Process for preparing b-aminoalcohols

Abstract

A process is disclosed. The process can include the preparation of β-aminoalcohols from an epoxide and an amine. The process can further comprise a concentrated, atom-efficient industrial scale process where the amine and the epoxide are in a ratio of between about 1.1:1.0 and 1.0:1.1, or narrower.

Description

Attorney Docket No.: F1-8149-WOPROCESS FOR PREPARING p-AMINOALCOHOLSCROSS REFERENCE TO RELATED APPLICATIONSThis application claims the benefit of U.S. Provisional Patent Applications Serial No. 63 / 687,216, filed August 26, 2024, and 63 / 717,435 filed November 7, 2024, the disclosure of which is incorporated herein by reference in its entirely.TECHNICAL FIELD

[0001] The various embodiments of the disclosure relate generally to processes and methods for a new commercially practical process for forming [3-aminoalcohols from secondary amines and epoxides in water.BACKGROUND

[0002] The preparation of (3-aminoalcohols by the addition of epoxides to aqueous ammonia, primarily ethylene oxide and propylene oxide, to form adducts of ethanol amines and propanol amines is long known in patent literature. The processes are conducted in reaction mixtures comprising water and entail feeding the epoxides to aqueous ammonia. The reaction proceeds sequentially such that primary (mono-adduct), secondary (di-adduct), and tertiary (tri-adducts) alcoholic amines are formed. The addition reaction can be highly exothermic, even explosive, and can lead to polymerization of the epoxide unless controlled by excess reagent, typically using substantial excesses of amine or ammonia. Depending on the particular adduct product desired, excess ammonia and / or sequential alcoholic amine adduct is used to maximize the yield of the product(s). For instance, when the tertiary alcoholic amine is desired - the tri-adduct, an excess of the di-adduct is present to minimize oligomerization of the tri-adduct to form polyethers (oligomeric ethoxylates and propoxylates). Given that all three adducts whether of ethylene oxide or propylene oxide (and mixtures thereof) are large volume chemicals, industrial scale processes can be adjusted to maximize any one of the three potential non-oligomeric adducts. It is pointed out that the annual production of triethanolamine (a commodity chemical) is from 100,000 to 500,000 tons. There is a need however to develop industrial chemical processes for formation of smaller scale, (i.e. fine and specialty chemical levels of production) of more complex and more expensive |3-aminoalcohols such as the ones of this disclosure.Attorney Docket No.: F1-8149-WO

[0003] P-Aminoalcohols play an important role in chemistry recently developed by this group. Lithium Alkoxide Complexed Saline Hydride (LOXSH) catalysts have been previously described in W02022051376 for the hydrogen mediated anionic polymerization of conjugated dienes, such as butadiene and isoprene. Selection of polar modifiers (PMs), such as p-aminoalcohols, in the LOXSH catalyst system allows for tailoring the vinyl content of the polymers formed from conjugated diene monomers. The p-aminoalcohol dimethylaminoethanol can be effective to achieve high vinyl LOXSH catalyst formulations. Alternatively, the p-aminoalcohols 1 -piperidino-Ao-propanol (PiP, also 1 -piperidino-2- propanol CAS 934-90-7)) and l-piperidino-^ec-butanol (PsB also l-piperidino-2-butanol. CAS 3140-33-8) are effective for LOXSH catalyst formulations used to produce low vinyl content polymers from conjugated diene monomers.

[0004] Unlike dimethylaminoethanol used for high vinyl catalysts formulations, 1- piperidino-Ao-propanol and 1-piperidino-sec-butanol are not commercially available. Consequently, a commercial process was needed for the production of these and similar PM ligands.BRIEF SUMMARY

[0005] The various embodiments of the disclosure relate generally to processes or methods for producing P-aminoalcohols.

[0006] An embodiment of the disclosure can be an industrial scale reaction as shown below:An embodiment of the disclosure can be a method or process for preparing a p- aminoalcohol of Formula I,Attorney Docket No.: F1-8149-WO wherein R1and R2are each independently H or Ci to C4 alkyl, provided at least one of R1and R2is not H, or R1and R2together with the two connecting carbons for a Cs to Cs carbocyclic ring; R3and R4are each independently a Ci to C3 alkyl or R3and R4together along with the nitrogen form a 5- or 6- member heterocyclic alkyl that optionally contains O or N-R5, where R5is a Ci to C alkyl. The method or process can comprise a) forming a reaction solution of 10-40 wt.% of an HNR3R4amine in an aqueous solution; b) feeding an epoxide of Formula II to the reaction solution to produce a reaction mixture;c) Controlling the temperature of the reaction mixture during the feeding in step b) to a temperature range of about 20° C to about 80° C; and d) Purifying the reaction mixture to obtain the P-aminoalcohol. In an embodiment of the disclosure, the molar ratio of amine to epoxide can be between 1 : 1.1 and 1.1: 1.

