RU2820479C2 - Method of producing [1.1.1] propellan - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, specifically to a method of producing [1.1.1]propellan. Method involves reaction of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an effective amount of solid magnesium in anhydrous reaction conditions, selected to obtain [1.1.1]propellan.

EFFECT: providing a method of producing an end product in mild reaction conditions with providing commercially acceptable production efficiency.

21 cl, 3 ex

Description

[0001] This application claims benefit from US Patent Application No. 62/886,769, filed August 14, 2019, the contents of which are incorporated herein by reference.

PREREQUISITES FOR CREATION OF THE INVENTION

Field of technology

[0002] This application relates to processes for the preparation of bicyclic compounds, and in particular for the preparation of [1.1.1]propellane under reaction conditions that involve the reaction of 1,1-dibromo-2,2-bis(chloromethyl)niclopropane with magnesium.

Description

[0003] The traditional method for producing tricyclo[1.1.1.0 ^1,3 ]pentane (also known as [1.1.1]propellane) is the following batch reaction of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with methyllithium ( MeLi) under harsh anhydrous reaction conditions:

[0004] See K.R. Mondanaro and W.P. Dailey, Org. Synth. 75 (1998) p. 98. The method described by Mondanaro et al. results in the formation of 2 equivalents of methyl bromide (MeBr) as a by-product. MeBr does not react with [1.1.1]propellane, but it is difficult to remove and can cause significant problems in downstream reactions using anionic chemistries such as organo-alkali or magnesium-organic reactions. Although there is an alternative method for preparing [1.1.1]propellane that uses phenyllithium (PhLi) instead of MeLi, the quality of PhLi can significantly affect the yield, and the corresponding 2 equivalents of phenyl bromide (PhBr) produced can interfere with subsequent reactions. The resulting PhBr can be removed by co-distilling solutions of [1.1.1]propellane with a low-boiling solvent carrier, but this method is expensive when used on a commercial scale. In addition, such traditional batch procedures typically require careful control of the reaction temperature (e.g., -78°C to -40°C), especially during the initial stages of the reaction, which leads to increased costs and problems for industrial/kilogram batches. with scalability.

[0005] In addition, the use of lithium dispersion instead of MeLi has been reported:

[0006] See J. Belzner et al., Chem. Ber. 122 (1989) 397-398. However, due to the potentially corrosive ability of alkali metals to react with air and moisture, reactions involving elemental lithium are difficult to control, especially on a large scale.

[0007] The use of solid magnesium for the cyclization of 1-bromo-2-(chloromethyl)cyclopropane to form bicyclo[1.1.0]butane (BBC) has been reported. However, significant amounts of unsaturated hydrocarbon by-products were obtained along with unacceptable yields and difficulty in isolating the VSV. See A.I. Dyachenko, Izvestia of the USSR Academy of Sciences, Chemical Series, No. 9 (1985), 2043-2047. Therefore, improved methods for producing [1.1.1]propellane are desirable.

SUMMARY OF THE INVENTION

[0008] A process has now been developed for the preparation of [1.1.1]propellane under substantially anhydrous reaction conditions, comprising the reaction of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an effective amount of elemental magnesium in accordance with scheme (I ) in the following way:

[0009] Surprisingly, it has been discovered that although elemental magnesium is generally considered to be much less reactive with alkyl halides than MeLi, PhLi and/or elemental lithium, relatively mild reaction conditions have been identified that provide commercially acceptable production efficiencies and yields of [1.1.1]propellane .

[0010] In an embodiment, a method for producing [1.1.1]propellane is provided, comprising reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an effective amount of solid magnesium under substantially anhydrous reaction conditions that are selected to produce [0010] 1.1.1]propellane.

[0011] These and other embodiments are described in more detail below.

DETAILED DESCRIPTION

Definitions

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as would be understood by one of ordinary skill in the art. Unless otherwise indicated, all patents, applications, published applications and other publications referenced herein are incorporated herein by reference in their entirety. Unless otherwise noted, where there are multiple definitions for a term presented herein, the definitions given in this section prevail.

