Method for preparing omega-nitroxy-1-alkanol

Abstract

The invention relates to a process for the preparation of omega-nitroxy-C3-10 alkane-1-ol, comprising nitrating an alpha, omega-C3-10 alkanediol with a nitrating agent, optionally in the presence of a nitrite trapping agent, characterized in that the nitrating agent is a mixture consisting of 50-75% by weight of an aqueous solution of nitric acid, and wherein the nitric acid is in the form of a mixture based on the alpha, omega-C3-10 alkanediol. The omega-C3-10 alkane diol is used in an amount selected in the range of 0.5 to 5 molar equivalents, and wherein the nitration is carried out at a temperature selected in the range of 65 to 100 DEG C.

Description

[0001] This application is a divisional application of Chinese patent application 201980059623.7 (PCT / EP2019 / 074072) with a filing date of September 10, 2019.

[0002] The present invention relates to a method for preparing ω-nitrooxy-C 3-10 A safe and effective method for the preparation of alkan-1-ols.

[0003] Global temperatures are rising, a process known as global warming or climate change. One of the main focuses in reducing this warming effect is to reduce the amount of greenhouse gases emitted into the atmosphere. Greenhouse gases are emitted from several different natural and anthropogenic sources; however, the two sources with the greatest impact are agriculture and the fossil fuel industry. In agriculture, ruminants, especially cattle, are the main contributors to biogenic methane formation, and it has been estimated that preventing methane formation from ruminants would nearly stabilize atmospheric methane concentrations. 3-Nitrooxypropanol (3-NOP, also known as 3-nitrooxy-propan-1-ol or 1,3-propanediol mononitrate) has been reported to be very effective in reducing the formation of methane in ruminants without affecting microbial fermentation in a way that would be detrimental to the host animal (WO-2012 / 084629).

[0004] The mononitration of polyols is usually poorly selective and rapidly leads to the formation of dinitrated alcohols or polynitrated alcohols due to the kinetics which are not easily controlled. In addition, strong decomposition reactions can be easily induced by carrying out the same reaction on short-chain alkane diols.

[0005] Thus, WO-2012 / 084629 discloses a process for preparing 3-nitrooxypropanol by reacting 3-bromopropanol with silver nitrate in acetonitrile, but this process is not economical in industrial-scale production.

[0006] Zikas et al. (Bioorganic & Medicinal Chemistry, 13 (2005) 6485-6492) disclose the mononitration of alkane diols with acetyl nitrate (produced from nitric acid, acetic acid and acetic anhydride) in the presence of ethyl acetate at room temperature. In addition to the need for an organic solvent, another disadvantage of this method is the use of acetyl nitrate, which, although an excellent nitrating agent, is also explosive and therefore not suitable for industrial-scale production.

[0007] WO-2004043898 discloses the batchwise mononitration of alkane diols with stabilized nitric acid in a water-immiscible chlorinated organic solvent at a reaction temperature below room temperature (RT), for example preferably equal to or below 0 °C. The stabilized nitric acid consists of fuming nitric acid diluted in water to a concentration of about 83 to 85 wt% and is substantially free of nitrous acid and nitrogen oxides. The weight ratio of the "stabilized" nitric acid to the alkane diol is from about 10:1 to about 15:1.

[0008] In addition to using chlorinated solvents that are highly undesirable in chemical production, a significant drawback of this method is the need for a high acid equivalent, which results in a high salt load. Moreover, this method uses a non-commercial nitric acid diluent. Also, the reaction requires low temperature (i.e., <RT) to control selectivity and avoid thermal runaway or even explosion.

[0009] Therefore, there is an urgent need to develop an efficient, economical, and safe industrial method for the direct nitration of α,ω-C 3-10 alkane diols, such as especially 1,3-propanediol, which can be carried out batchwise and in the absence of organic solvents, requires a small amount of nitric acid equivalent, and is easy to scale up.

[0010] Surprisingly and contrary to the common general knowledge in the art, it has now been found that ω-nitrooxy C 3-10 alkane-1-ols, such as especially 3-nitrooxypropanol, can also be obtained in an economical and safe manner in a batchwise "solvent-free" one-pot process at high temperature using a small amount of nitric acid as the nitrating agent.