[0007] An embodiment of the disclosure can be the method or process above, wherein purifying the reaction mixture in step d) further comprises forming an organic layer comprising the P-aminoalcohol and an aqueous layer from the reaction mixture wherein a salt is optionally added to decrease the aqueous solubility of the p-aminoalcohol, and separating the two layers. In some embodiments, the aqueous layer can be recycled as the reaction solution in step a).

[0008] An embodiment of the disclosure can be the method or process above, where the molar ratio of amino to epoxide is between 1 : 1.07 and 1.07: 1 , or between 1 : 1.05 and 1.05: 1.

[0009] An embodiment of the disclosure can be the method or process above wherein R2is H; or wherein R1is methyl or ethyl and R2is H; or wherein R3and R4together along with the nitrogen form a 5- or 6- member heterocyclic alky l that is piperidinyl, pyrrolidinyl, morpholinyl, or piperazinyl; or wherein R1is methyl or ethyl, R2is H. and R3and R4together along with the nitrogen form a 5- or 6- member heterocyclic alkyl that is piperidinyl, pyrrolidinyl, morpholinyl, or piperazinyl; or wherein R3and R4are both Cl alkyl; or wherein R1is methyl or ethyl, R2is H, and R3and R4are both Cl alkyl.

[0010] An embodiment of the disclosure can be the method or process above wherein the temperature of step c) is about 30 to 60 °C.Attorney Docket No.: F1-8149-WO

[0011] An embodiment of the disclosure can be the method or process above wherein the forming an organic layer and an aqueous layer comprises cooling the reaction mixture and either separating out a neat organic layer or adding an organic solvent to generate the organic layer. In some embodiments, the organic solvent can comprise an ether, alkyl ester, dialkyl carbonate, alkane, or cycloalkane, and combinations thereof. In some embodiments when the salt that is optionally added, the salt can be one or more of non-oxi dative aqueous soluble salts of sodium, and / or potassium, and / or magnesium, and / or calcium.DETAILED DESCRIPTION

[0012] The term "alkyd", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Examples of alkyd groups include, but are not limited to. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl and hexyl.

[0013] The term "alkenyl", as used herein, unless otherwise indicated, includes alkyd moieties having at least one carbon-carbon double bond wherein alkyl is as defined above. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

[0014] The term "alkynyl", as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, and butynyl.

[0015] The term ’’alkoxy". as used herein, unless otherwise indicated, includes an -O-alkyl group, wherein alkyd is as defined above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, / -butoxy, pentoxy and hexoxy.

[0016] The term "alkylhydroxyi". as used herein, unless otherwise indicated, includes an alkyl-OH group, wherein the alkyl is as defined above. The -OH is the alkylhydroxy 1 can be any of the carbons of the alkyl, producing primary7secondary and tertiary hydroxyls, and can also include more than one hydroxyl in the alkylhydroxyi. Examples of alkylhydroxyl include, but are not limited to, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH(OH)CH3, - CH(OH)CH2CH3. and -CH2C(CH3)2(OH)

[0017] The term "cycloalkyl", as used herein, unless otherwise indicated, includes nonaromatic saturated cyclic alkyl moieties wherein alkyl is as defined above. Examples ofAttorney Docket No.: F1-8149-WO cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopenty l, cyclohexyl, cycloheptyl, and cyclooctyl.

[0018] The term "cycloalkenyl", as used herein, unless otherwise indicated, includes nonaromatic cyclic alkenyl moieties wherein alkenyl is as defined above. Examples of cycloalkyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0019] The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl, naphthyl, indenyl, and fluorenyl. "Aryl" encompasses fused ring groups wherein at least one ring is aromatic.

[0020] The term “epoxide'’ or “alkene oxide” can be used interchangeably and. unless otherwise indicated, include organic radicals having a three member ring of carbon-carbon- oxygen, sometimes also called an oxirane, along with any substitution on the carbons of the oxirane. For instance, within the disclosure the more common name 1 ,2-epoxy butane is used interchangeably with the less common name 1.2-butylene oxide as a matter of convenience. One of skill in the art will understand and appreciate that they two different names for the same reagent.

[0021] Although preferred embodiments of the disclosure are explained in detail, it is to be understood that other embodiments are contemplated. Accordingly, it is not intended that the disclosure is limited in its scope to the details of construction and arrangement of components set forth in the following description or illustrated in the drawings. The disclosure is capable of other embodiments and of being practiced or carried out in various ways. Also, in describing the preferred embodiments, specific terminology7will be resorted to for the sake of clarity.