[0013] The terms and phrases used herein, and variations thereof, particularly in the appended claims, unless expressly stated otherwise, are to be considered non-limiting and not restrictive. As examples of the above, the term "including" should be considered "including without limitation", "including but not limited to" or the like; as used herein, the term “comprising” is synonymous with the terms “including,” “comprising,” or “characterized by,” and is inclusive or non-limiting, and does not exclude additional unspecified elements or process steps; the term "having" should be interpreted as "having at least"; the term “includes” should be interpreted as “includes without limitation”; the term “example” is used to provide examples of implementation of an element of the description, but not an exhaustive or limiting list of them; and the use of terms such as “preferably”, “preferred”, “desirable” or “desirable”, or similar words, should not be understood as implying that certain features are critical, essential or even important to structure or function, but are intended to highlight alternative or additional features that may or may not be used in a particular embodiment. Additionally, the term “comprising” should be interpreted as synonymous with the phrases “having at least” or “comprising at least.” In the context of a method, the term “comprising” means that the method includes at least the specified steps, but may include additional steps. In the context of a compound, composition, or device, the term “comprising” means that the compound, composition, or device includes at least the listed features or components, but may include additional features or components. Likewise, a group of elements linked by “and” should not be interpreted as requiring each and every element to be present in the group, but should be interpreted as “and/or” unless otherwise indicated in the context (for example, in the claims). A group of elements linked by "or" should not be interpreted as requiring the mutual exclusivity of the elements in the group, but should be interpreted as "and/or" unless the context otherwise indicates. If a range of values is proposed, it should be understood that the embodiments include upper and lower limits, as well as any intermediate value between the upper and lower limits.

[0014] With respect to the use of substantially any plural and/or singular variations for terms herein, those skilled in the art may change plural to singular and/or singular to plural as the context and/or application requires. Various singular/plural combinations may be explicitly stated herein for clarity. The use of the singular does not exclude plurality. The mere fact of indicating certain indicators in mutually different dependent claims does not mean that these indicators cannot be combined if necessary. Any reference symbols in the claims should not be considered limiting the scope.

[0015] As used herein, the term "substantially anhydrous" has the usual meaning understood by those skilled in the art in the context of describing conditions suitable for reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an effective amount of solid magnesium, and thus includes reaction conditions in which the amount of water and/or oxygen is minimized to reduce unwanted side reactions. Such essentially anhydrous reaction conditions are generally similar to the well understood conditions used for Grignard reactions.

[0016] As used herein, the term “continuous flow process” and similar terms are used to refer to a chemical process that utilizes in-line chemical production and technology. Examples of such processes are described in WO 2019/051038, published March 14, 2019, which is incorporated herein by reference and in particular for the purpose of describing continuous flow process methods, equipment and reaction conditions.

[0017] It should be understood that if there are unfilled valencies in the compounds described herein, these valences should be filled with hydrogen atoms or isotopes thereof, for example, hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0018] It should be understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium may provide certain treatment advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or lower dose requirement. Each chemical element present in the structure of a compound can include any isotope of that element. For example, a hydrogen atom may be explicitly described in the structure of a compound, or its presence in the structure of the compound may be implied. At any location in a compound at which a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, without limitation, hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, as used herein, reference to a compound includes all potential isotopic forms unless the context clearly indicates otherwise.

Methods for obtaining [1.1.11 propedlan

[0019] In various embodiments, a method for producing [1.1.1]propellane is provided, comprising reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an effective amount of solid magnesium under substantially anhydrous reaction conditions selected to produce [0019] 1.1.1]propellane. The relative amounts of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane and solid magnesium can be selected to achieve the desired yield according to the stoichiometry of the reaction. For example, in an embodiment, the effective amount of solid magnesium is a molar excess that is at least 2 times the amount of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane, e.g., at least 2.1 times or 2.2 times. Solid magnesium can be in various forms, such as commercially available magnesium turnings, which advantageously have a large surface area for heterogeneous reaction with 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane.

[0020] Unlike the harsh anhydrous reaction conditions used when using MeLi and elemental lithium reagents as described above, embodiments of the substantially anhydrous reaction conditions described herein use solid elemental magnesium, which is generally less sensitive to water and /or oxygen than lithium. In various embodiments, this reduced sensitivity improves safety without compromising production efficiency, facilitating fruitful scale-up and commercial viability. For example, in an embodiment, a method for producing [1.1.1]propellane includes contacting at least about one kilogram of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an effective amount of solid magnesium under substantially anhydrous reaction conditions, as described herein.