[0011] Accordingly, the present invention relates to a method for preparing ω-nitrooxy C 3-10 alkane-1-ols, the method comprising nitrating an α,ω-C 3-10 alkane diol with a nitrating agent, characterized in that the nitrating agent is a mixture consisting of an aqueous nitric acid solution of 50 to 75 wt%, preferably 50 to 72 wt%, and wherein the nitric acid is used in an amount selected in the range of 0.5 to 5 molar equivalents based on the α,ω-C 3-10 alkane diol, and wherein the nitration is carried out at a temperature selected in the range of 65 - 100 °C (nitration temperature).

[0012] The term "α,ω-C 3-10 alkane diol" as used herein refers to a straight-chain α,ω-alkane diol having 3 to 10 carbon atoms, such as 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, and 1,10-decanediol. In all embodiments according to the present invention, 1,3-propanediol is particularly preferred.

[0013] The term "ω-nitrooxy C3-10 By "alkane-1-ol" is meant a linear ω-nitrooxyalkane-1-ol having 3 to 10 carbon atoms, for example 3-nitrooxypropane-1-ol (also known as 3-nitrooxypropanol), 4-nitrooxybutane-1-ol, 5-nitrooxypentane-1-ol, 6-nitrooxyhexane-1-ol, 7-nitrooxyheptane-1-ol, 8-nitrooxyoctane-1-ol, 9-nitrooxynonane-1-ol and 10-nitrooxydecan-1-ol. Particularly preferred in all embodiments according to the invention is 3-nitrooxypropanol.

[0014] In all embodiments of the present invention, the α,ω-C 3-10 Alkanediols, such as 1,3-propylene glycol in particular, are preferably used in 1 to 4 molar equivalents, more preferably 1 to 3 molar equivalents, and most preferably 1.5 to 2.5 molar equivalents of nitric acid. Other advantageous ranges include 1 to 2, 1 to 1.5, 1.5 to 5, 2 to 5, 3 to 5, and 2 to 4 molar equivalents.

[0015] In all embodiments of the present invention, the concentration of nitric acid in the nitric acid-water mixture is preferably selected in the range of 60 to 72 wt. %, even more preferably in the range of 62 to 68 wt. %. Such nitric acid is readily commercially available (e.g. at Lonza or Yara). Alternatively, regenerated nitric acid may be used.

[0016] As is known, in all embodiments of the present invention, nitric acid is used as the sole nitrating agent, ie nitric acid is used in the absence of any sulfuric acid or reagents leading to the formation of activated nitrates (eg acetyl nitrates), such as acetic anhydride.

[0017] In an advantageous embodiment, the reaction is carried out in the presence of an agent capable of removing nitrous acid and nitrogen oxides (ie in the presence of a suitable nitrite trap), for example in particular in the presence of urea and / or aminosulfonic acid, most preferably in the presence of urea.

[0018] In all embodiments of the present invention, the α,ω-C 3-10 The amount of alkanediol, for example, the amount of the agent capable of removing nitrous acid and nitrogen oxides (hereinafter referred to as "nitrite trap") is preferably selected in the range of 0.1 to 0.7 molar equivalents, preferably in the range of 0.2 to 0.5 molar equivalents, most preferably in the range of 0.2 to 0.4 molar equivalents, especially based on the amount of 1,3-propanediol.

[0019] Furthermore, in all embodiments of the present invention, the nitration is preferably carried out in the absence of (i.e. without adding) any organic solvent, but only in water, i.e., the nitration is carried out in a solution consisting essentially of nitric acid, water, α,ω-C 3-10The method is carried out in a reaction mixture consisting of an alkane diol and an optional nitrite trapping agent. Preferably, in all embodiments of the present invention, a nitrite trapping agent is also present.

[0020] As used herein, the term "organic solvent" is well known to those skilled in the art and refers to a carbon-based solvent that can dissolve other substances and is generally liquid at room temperature. Typical organic solvents include aliphatic chain compounds such as hexane, halogenated hydrocarbons such as dichloromethane, esters such as ethyl acetate, ethers such as diethyl ether, aromatic hydrocarbons such as toluene or xylene, alcohols such as methanol or ethanol, and ketones such as acetone, but are not limited thereto.