[0022] It must also be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0023] Also, in describing the preferred embodiments, terminology will be resorted to for the sake of clarity. It is intended that each term contemplates its broadest meaning as understood by those skilled in the art and includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.Attorney Docket No.: F1-8149-WO

[0024] Ranges can be expressed herein as from “about” or “approximately” one particular value and / or to “about” or “approximately” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value.

[0025] By “comprising” or “comprising” or “including” is meant that at least the named compound, element, particle, or method step is present in the composition or article or method, but does not exclude the presence of other compounds, materials, particles, method steps, even if the other such compounds, material, particles, method steps have the same function as what is named.

[0026] It is also to be understood that the mention of one or more method steps does not preclude the presence of additional method steps or intervening method steps between those steps expressly identified. Similarly, it is also to be understood that the mention of one or more components in a device or system does not preclude the presence of additional components or intervening components between those components expressly identified.

[0027] The disclosure includes an industrial scale method for preparing P-aminoalcohols in water at minimal stoichiometric excess of reactants. The industrial scale method includes the preparation of a |3-aminoalcohol of Formula I,by reacting, in an aqueous solution, a secondary amine of the formula HNR3R4with an epoxide of Formula II,to obtain the |3-aminoalcohol. This chemical reaction is known to one of skill in the art as an addition reaction in that I is formed by the addition of epoxide molecule II to the amine molecule to make a new molecule I that comprises the entirety of NR3R4H and of II. Because 100% of the NR3R4H molecule is combined with epoxide molecule II to form I. a monoadduct, the chemical reaction is deemed as atom efficient - meaning no co-productsAttorney Docket No.: F1-8149-WO are formed such as occurs in substitution or condensation reactions. However, there are competing side reactions of such addition reactions of an epoxide to an aminoalcohol wherein the product P-aminoalcohol can add a second or third or more epoxide monomers to form higher adducts in the form of polyether oligomers. It is well understood in the art that a large molar excess (>30% to >40% molar excess) of amine NR3R4H over epoxide II can suppress formation of such polyether oligomers. However, such large excess of amine NR3R4H reduces the efficiency of the chemical process and can greatly add to the expense of a commercial process especially if the excess amine is not easily recovered and recycled. This added expense is especially true for the more expensive heterocyclic amines of the disclosure. Higher boiling amines may take longer to fully recover from the product stream by careful and potentially time-consuming fractional distillation. With respect to the LOXSH hydrogen mediated conjugated diene catalysts, such amines also are desirably below 500 ppm because residual amine levels above 500 ppm have been observed to contribute to the formation of emulsions during work up and recovery of liquid butadiene rubbers formed using a LOXSH catalyst. Accordingly, preferred industrial processes of this disclosure will utilize very closely matched stoichiometry of amines with epoxides, especially in cases where two-phase reaction mixture can form during the process.

[0028] The industrial method comprises a) forming a reaction solution comprising 10-40 wt% of the HNR?R4amine in an aqueous solution: b) feeding the epoxide of Formula II to the reaction solution to produce a reaction mixture; c) controlling the temperature of the reaction mixture during the feeding in step b) to a temperature range of about 20° C to about 80° C; and d) purifying the reaction mixture to obtain the P-aminoalcohol. Some embodiments of this industrial method entail processes wherein during feeding of the epoxide II to the reaction solution containing the amine NR3R4H, a separate organic product phase can form. Such embodiments generally result in increased yields because recovery of the product P-aminoalcohol is enhanced and the selectivity away from polyether oligomer formation is greatly enhanced. Without wishing to be bound by theory, a concept of this disclosure is that reactions of the epoxide are fast in the aqueous reaction mixture and relatively slow in the separated organic product phase especially when that phase has little water present to activate the epoxide towards the addition reaction. This helps to suppress formation of polyether oligomers during the reaction.Attorney Docket No.: F1-8149-WO

[0029] Table 1 provides a non-limiting matrix of twenty products that can be produced by the disclosure. It also loosely relates the literature LogP values (octanol / water coefficient also known as Kow) of the amines and epoxides to the calculated (ACD Lab which has a wide ± error) LogP values of the adduct P-aminoalcohols. [3- Aminoalcohols 1, 2, 5, 6, 7, 10, 11, 12, 15, 16, 17 and 20 have been prepared. Of these compositions 5, 10, 16, 17, and 20 formed separate phases. One of ordinary skill can use the calculated LogP value of about 1.37 as a guide as to whether a particular p-aminoalcohols will form a separate phase or not during the addition reaction. P-Aminoalcohol 7 remained as a single phase and P- aminoalcohol 10 formed a separate phase. Accordingly, and P-aminoalcohol 5 notwithstanding, it is anticipated that P-aminoalcohols having a calculated LogP value less than 1.37 are likely to remain as one phase and P-aminoalcohols having a calculated LogP value greater than 1.37 are likely to form a separate phase at some point during the progress of the addition reaction. Again, the calculated LogP values have a wide ± error so this loose correlation is meant only to be a guide to help the practitioner in advance to anti cipate / design the steps of an industrial scale process of this disclosure.