[0021] In various embodiments, the substantially anhydrous reaction conditions involve reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with solid magnesium in the presence of an aprotic ether solvent. In an embodiment, the aprotic ether solvent contains tetrahydrofuran (THF). In various embodiments, the aprotic ether solvent contains THF and further contains an ether selected from diethyl ether, diethoxymethane, dibutyl ether, methyl tert-butyl ether, diocean, 2-methyltetrahydrofuran, cyclopentyl methyl ether, and mixtures thereof. In other embodiments, the aprotic ether solvent further comprises a hydrocarbon solvent for 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane and [1.1.1]propellane. In an embodiment, the hydrocarbon solvent is toluene, heptane, or a mixture thereof. The amount of hydrocarbon solvent mixed with the aprotic ether solvent may be selected to provide at least partial insolubility of the resulting salts (eg, MgBrCl, MgBr ₂ and/or MgCl ₂ ), thereby facilitating workup of the resulting [1.1.1]propellane reaction mixture at least partially removing the resulting insoluble salt(s) by a suitable separation technique (eg, filtration) to obtain purified [1.1.1]propellane or a partially purified mixture thereof.

[0022] Surprisingly, it has been discovered that the amount of THF in the dissolution mixture can affect the yield of the resulting [1.1.1]propellane under the substantially anhydrous reaction conditions described herein. In an embodiment, the aprotic ether solvent contains an amount of THF that is effective in increasing the yield of [1.1.1]propellane produced compared to another comparable solvent that does not contain that amount of THF.

[0023] Substantially anhydrous reaction conditions may provide for a relatively wide range of reaction temperatures. As noted above, traditional batch reaction conditions for the production of [1.1.1]propellane typically require low initial temperatures in the range of -78°C to -40°C, with gradual heating to temperatures above -40°C carried out carefully at later stages. stages towards the end of the reaction. It has been found that when [1.1.1]propellane is produced using an effective amount of magnesium as described herein, the initial reaction step can be carried out at significantly higher temperatures, for example at about -20° C. or higher. For example, in various embodiments, such significantly higher temperatures for substantially anhydrous reaction conditions may provide a reaction temperature much more suitable for commercial production, such as a temperature in the range of about 0° C. to the reflux temperature of the reaction mixture. In an embodiment, the substantially anhydrous reaction conditions include a reaction temperature ranging from about 0°C to about 85°C. The reaction temperature can be selected through routine experimentation in light of the teachings presented herein. Control of the reaction temperature can be accomplished in a variety of ways known to those skilled in the art, such as by applying external heating or cooling, controlling the relative feed rates of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane and solid magnesium reactants, and/or controlling pressure reactions (and thus, for example, reflux temperature).

[0024] Substantially anhydrous reaction conditions can provide for a relatively wide range of reaction pressures. For example, in various embodiments, the substantially anhydrous reaction conditions provide a reaction pressure ranging from about 10 kPa to about 500 kPa. The reaction pressure can be selected through routine experimentation in light of the teachings presented herein. Control of the reaction pressure can be accomplished in a variety of ways known to those skilled in the art, such as by conducting the reaction in a pressure vessel (eg, by matching a reaction vessel with a balloon) and/or by applying an external vacuum. Pressures ranging from slightly above ambient pressure (eg, about 102 kPa) to about 1000 kPa are used to increase the boiling point of the resulting [1.1.1]propellane, thereby reducing volatility and/or increasing yield.

[0025] Substantially anhydrous reaction conditions can provide a relatively wide range of reaction times for the 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane and solid magnesium reactants. For example, in various embodiments, the substantially anhydrous reaction conditions provide a reaction time ranging from about 30 minutes to about 10 hours. In some embodiments, for example when the reaction conditions provide for continuous flow conditions as described elsewhere herein, the reaction time may be shorter. For example, in various embodiments, the substantially anhydrous reaction conditions provide a reaction time ranging from about 30 seconds to about 30 minutes. The reaction time can be selected through routine experimentation in light of the ideas presented herein. Surprisingly, it has been discovered that relatively high yields of [1.1.1]propellane can be obtained at convenient reaction temperatures and short reaction times by practicing the embodiments described herein, for example, as shown in Examples 1-3 below. In practice, the reaction time is usually selected in combination with the reaction temperature and/or the relative feed rates of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane and solid magnesium reagents to achieve the desired production efficiency of the resulting [1.1.1]propellane.

[0026] Substantially anhydrous reaction conditions may include a batch condition and/or a continuous flow condition. For example, the examples below show periodic conditions. Suitable conditions for continuous flow can be identified by those skilled in the art, as described in WO 2019/051038, through routine experimentation in light of the ideas presented herein.