[0021] In a particularly advantageous embodiment, the present invention relates to a method for preparing ω-nitrooxy C 3-10 A process for preparing an alkane-1-ol, the process comprising preparing a alkane-1-ol by substantially reacting nitric acid, water, α,ω-C 3-10 The method comprises nitrating a reaction mixture composed of an alkanediol and a nitrite scavenger with a nitrating agent, wherein the nitrating agent is a mixture composed of a 50 to 75 weight % nitric acid aqueous solution, wherein the nitric acid is based on α, ω-C 3-10 The alkanediol is used in an amount selected in the range of 0.5 to 5 mol equivalents and wherein the nitration is carried out at a temperature selected in the range of 65-100° C., with the proviso that all preferences and definitions as given herein also apply to the process.

[0022] Advantageously, in all embodiments of the present invention, the reaction temperature during the nitration (nitration temperature) is selected in the range of 70-100° C., preferably in the range of 75-100° C., more preferably in the range of 80-100° C., most preferably in the range of 85-100° C., as this leads to particularly good results, especially when the α,ω-C 3-10 The amount of the alkanediol is 2 to 3 molar equivalents of nitric acid.

[0023] In an advantageous embodiment, when the α,ω-C 3-10 The amount of alkanediol, in particular based on the amount of 1,3-propylene glycol, when 4-5 molar equivalents of nitric acid are used, the nitration temperature is selected in the range of about 65 to 75° C. In another advantageous embodiment, when based on α,ω-C 3-10 The amount of alkanediol, in particular when less than 4 molar equivalents of nitric acid are used based on the amount of 1,3-propanediol, the nitration temperature is advantageously selected in the range of 75 to 100° C., preferably in the range of 80 to 100° C., most preferably in the range of 85 to 100° C., for example 90 to 100° C., as these process conditions lead to minimization of undesirable by-products (especially dinitration) while still providing good yields, enabling economical industrial-scale production.

[0024] α,ω-C 3-10 The nitration of the alkane diol, preferably 1,3-propanediol, is preferably carried out at a reaction time in the range of about 30 to about 300 minutes, preferably about 60 to about 120 minutes, most preferably 60 to 100 minutes.

[0025] The progress of the reaction can be monitored with conventional analytical methods and the optimum reaction time can thus be determined. Therefore, in a preferred embodiment, the present invention relates to a method according to the invention, wherein the reaction is monitored and terminated at a process yield in the range of 40% to 65%, preferably at a process yield in the range of 40% to 55%, most preferably at a process yield in the range of 40% to 55%, as determined by HPLC or GC in the range of 45% to 55%, for example by RP-HPLC based on an external standard.

[0026] As is known, the process according to the invention is designed to be carried out batchwise (discontinuously) in a safe and economical manner. Therefore, in a preferred embodiment, the invention relates to a method for preparing a ω-nitrooxy C 3-10 Process for the batch nitration of alkane-1-ols. However, a person skilled in the art can of course also easily adapt the process to a continuous process.

[0027] In a particularly advantageous embodiment, the process according to the invention with all the definitions and preferences as given herein is a process (I) comprising the following consecutive steps:

[0028] i. providing a nitrating agent (e.g., by loading a reactor vessel with a nitric acid water mixture), and then

[0029] ii. adding a reagent capable of removing nitrous acid and nitrogen oxides (i.e., a nitrite trapping agent) and stirring the obtained reaction mixture, preferably for 10 to 60 minutes, more preferably for 15 to 45 minutes, and then

[0030] iii. Add α,ω-C 3-10 Alkanediol, preferably 1,3-propanediol (actual nitration reaction).

[0031] In a particularly advantageous embodiment, the process of the invention is process (II) as process (I) comprising the following step of the consecutive steps (i) to (iii), in addition the subsequent step is

[0032] iv. quenching the reaction mixture obtained in (iii) with water and / or a base to obtain a product containing an ω-nitrooxy group C 3-10 An aqueous reaction mixture of an alkane-1-ol, preferably 3-nitrooxypropanol.

[0033] Optionally, the aqueous reaction mixture obtained in (iv) may be further neutralized with a suitable base, in particular in case of quenching with water (ie the process comprises a subsequent neutralization step (v)).

[0034] In all embodiments of the present invention, suitable bases include alkali metal or alkaline earth metal bases, such as alkali metal or alkaline earth metal hydroxides or carbonates and amines, but are not limited thereto. The base can be added as such or in the form of an aqueous solution thereof.