[0030] Throughout the disclosure, R1, R2. R3. R4, and R5are used consistently between each of the P-aminoalcohol product of Formula I, the secondary amine, and the epoxide of Formula II. R1and R2are each independently H or Ci to C4 alkyl, provided at least one of R1and R2is not H, or R1and R2together with the two connecting carbons for a Cs to Cs carbocyclic ring. R3and R4are each independently a Ci to C3 alkyl or R3and R4together with the nitrogen form a 5- or 6- member heterocyclic alkyl that optionally contains O or N-R5, where R5is a Ci to C3 alkyl. The descriptions of R1, R2, R3, R4, and R5are not meant to be limiting. Higher values than C4 such as Ce or Cs even C10 are anticipated by the disclosure. The limitation of the epoxide is in the reagent’s solubility in the aqueous reaction zone. Accordingly, 1 ,2-epoxyoctane is known to be slightly soluble in water. 1,2- epoxy decane is known to be insoluble in water and 1,2-epoxy dodecane is known to be soluble to less than Img / ml. It is a concept of this disclosure that the high 10 wt.% to 40 wt.% even 60 wt.% aqueous organic amine concentrations increase the solubility of otherwise insoluble epoxides in the aqueous reaction mixture. It is further to be understood and appreciated that as the product P-aminoalcohol builds in the aqueous phase this too can help solubilize otherwise insoluble epoxides in the aqueous reaction mixture. It is pointedAttorney Docket No.: F1-8149-WO out that cyclohexene oxide is only slightly soluble in water. The use of such epoxides of low water solubility may require longer reaction times once a separate organic phase is formed during the addition reaction.

[0031] Some various preferred embodiments can include that:

[0032] In the disclosure, R2can be H.

[0033] In the disclosure, the R1can be a Ci to C3 alkyl, and R2can be H. In some embodiments. R1can be methyl or ethyl and R2can be H.

[0034] In the disclosure, R3and R4together along with the nitrogen form a 5- or 6- member heterocyclic alkylamine. In the disclosure, R3and R4together with the nitrogen can be a heterocyclic alkylamine that is piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl or tetrahydroisoquinolinyl. The limitation of an amine whether acyclic or heterocyclic is the limitation of its solubility in the aqueous reaction mixture of at least about 10 wt.% relative to w ater.

[0035] In the disclosure, R1can be methyl or ethyl, R2can be H, and R3and R4together along with the nitrogen can form a 5- or 6- member heterocyclic alkylamine that is piperidinyl, pyrrolidinyl, morpholinyl, or 1 -methyl -piperazinyl.

[0036] In the disclosure, R3and R4can both be a Cl alkyl.

[0037] In the disclosure, R1can be methyl or ethyl, R2can be H, and R3and R4can both be a Cl alkyl.

[0038] Thus, the disclosure can be used to form -aminoalcohols with the structure of a 1- amino-2-alkanol by reacting an epoxide with dimethylamine, piperidine, morpholine, pyrrolidine and 1 -methylpiperazine. Likewise, the disclosure can be used to form the - aminoalcohols having the tra -2-amino-cyclohexanol structure from cyclohexene oxide with dimethylamine, piperidine, morpholine, pyrrolidine and 1 -methylpiperazine. For the disclosure, the method can provide -aminoalcohols having the chemoselective ratio of 1 - amino-2-alkanol: 2-amino-l -alkanol of greater than 90: 10, greater than 95:5, and greater than 97:3.

[0039] One of skill in the art would understand that the term “industrial chemical process” or “industrial scale” used herein reflects vastly larger masses and concentrations of reagents compared to a simple “discovery” or “screening” type chemical reactions conducted on the order from about 0.1 grams to say less than 10 grams of total reagents. One of skill willAttorney Docket No.: F1-8149-WO also understand that between “discovery7’" type reactions and “industrial scale” processes are laboratory preparations typically from tens of grams to tens of kilograms. At this scale, the preparation reaction and processes may take on many of the characteristics of an industrial process. An industrial chemical process for fine and specialty chemicals can entail processes comprising from about 10 kilograms to 100s even 1000s of kilograms of a reagent. There are many considerations that the practitioner and developer of industrial scale chemical processes must consider when developing, implementing, and conducting an industrial chemical process. Processes that entail highly reactive, polymerizable, and potentially toxic reagents such as epoxides require special consideration of how such reagents are physically handled and how they are charged and reacted or converted to form a product. Accordingly, one should understand and appreciate that the chemical transformation of the epoxide to form a new monomeric product - that chemical reaction - should be kinetically fast. Such a fast reaction is needed to prevent the buildup of the epoxide in the reaction mixture and thereby having the potential to create an uncontrollable runaway chemical reaction within the industrial scale process.