[0027] Surprisingly, it was discovered that, contrary to the generally lower expectations regarding the reactivity of solid magnesium compared to MeLi or solid lithium, substantially anhydrous reaction conditions using it were found to result in relatively high yields of the resulting [1.1.1] propellana. In an embodiment, substantially anhydrous reaction conditions are selected to produce a yield of [1.1.1]propellane product that is about 10% or higher (eg, in the range of about 10% to about 90%). In another embodiment, substantially anhydrous reaction conditions are selected to produce a yield of [1.1.1]propellane product that is about 20% or higher (eg, in the range of about 20% to about 90%). In another embodiment, substantially anhydrous reaction conditions are selected to produce a yield of [1.1.1]propellane product that is about 30% or higher (eg, in the range of about 30% to about 90%). In another embodiment, substantially anhydrous reaction conditions are selected to produce a yield of [1.1.1]propellane product that is about 40% or higher (eg, in the range of about 40% to about 90%). In another embodiment, substantially anhydrous reaction conditions are selected to produce a yield of [1.1.1]propellane product that is about 50% or higher (eg, in the range of about 50% to about 90%). Those skilled in the art may employ routine experimentation in light of the detailed teachings presented herein to identify suitable substantially anhydrous reaction conditions to obtain the desired results. For example, in an embodiment, the desired yield (e.g., at least about 10%, 20%, 30%, 40%, or 50%) is obtained by using a combination of any two or more of reaction temperature, reaction time, reaction pressure, THF content in an aprotic ethereal solvent and/or the relative feed rate of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane and solid magnesium as described herein.

[0028] In various embodiments, the starting product of the reaction of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an effective amount of solid magnesium is a reaction mixture that contains the resulting [1.1.1]propellane along with the remaining(s) reagent(s), solvent(s) and/or by-products formed (such as salts). The resulting [1.1.1]propellane can be isolated from the reaction mixture and purified by various methods. For example, standard aqueous processing followed by organic solvent extraction can be used to purify [1.1.1]propellane, which may be preferable for laboratory scale processing. On larger scales, it may be preferable to remove the [1.1.1]propellane during the reaction and/or after the reaction is substantially complete. For example, in an embodiment, the resulting [1.1.1]propellane is isolated from the reaction mixture by distillation under reduced pressure, as shown in Examples 1-2 below. In addition, other isolation methods may be used (eg, filtration to remove insoluble salt, as described herein).

[0029] The product obtained by purifying the reaction mixture can be used as isolated or can be further purified if necessary. For example, the resulting [1.1.1]propellane, which is isolated from the reaction mixture by distillation under reduced pressure, may be sufficiently pure for subsequent use. In an embodiment, the resulting [1.1.1]propellane is purified to produce purified [1.1.1]propellane having a purity of about 90% or greater. In some embodiments, further purification of the [1.1.1]propellane-containing product obtained in the initial isolation step is desirable. Such purification can be accomplished by methods known to those skilled in the art in accordance with the teachings set forth herein, such as distillation. In an embodiment, the resulting [1.1.1]propellane is purified to produce purified [1.1.1]propellane having a purity of about 95% or greater. In another embodiment, the resulting [1.1.1]propellane is purified to produce purified [1.1.1]propellane having a purity of about 99% or greater. Purity can be determined by methods known to those skilled in the art, such as gas chromatography (GC).

EXAMPLES

[0030] Additional examples describe additional embodiments in more detail, and the examples are not intended to limit the scope of the claims.

EXAMPLE 1

[0031] 1 g of magnesium turnings was added to a dry flask under nitrogen atmosphere. 10 mL of anhydrous THF was added to coat the chips. The reaction flask and the empty flask kept in a dry ice/acetone bath were connected to each other by a cannula. Substantially anhydrous reaction conditions were created by gradually adding a solution of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (6 g) in 20 ml THF to the reaction flask while maintaining gentle reflux using a heating bath. The resulting [1.1.1]propellane was continuously recovered by applying a partial vacuum to the cold receiving flask. The collected THF solution of propellane was weighed and analyzed by *H NMR, which showed a yield of [1.1.1]propellane of 36%.

