxyethylamine) trifluoroacetate (111.2 g, yield: 100%), wherein the nuclear magnetic resonance spectrum is shown in figure 3,1H-NMR (400 MHz, CDCl 3): delta 7.5 (m, 3H), 3.73 (m, 2H), 3.33 (m, 1H), 3.25 (m, 2H), 0.40-0.50 (m, 4H).
Example 2
(1): synthesis of Compound I (methyl 3-cyclopropoxypropionate)
200 mL dimethyl sulfoxide, 23.5 g (0.41 mol) cyclopropyl alcohol and 52.5 g (0.61 mol) methyl acrylate were added sequentially to a 1L three-necked flask, followed by stirring, and 8mL of 5N aqueous sodium hydroxide solution (40 mmol) was added under cooling in a normal temperature water bath. After the addition was completed, the reaction mixture was stirred at room temperature for 40 hours. The reaction mixture was poured into 1L of water, stirred, and extracted with methylene chloride (500 mL. Times.3). The organic phases were combined, washed once with water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to give crude product (70.0. 70.0 g, yield. About.100%) as an oil, which was reacted directly next.
The remaining steps (2), (3) and (4) were carried out in the same manner as in example 1, and the combined yield was 50.3%.
Example 3
(1): synthesis of Compound I (benzyl 3-cyclopropoxy propionate)
200 mL dimethyl sulfoxide, 23.5 g (0.41 mol) cyclopropyl alcohol and 98.8 g (0.61 mol) benzyl acrylate were added sequentially to a 1L three-necked flask, followed by stirring, and 8mL of 5N aqueous sodium hydroxide solution (40 mmol) was added under cooling in a normal temperature water bath. After the addition was completed, the reaction mixture was stirred at room temperature for 40 hours. The reaction mixture was poured into 1L of water, stirred, and extracted with methylene chloride (500 mL. Times.3). The organic phases were combined, washed once with water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to give crude product (130.0. 130.0 g, yield. About.100%) as an oil, which was reacted directly next.
The remaining steps (2), (3) and (4) were carried out in the same manner as in example 1, and the combined yield was 48.3%.
Example 4
(1) 200 mL dimethyl sulfoxide, 23.5 g (0.41 mol) cyclopropyl alcohol and 61.0 g (0.61 mol) ethyl acrylate were sequentially added to a 1L three-necked flask, followed by stirring, and 8mL of 5N aqueous sodium potassium hydroxide solution (40 mmol) was added under cooling in a normal temperature water bath. After the addition was completed, the reaction mixture was stirred at room temperature for 40 hours. The reaction mixture was poured into 1L of water, stirred, and extracted with methylene chloride (500 mL. Times.3). The organic phases were combined, washed once with water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to give crude product (68.3 g, yield. About.100%) as an oil, which was reacted directly in the next step.
The remaining steps (2), (3) and (4) were carried out in the same manner as in example 1, and the combined yield was 49.1%.
Example 5
Step (1) is the same as in example 1;
step (2): into a 0.5L three-necked flask, 100 mL tetrahydrofuran, compound I (ethyl 3-cyclopropoxypropionate, 68.0 g, based on 0.41 mol) and an aqueous sodium hydroxide solution [ prepared from 32.8g (0.82 mol) of sodium hydroxide and 100 mL water ] were successively added, and the mixture was stirred at room temperature to react for 10 hours. The organic solvent was removed by concentration under reduced pressure, the remaining aqueous phase was cooled, washed twice with ethyl acetate, acidified to ph=3 with 4N hydrochloric acid and extracted with dichloromethane (300 ml×5). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the crude product (33.7. 33.7 g, yield 63%), oil, which was reacted directly next.
The remaining steps were combined in 45% yield with example 1, steps (1), (2), (3) and (4).
Example 6
Step (1) is the same as in example 1;
step (2): into a 0.5L three-necked flask, 100 mL tetrahydrofuran, compound I (ethyl 3-cyclopropoxypropionate, 68.0 g, based on 0.41 mol) and an aqueous potassium hydroxide solution [ prepared from 46 g (0.82 mol) potassium hydroxide and 100 mL water ] were successively added, and the mixture was stirred at room temperature to react for 10 hours. The organic solvent was removed by concentration under reduced pressure, the remaining aqueous phase was cooled, washed twice with ethyl acetate, acidified to ph=3 with 4N hydrochloric acid and extracted with dichloromethane (300 ml×5). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the crude product (33.7. 33.7 g, yield 63%), oil, which was reacted directly next.
The remaining steps were combined in a yield of 47% as in example 1, steps (1), (2), (3) and (4).

Claims (9)

1. A preparation method of cyclopropoxy ethylamine is characterized in that: the method comprises the following steps: (1) Stirring and reacting the cyclopropyl alcohol and acrylic ester in sodium hydroxide aqueous solution and DMSO at room temperature to obtain a compound I; (3) The compound II reacts with diphenyl azide phosphate to produce acyl azide compound, the acyl azide compound is directly heated with tertiary butanol in toluene solution without purification, and the compound III is obtained through Ke Disi rearrangement reaction; (4) Protecting the compound III by acid t-butyloxycarbonyl to obtain a target product IV; the reaction route is as follows:
。
2. the method for preparing the cyclopropoxy-ethylamine according to claim 1, wherein the method comprises the following steps: the acrylic ester in the step (1) is one of methyl acrylate, ethyl acrylate or benzyl acrylate.
3. The method for preparing the cyclopropoxy-ethylamine according to claim 1, wherein the method comprises the following steps: the mol ratio of the cyclopropyl alcohol to the acrylic ester is 1:1.1-1.5.
4. The method for preparing the cyclopropoxy-ethylamine according to claim 2, wherein the method comprises the following steps: the acrylic ester in the step (1) is methyl acrylate or ethyl acrylate.
5. The method for preparing the cyclopropoxy-ethylamine according to claim 2, wherein the method comprises the following steps: the molar ratio of the cyclopropyl alcohol to the acrylic ester in the step (1) is 1:1.3.
6. The method for preparing the cyclopropoxy-ethylamine according to claim 1, wherein the method comprises the following steps: the alkaline metal hydroxide in the step (2) is one of sodium hydroxide, potassium hydroxide or lithium hydroxide.
7. The method for preparing the cyclopropoxy-ethylamine according to claim 1, wherein the method comprises the following steps: the heating temperature of the substrate and the tertiary butanol in the toluene solution in the step (3) is 100-120 ℃, and the weight ratio of the substrate to the toluene solution to the tertiary butanol is 1: 5-10.
8. The method for preparing the cyclopropoxy-ethylamine according to claim 1, wherein the method comprises the following steps: the acid in the step (4) is trifluoroacetic acid or hydrogen chloride-organic solvent solution.
9. The method for preparing the cyclopropoxy-ethylamine according to claim 1, wherein the method comprises the following steps: the acid in the step (4) is trifluoroacetic acid.
CN202310607590.3A 2023-05-26 2023-05-26 Preparation method of cyclopropoxy ethylamine Pending CN116789556A (en)

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