[0040] Industrial scale commercially attractive chemical processes will inherently feature or possess many if not all the following aspects:1. Highly atom efficient such that by-products are kept at a minimum.2. Provides for direct recycling without undue purification steps of excess reagents, unrecovered products and solvents.3. Energy input such as external heating and refrigeration can be kept at a minimum.4. Exothermic reactions that generate a significant amount of their own heat can be monitored for progress and completion thermally.5. Kinetically fast reactions that approach diffusion-controlled limit allowing controlled feed and co-feed rates of the reactants and thereby allow for the industrial process to be run up to the heat transfer limitation of the industrial equipment.6. Highly selective reactions with minimum side reactions such that a large excess of one reactant over the other can be avoided.7. Entails the use of a minimum of extraneous reagents such as catalyst with low turnover numbers, added salts to alter product solubility during recovery and drying agents.Attorney Docket No.: F1-8149-WO8. Litle if any solids handling such as filtration of drying agents or crystallization prior to recovery' by filtration of solid products.9. Can be run at high concentrations and at fast rates such that the size of the industrial equipment can be relatively small while still be highly productive in terms of Kg / unit volume and Kg / unit volume / hour.The processes as presented in the Examples demonstrate that most if not all of the 9 characteristics listed above are met.

[0041] Laboratory scale discovery reactions generally feature small masses, are designed for easy handling / screening, and ty pically run at low concentrations in excess volumes of solvent to control kinetics or reactivities of the combined reagents. For reactions that are highly exothermic or temperature sensitive, or concentration dependent (including runaway polymerizations), the low concentration values and small scale often hide the complexity of scaling a reaction. For example, it’s well known that the surface area of a spherical reactor scales as the square of the radius (r2) while the volume of the same sphere scales as a cube of the radius (r?), which is highly relevant for many reaction issues, e.g. dissipation of heat from an exothermic reaction, so scaling a reaction can lead to problems controlling reaction temperatures and dissipating heat. Very fast and exothermic chemical reactions might be at the preparative and certainly at the industrial scale, desirably run at “heat transfer limited” rates. That is to say that heat removal from the system limits the rate at which the components / reagents that comprise the chemical reaction(s) of the process can be combined and converted to product. Accordingly, one can understand that combining such reagents at rates faster than the heat produced by the reaction can lead to one or more of: a) loss of selectivity' at higher temperatures; b) deleterious side reactions potentially leading to autocatalytic reactions; c) over pressurization by flooding of a condenser due to too much reflux of a solvent; and d) runaway reactions that cannot be contained within the industrial or preparative scale process equipment.

[0042] Direct scale up of discovery' and screening chemical reactions that feature dilute or low concentration of reagents in small-scale even micro-scale lab equipment leads to extremely large volumes of solvents, reactors and equipment that are impractical from a capital expense and operations standpoint. Likewise, such discovery and screening chemical reactions can feature the use of: a) large volumes of solvents 10s to 100s of times moreAttorney Docket No.: F1-8149-WO solvent than product for product extraction; b) large amounts of dry ing reagents; c) require fdtration (solids handling); and d) use of solvents for preparative chromatography and all the consequent hazardous waste. But what really differentiates a discovery / screening chemical reaction from an industrial chemical process is how the reagents are combined. Characteristic of such discovery / screening chemical reactions is that all the reagents are combined at once and left to stand or stir for long reaction times - hours to days. The reactor can be only a test tube or a small screw cap vial. Such discovery / screening chemical reactions are nothing more than a starting point from which safe, efficient and cost-effective industrial scale chemical processes are invented and improvised.