[0035] Preferably, in all embodiments of the present invention, the base used in step (iv) and the optional neutralization step (v) is selected from NaOH, KOH, Ca (OH) 2 or ammonia, more preferably an aqueous solution thereof is used. Most preferably, in all embodiments of the present invention, the base is aqueous NaOH or ammonia (NH 4 OH).

[0036] In the case of quenching with water, process (II) preferably comprises a neutralization step (v).

[0037] The temperature in step (i) and the starting temperature in step (ii) may already be the nitration temperature. However, it is preferred that the temperature in step (i) and the starting temperature in step (ii) are selected in the range of 18-30°C, for example at ambient temperature (usually about 20-22°C), and that the α,ω-C 3-10 Prior to the addition of the alkanediol, preferably 1,3-propanediol (ie before step (iii)), the reaction mixture obtained in (ii) is heated to the desired nitration temperature with all preferences and definitions as given herein.

[0038] In another advantageous embodiment, the quenching of the reaction (step (iv)) is carried out with cold water, for example with water having a temperature selected in the range of 0 to 20° C., more preferably in the range of 5 to 15° C., or with a base selected in the range of (-20) to 15° C., more preferably in the range of (-10) to 10° C., such as in particular aqueous NaOH, KOH, Ca(OH) 2 or NH 4 OH.

[0039] In a particularly advantageous embodiment, in the respective quenching and neutralization steps, the ω-nitrooxy group C 3-10 The pH of the aqueous reaction mixture of alkane-1-ols, such as in particular 3-nitrooxypropanol, is adjusted to a pH of 8-12, more preferably to a pH of 9-11, most preferably with aqueous sodium hydroxide (NaOH), potassium hydroxide (KOH) or ammonia (NH4OH).

[0040] Preferably, in all embodiments of the present invention, during the work-up, the ω-nitrooxyalkane-1-ol, more preferably 3-nitrooxypropanol, is separated from the residual starting material (i.e., α,ω-C 3-10 Alkanediol, preferably 1,3-propylene glycol) and by-products (i.e., α,ω-C 3-10 Alkanediol dinitrate, preferably 1,3-propylene glycol dinitrate).

[0041] Therefore, the present invention also relates to process (III), which is process (I) or (II), comprising a further extraction step (vi) after step (iii), step (iv) or step (v).

[0042] Particularly preferred in all embodiments of the present invention is process (IV) which comprises a selective extraction step (vi) after a quenching step (iv) and a neutralization step (v).

[0043] Prior to the selective extraction, it is preferred to 3-10 The pH of the aqueous mixture of alkane-1-ols, such as in particular 3-nitrooxypropanol, is adjusted to a pH of 8-12, more preferably to a pH of 9 to 11, most preferably with aqueous sodium hydroxide (NaOH), potassium hydroxide (KOH) or ammonia (NH4OH).

[0044] The selective extraction according to the present invention comprises obtaining in step (iii), (iv) or (v) the ω-nitrooxyl C 3-10 The aqueous reaction mixture of alkane-1-ol, preferably 3-nitrooxypropanol, is first treated with a non-polar solvent, such as preferably an aliphatic or aromatic hydrocarbon solvent, more preferably an aromatic solvent such as xylene or toluene, most preferably toluene (to remove impurities / by-products, such as dinitrated α,ω-C 3-10 The alkylene glycol is then extracted with an ether solvent (e.g. a cyclic ether, such as tetrahydrofuran or dioxane or an alkyl ether, such as diethyl ether, dibutyl ether, diisobutyl ether or methyl tert-butyl ether), such as in particular methyl tert-butyl ether (MtBE) (to extract the ω-nitrooxy group C 3-10 Alkan-1-ols, such as, in particular, 3-nitrooxypropanol) are used for extraction.

[0045] Furthermore, the obtained ether phase is preferably washed with water to ensure complete removal of the α,ω-C 3-10 After evaporation of the ether solvent (optionally after a drying step, for example with MgSO 4 ), the pure ω-nitrooxy C 3-10Even more preferably, the nonpolar solvent used in the selective extraction, such as in particular a hydrocarbon, even more in particular an aromatic hydrocarbon solvent phase, is re-extracted with an aqueous solvent, such as an aqueous solution obtained by washing the ether phase, to further increase the ω-nitrooxyl C 3-10 Yield of alkane-1-ols.