EXAMPLE 2

[0032] To a dry flask containing a stirrer and thermocouple probe, 0.58 grams of magnesium turnings was added through a septum in the flask, and then the flask was placed under a nitrogen atmosphere. An aprotic ether solvent containing 10 ml of THF and methyl tert-butyl ether in a 1:1 volume ratio was added to the flask. The flask was then heated to 30°C. Separately, 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (3 g) was dissolved in 10 ml of THF and methyl tert-butyl ether in a 1:1 volume ratio. Substantially anhydrous reaction conditions were created by adding about 1/10 of this solution to the reaction flask followed by the addition of 0.48 ml of diisobutylaluminum hydride (1 M in THF). After 15 minutes, the rest of the 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane solution was gradually added under anhydrous reaction conditions to maintain the reaction temperature around 40-50°C. After another 30 min, the resulting mixture of aprotic ether solvent and the resulting [1.1.1]propellane solution was transferred under partial vacuum into a cold receiving flask. The collected [1.1.1]propellane solution and solvents were weighed and analyzed by ^1H NMR, which showed a [1.1.1]propellane yield of 42%.

EXAMPLE 3

[0033] 0.73 grams of magnesium turnings was added to a flask containing a stirrer. The flask was equipped with a rubber membrane septum with a digital thermocouple and then placed under a nitrogen atmosphere. 10 ml of THF and 1.0 ml of diisobutylaluminum hydride (1M in THF) were added to the flask. After 1 hour, substantially anhydrous reaction conditions were created by adding a solution of dibromo-2,2-bis(chloromethyl)cyclopropane (3 g) in THF (9 ml) to the flask at a rate to maintain the reaction temperature to 20-25°C. After an additional 1 hour, an aliquot of the solution was checked using ¹ H NMR, which showed a propellane yield of 54%.

Claims (21)

1. A process for producing [1.1.1]propellane, comprising reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an effective amount of solid magnesium under substantially anhydrous reaction conditions selected to produce [1.1.1]propellane. 2. The method of claim 1, wherein the substantially anhydrous reaction conditions involve reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with solid magnesium in the presence of an aprotic ether solvent that contains tetrahydrofuran. 3. The method of claim 2, wherein the aprotic ether solvent further comprises an ether selected from diethyl ether, diethoxymethane, dibutyl ether, methyl tert-butyl ether, dioxane, 2-methyltetrahydrofuran, cyclopentyl methyl ether and mixtures thereof. 4. The method according to claim 2 or 3, in which the aprotic ether solvent further contains a hydrocarbon solvent for 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane and [1.1.1]propellane. 5. The method according to claim 4, in which the hydrocarbon solvent is selected from toluene and heptane. 6. The method of claim 4 or 5, further comprising filtering the reaction mixture resulting from the reaction, thereby at least partially removing at least one insoluble salt. 7. Method according to any one of paragraphs. 1-6, wherein the effective amount of solid magnesium is a molar excess that is at least 2 times the amount of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane. 8. Method according to any one of paragraphs. 1-7, wherein substantially anhydrous reaction conditions are further selected to obtain a yield of resulting [1.1.1]propellane that is 10% or higher. 9. The method according to claim 8, wherein the yield is 20% or higher. 10. The method according to claim 8, wherein the yield is 30% or higher. 11. The method according to claim 8, in which the yield is 40% or higher. 12. The method according to claim 8, in which the yield is 50% or higher. 13. Method according to any one of paragraphs. 1-12, in which the substantially anhydrous reaction conditions include a reaction temperature ranging from 0°C to 85°C. 14. Method according to any one of paragraphs. 1-13, wherein the substantially anhydrous reaction conditions provide a reaction time ranging from 30 minutes to 10 hours. 15. Method according to any one of paragraphs. 1-14, further comprising separating at least a portion of the resulting [1.1.1]propellane from a reaction mixture containing 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane and solid magnesium. 16. Method according to any one of paragraphs. 1-15, comprising contacting at least one kilogram of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an effective amount of solid magnesium. 17. Method according to any one of paragraphs. 1-16, further comprising purifying the resulting [1.1.1]propellane to obtain purified [1.1.1]propellane having a purity of 90% or greater. 18. The method of claim 17, wherein the purity is 95% or higher. 19. The method of claim 18, wherein the purity is 99% or higher. 20. Method according to any one of paragraphs. 1-19, in which the substantially anhydrous reaction conditions provide for a batch condition. 21. The method of claim 1, wherein the substantially anhydrous reaction conditions include a continuous flow reaction condition carried out in a continuous flow reactor.