[0043] There are open literature reports that provide therein small-scale discovery / screening chemical reactions that entail the aminolysis of epoxides with secondary and primary amines to yield p-aminoalcohols. In this connection see: 1) Bonollo, S., Lanark D. and Vaccaro, L., “Ring-Opening of Epoxides in Water” European Journal of Organic Chemistry, 2011 14, 2587-2598 (Bonollo-2011); 2) N. Azizi. M. R. Saidi. Org. Lett. 2005. 7, 3649-3651 (Azizi-2005); and 3) S. Bonollo, F. Fringuelli, F. Pizzo, L. Vaccaro. Green Chem .2006, 8, 960-964 (Bonollo-2006). The two excerpts below should make clear what is meant by a simple discovery / screening chemical reaction and not an industrial scale chemical process or even a preparative scale chemical process.From Azizi-2005: "General Procedure for the Synthesis of -Amino Alcohols. An epoxide (5 mmol) and water (2 mL) were placed in a test tube equipped with a magnetic stirrer. Then, an amine (6 mmol) was added in one portion, and the test tube was kept at room temperature under vigorous magnetic stirring for 5 24 h. The reaction was monitored with TLC. Then, water (2 mL) was added, and the organic materials were extracted with diethyl ether (2 x 10 mL). The organic layer was separated and dried over anhydrous NazSCh. The solvent was removed under reduced pressure to give the f -amino alcohols in the almost pure form. The crude product was analyzed by GC and ‘H andI3C NMR. In some cases, further purification was carried out by short-column chromatography on silica gel (ethyl acetate / petroleum ether). "Attorney Docket No.: F1-8149-WOFrom Bonollo-2006: “Aminolysis of 1 ,2-hexadecene oxide (1c) by aniline (2a): in a screw capped vial equipped with a magnetic stirrer, aniline (2a) (0.190 g, 2.04 mmol) and 1 ,2-hexadecene oxide (1c) (0.481 g, 2.0 mmol) were consecutively added in water (4 mL) and the resulting mixture was left under vigorous stirring at 60 °C for 170 h. The mixture was basified with NaOH 5 M until pH 10 and extracted with AcOEt (2X 4 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was evaporated, and the crude product was charged on a triethylamine pretreated silica gel column chromatography (diethyl ether / petroleum ether 3 / 7; silica / sample: 60 : 1). Pure l-(phenylamino)hexadecan-2-ol (3c) was isolated as a while solid (70% overall yield 3c + 4c, 0.466 g). "

[0044] In the disclosure epoxides of Formula II are fed as a function of time to a reaction mixture comprising at least one amine of formulaNR3R4H in a reaction medium comprising water. The feed rate of the epoxide and the reaction temperature are such that the epoxide and amine undergo an addition reaction to selectively form p-aminoalcohols. In general, the introduction of the epoxide to the reaction medium is done at a rate that on an industrial scale would be considered approaching “heat capacity limited” - the rate at which heat can be removed from an industrial size reactor and thereby allow for a constant or near constant reaction temperature. At such rates under the most ideal process conditions the epoxide is consumed at the rate at which it is charged and thereby providing a low steady state epoxide concentration. This low steady state concentration provides an inherently safer industrial scale process and higher selectivity for the desired addition reaction. Based on the Examples of this disclosure, it is deemed that so long as the industrial equipment is designed for efficient heat removal, the chemical reaction step of the process can be conducted over a period as short as 2 to 7 hours - and optionally longer if so desired. As will be seen, the development of such commercially viable chemical processes of the disclosure have only arisen through careful and extensive experimentation around all aspects of the chemical processes of the disclosure designed to be conducted on an industrial scale by industrial means.

[0045] In the disclosure, the epoxide of Formula II and the R1and R2groups associated with it can be a 1,2-epoxide derived ty pically from a terminal, primary7alkene; an internalAttorney Docket No.: F1-8149-WO epoxide derived from an internal, secondary' alkene; or a cyclic epoxide derived from an cycloalkene. Such non-limiting examples could include the epoxides derived from propylene, 1 -butene or 2-butene, 1 -pentene or 2-pentene. different isomers of hexene, cyclopentene, cyclohexene, and so forth. Tn a preferred disclosure, the epoxide of Formula II can be a 1,2-epoxide or an epoxide of a cycloalkene. In a preferred disclosure, the epoxide can contain less than 12 total carbons, or less than 10 total carbons. In a preferred disclosure, the epoxide has a solubility in water of at least 1 wt.%.

[0046] The epoxides of the disclosure can contain one or two chiral carbon centers as part of the oxirane ring. In general, the epoxide can be a racemic mixture of enantiomers or diastereomers at the one or two centers. However, a chiral epoxide or epoxide enriched in one enantiomer can also be used in this system.