[0046] In principle, the reaction of the process according to the invention can be carried out in any reactor suitable for the respective reaction type. Without limiting the generality, the following are mentioned by way of example: suspension reactors, stirred tanks, stirred tank cascades, tubular reactors, tubular reactors comprising mixing elements such as static mixers, shell reactors, shell-and-tube reactors, reactive distillation columns.

[0047] As mentioned above, for economic reasons, the aqueous reaction mixture obtained in step (iv) or (v) may be fed directly to ruminants such as, in particular, cattle.

[0048] Due to the ω-nitrooxy 3-10 The aqueous solution of alkane-1-ol, preferably 3-nitrooxypropanol, is still novel, and the present invention also relates to the aqueous solution obtainable from the above step (iv) or (v), and its use for supplementing ruminants, such as in particular cattle, to reduce the formation of methane in said ruminants. Such aqueous solutions are characterized by high stability, low toxicity and increased cost efficiency, since there is no need to separate the ω-nitrooxy C before supplementing to the ruminants. 3-10 Alkane-1-ol.

[0049] In a particularly advantageous embodiment, the aqueous solution (all wt. % are based on the total weight of the aqueous solution) consists essentially of:

[0050] (a) 1 to 30 wt%, preferably 1 to 15 wt%, more preferably 2 to 10 wt%, most preferably 5 to 9 wt% of α,ω-C 3-10 Alkanediol, preferably 1,3-propylene glycol,

[0051] (b) 2.5 to 40 wt%, preferably 5 to 30 wt%, more preferably 5 to 20 wt%, most preferably 7.5 to 20 wt% of ω-nitrooxy C 3-10 Alkane-1-ol, preferably 3-nitrooxypropanol,

[0052] (c) 0.1 to 5 wt%, preferably 0.3 to 3 wt%, most preferably 0.5 to 2 wt% of α,ω-dinitrooxy C 3-10 an alkane, preferably 1,3-dinitrooxypropane,

[0053] (d) 0.1 to 10 wt%, preferably 0.1 to 6 wt%, more preferably 0.3 to 4 wt%, most preferably 0.5 to 2 wt% of a nitrite trap, preferably aminosulfonic acid or urea,

[0054] (e) 5 to 30 wt. %, preferably 10 to 25 wt. %, most preferably 15 to 20 wt. % of a nitrate, preferably sodium nitrate,

[0055] (f) 0.1 to 5 wt %, preferably 0.3 to 3 wt %, most preferably 0.5 to 2 wt % of a base, preferably sodium hydroxide, and

[0056] (g) 30 to 80 wt %, preferably 40 to 70 wt %, most preferably 50 to 65 wt % water.

[0057] Preferred aqueous solutions according to the invention (all weight % are based on the total weight of the aqueous solution) consist essentially of:

[0058] (a) 5 to 10% by weight of 1,3-propylene glycol,

[0059] (b) 5 to 20% by weight of 3-nitrooxypropanol,

[0060] (c) 0.5 to 3% by weight of 1,3-dinitrooxypropane,

[0061] (d) 0.5 to 4% by weight of urea,

[0062] (e) 15 to 20% by weight of sodium nitrate,

[0063] (f) 0.5 to 3% by weight of sodium hydroxide, and

[0064] (g) 50 to 65% by weight of water.

[0065] The most preferred aqueous solution according to the invention (all weight % are based on the total weight of the aqueous solution) consists essentially of:

[0066] (a) 5 to 9% by weight of 1,3-propylene glycol,

[0067] (b) 5 to 20% by weight of 3-nitrooxypropanol,

[0068] (c) 0.5 to 2% by weight of 1,3-dinitrooxypropane,

[0069] (d) 0.5 to 2% by weight of urea,

[0070] (e) 15 to 20% by weight of sodium nitrate,

[0071] (f) 0.5 to 2% by weight of sodium hydroxide, and

[0072] (g) 50 to 65% by weight of water.

[0073] The term "consisting essentially of" used in accordance with the present invention means that the amounts of components (a) to (g) add up to 100% by weight. However, the presence of small amounts of impurities or additives introduced, for example, by the individual raw materials of components (a) to (g) is not excluded.