[0047] In the disclosure, the reaction solution comprising the secondary amine can be about 10 to about 40 wt% of the HNR3R4in an aqueous solution. The secondary amine can be about 10 to about 40 wt%, about 15 to about 40 wt%, or about 20 to about 40 wt% of the aqueous solution. Accordingly in the disclosure the solubility of the amine should be at least 10 wt.% at the desired reaction temperature. Therefore 1,2,3,4-tetrahydroquinoline having a water solubility of < Ig / L would not likely be useful in the disclosure. However, 1,2,3,4-tetrahydroisoquinoline having a water solubility of 4.8g / L may be useful in the disclosure especially if a portion of a solvent like THF is used in forming the reaction mixture. One of skill in the art would recognize that aqueous solution means a solution comprising water. The aqueous solution may also contain other solvents, especially if the solution is part of the recycle stream described further below, but generally should not contain solvents with reactive groups that would compete with the secondary' amine for reaction with the epoxide. The reaction solution can be quite concentrated compared to traditional examples - the starting reaction solution can have a molar concentration of 2M to 10M, or 2M to 5M. However, the weight ratio used herein is more effective than molarity because it is associated with reaction mass, industrial processes, and reaction calorimetry for the current reaction.

[0048] In the disclosure, the ratio of secondary amine to epoxide can be from 1. 1 : 1 to 1 : 1. 1. The ratio of secondary' amine to epoxide can be from 1.07: 1 to 1 : 1.07, from 1.05: 1 to 1 : 1.05, from 1.04: 1 to 1: 1.04, or from 1.03: 1 to 1: 1.03. Controlling the ratio of reagents at thisAttorney Docket No.: F1-8149-WO narrow range enables control of the rate of reaction, concentration of final product in the reaction mixture, and limiting the amount of waste associated with the industrial process. Also surprisingly, the narrow stoichiometry runs counter to the traditional strategy of using excess amine to prevent oligomer formation. Oligomer formation should be predicted at lower stoichiometry' due to competition between the product aminoalcohol and the reaction diamine for incoming epoxide at the end of reaction.

[0049] In the disclosure the reaction mixture can comprise modest levels (amounts greater than zero to as much as 25 wt.%) of water soluble non-nucleophilic solvents (e.g. THF). Such solvents help solubilize epoxides of low water solubility into the aqueous reaction medium. Water is deemed to catalyze the addition reaction of the epoxide to the amine, however other catalysts can be added such as a strong organic acid (e.g. p-toluenesulfonic acid PTSA and / or methanesulfonic acid) or inorganic compounds such as zinc iodide or sodium iodide or magnesium sulfate. Likewise, the practitioner can add nonnucleophilic tertiary amine bases or inorganic bases to the reaction mixtures of the disclosure. It has not escaped our attention that a practitioner wished to extend the disclosure to include aromatic amines such as / V-mono-subslituted anilines and the like, the practitioner could add such bases. However, the addition of other such catalysts should not substantially create a negative effect on the regioselectivity' (2,1- vs. desired 1 ,2-substitution) and / or relative stereochemistry (cis vs. desired trans relationship of the amine to the hydroxyl).

[0050] In the disclosure, the reaction mixture can have a steady or a variable temperature, and temperature can be controlled during the feeding in step b) to a temperature range of about 20° C to about 80° C; to a temperature range of about 25° C to about 80° C; to a temperature range of about 30° C to about 80° C; to a temperature range of about 30° C to about 70° C; or to a temperature range of about 30° C to about 60° C. The temperature can be held in a relatively steady and lower range during the initial part of the epoxide feed and then be increased to another steady range as the concentration of the starting amine is reduced as it is consumed by the addition reaction. Though we wish not to be bound by theory, it is believed that the amine at higher concentrations helps to solubilize into the aqueous reaction mixture epoxides of lower solubility like cyclohexane oxide. It is deemed that the aqueous reaction medium is the reaction zone. For preferred embodiments whereinAttorney Docket No.: F1-8149-WO a second organic phase forms, it may be beneficial to maintain the desired rate of reaction by increasing the reaction temperature.

[0051] In the disclosure, the method can include purifying the reaction mixture to obtain the P-aminoalcohol. The P-aminoalcohol can be obtained by any method known in the art. The purifying step can include forming an organic layer comprising the P-aminoalcohol and an aqueous layer from the reaction mixture. The two layers can be obtained by including a step of cooling the reaction mixture to allow the organic layer and the aqueous layer to separate. The organic layer can be the neat P-aminoalcohol. The two layers can be obtained by forming an organic layer and an aqueous layer by including a step of cooling the reaction mixture and adding an organic solvent to generate the organic layer. The two layers can be obtained by including a step of cooling the reaction mixture and optionally adding a salt to decrease the aqueous solubility of the P-aminoalcohol to separate the two layers. When an organic solvent is used to separate the two layers, the organic solvent can be any organic solvent that separates the two layers, preferably provided that it does not have a group that reacts with epoxide, either as a residual or as part of a recycled stream. The organic solvent can be an ether, alkyl ester, dialkyl carbonate, alkane, or cycloalkane, and combinations thereof. When a salt is added to form the tw o layers, the salt can be one or more of non- oxidative aqueous soluble salts of sodium, potassium, magnesium, or calcium, including those salts with counterions selected from sulphates, carbonates, chlorides, and acetates. Bromides and iodides might also be suitable but are less economical and may displace the hydroxyl group on the aminoalcohol, thus reducing yield.