[0074] The following examples are used to further illustrate the present invention, but are not limited thereto.

[0075] Example 1: Preparation of 3-nitrooxypropanol (3-NOP)

[0076] A) Formation of nitrate esters

[0077] Throughout the nitration process, the nitration is carried out in a double-jacketed reactor that remains open, preferably with a light nitrogen flow above the reaction. Nitric acid (1.5-4 equivalents based on 1,3-propylene glycol shown in Table 1) is loaded into the reactor and stirred at 20°C for 15 minutes. Urea (0.3 molar equivalent) is added and stirring is continued for 30 minutes. At the same time, the jacket temperature is set to the reaction temperature (65-100°C). Then 1,3-propylene glycol (1 molar equivalent) is dosed into the acid via a dropping funnel within 15 minutes, and the reaction is stirred for 60-100 minutes. The reaction is then quenched by pouring it into water cooled to 10-15°C to dilute the nitric acid to an amount of ~20%. The quenched reaction solution is slowly adjusted to pH 9-11 with 30% aqueous NaOH. Alternatively, the reaction is quenched by pouring the reaction into 20% aqueous NaOH cooled to (-10) to 10°C to obtain an aqueous solution of pH 9-11.

[0078] B) Post-treatment (selective extraction)

[0079] The aqueous solution obtained in step A is subsequently extracted with toluene and then methyl tert-butyl ether (MtBE). The MtBE phase is washed with water and evaporated to dryness to give 3-nitrooxypropanol (1,3-propylene glycol mononitrate) as a colorless to pale yellow oil.

[0080] Table 1

[0081]

[0082]

[0083] * Deep nitration, the reaction is slightly unstable during the addition of 1,3-propylene glycol

[0084] # The isolated yield is reduced by about 1-10% compared to the in-process yield

[0085] The above synthesis of 3-nitrooxypropanol (PDMN) using the conditions in Table 1, entry 5 (4 eq. 65% HNO3, 70°C, 60 min) with quenching on 20% NaOH gave a 52% yield for a 25 g scale.

[0086] The above synthesis of 3-nitrooxypropanol (PDMN) using the conditions in entry 6 of Table 1 with quenching on 20% NaOH gave an isolated yield of 38% for a 50 g scale.

[0087] C.) Composition of the neutralized reaction mixture

[0088] (Conditions: Table 1, entry 2, quenched on 20% NaOH)

[0089]

[0090]

[0091] Example 2

[0092] The synthesis of propylene glycol mononitrate (PDMN) as described above (4 eq. 65% HNO3, 60°C, 90 min) with 0.3 eq. of aminosulfonic acid replacing urea gave an isolated yield of 34%.

[0093] Example 3

[0094] Repeating the above example (Entry 1: 4 equivalents of 65% HNO3, 60°C, 90 minutes) with 1,4-butanediol instead of 1,3-propanediol gave a 19% isolated yield of butanediol mononitrate.

Claims

1. A method for preparing 3-nitrooxypropanol, the method comprising nitrating 1,3-propanediol with a nitrating agent optionally in the presence of a nitrite trapping agent, characterized in that The nitrating agent is a mixture consisting of a 50-75 wt % aqueous nitric acid solution, wherein the nitric acid is used in an amount selected in the range of 0.5 to 5 molar equivalents based on 1,3-propylene glycol, and wherein the nitration is performed at a temperature selected in the range of 65-100° C.

2. The process according to claim 1, wherein 1 to 4 molar equivalents of nitric acid are used based on 1,3-propanediol.

3. The method according to claim 1, wherein the concentration of the aqueous nitric acid solution is selected within the range of 60 to 72 wt %.

4. The method according to claim 1, wherein the nitrite capture agent is aminosulfonic acid and / or urea.

5. The method according to any one of claims 1 to 4, wherein the amount of the nitrite trapping agent is selected within the range of 0.1 to 0.7 molar equivalents based on 1,3-propanediol.

6. The process according to any one of claims 1 to 4, wherein the reaction temperature is selected in the range of 70-100°C.

7. The method according to any one of claims 1 to 4, wherein the nitrification is carried out for a time in the range of 10 to 300 minutes.

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