[0052] In the disclosure, the method can include recycling the aqueous layer, which is separated from the organic layer, to be used to create another batch of aqueous reaction solution. To the recycled aqueous layer can be added additional secondary' amine for the next reaction and any additional water to make up the correct volume. In some cases, the aqueous layer may contain residual amine from the previous reaction in an embodiment wherein the amine w as in excess or may contain residual diol or polyol if the epoxide was used in excess. By controlling the reaction stoichiometry of epoxide and amine at nearly 1: 1, the recycled aqueous solution can be reused, thus eliminating waste from the process. In some embodiments it is desirable after several recycle-runs (runs wherein the aqueous phase and any recovered extraneous water are directly recycled and used to form aAttorney Docket No.: F1-8149-WO subsequent reaction mixture) to distill the aqueous phase. Such an operation allows for recover}' via steam distillation of residual [3-aminoalcohol that did not phase separate from the aqueous phase. In such an embodiment 75% to 95% of the recovered aqueous phase is distilled. This distilled water can then be recycled into subsequent batches immediately or sometime later in another production campaign. The steam distilled P-aminoalcohol product is then combined with another product stream for later recover}'. Preferred embodiments of this disclosure entail combining the recovered steam distilled p- aminoalcohol with the P-aminoalcohol aliphatic and / or cycloaliphatic solvent solutions obtained from the process. Such preferred embodiments allow for the removal of water from the steam distilled P-aminoalcohol at the same time as the bulk of the P-aminoalcohol in the solvent solution via azeotropic removal of all or a portion of the water in the solution.

[0053] In view of this disclosure, the method can thus feature the following:1. Forming a reaction medium comprising a 10 to 40 wt.% solution of a secondary amine (e.g. dimethylamine, piperidine, pyrrolidine, morpholine or 1 -methyl-piperazine) in water.2. Feeding an epoxide (e.g. propylene oxide, cyclohexene oxide. 1,2-epoxybutane) at temperature between 20°C and 80°C depending on the boiling point of the epoxide and the reactivity of the amine toward the epoxide, where the ratio of secondary amine to epoxide is set at near 1 : 1 with an molar excess of no more than 10%, or 7%, or 5%, or preferably no more than a 2-4% molar excess of one reagent over the other depending on the tendency of a particular product to form poly ether oligomers.3. Monitoring the exothermic reaction progress thermally.4. Adding an organic solvent (e.g. diethyl ether, ethyl acetate, heptanes, methylcyclohexane, etc.) to recover the product. As will be demonstrated in the examples below, diethyl ether with / without ethyl acetate is a preferred solvent or solvent combination to extract the aminoalcohol product when the final reaction mixture is homogenous or substantially homogenous. An aliphatic and / or cycloaliphatic solvent(s) is preferred when the aminoalcohol forms a second phase separate from the aqueous phase.5. Drying ethereal solutions of the product over potassium carbonate and then separating the aminoal cohol / ether solution from the resulting dissolved aqueous potassium carbonate. Other desiccating agents (e.g. magnesium sulfate, sodium sulfate, calcium oxide,Attorney Docket No.: F1-8149-WO etc.) can be used but these generally do not dissolve and require decantation or solids filtration. Potassium carbonate generally dissolves in the water it absorbs forming about a 50 wt.% aqueous solution.6. Alternatively drying the hydrocarbon solutions of the -aminoalcohol by azeotropic removal of all or a portion of the water in the solution.7. Fractional distillation of the product to remove solvent and any hydrated water (i.e. that is the tertiary-p-aminoalcohol as its ammonium hydroxide). Then recovering the product including the minor regioisomer by vacuum distillation.8. In an ideal circumstance, once the product is made anhydrous during the hydrocarbon strip (pot temperature > 140-160°C) the product, still containing a portion of the hydrocarbon solvent, can be used as is in preparing the LOXSH catalyst.9. The aqueous reaction media after one or more runs once separated from the organic product phase can be directly recycled or alternatively distilled to steam distill product that had not separated with the organic product for further recovery' and to purge as still bottoms any co-products (e.g. higher amino alcohol ether adducts, or diols from the epoxide) from the system prior to recycle of the water.EXAMPLES

[0054] The examples presented below entail I) intermediate scale preparative processes; II) larger scale batch process and III) large scale sequential recycle runs meant to model industrial scale production process operations for forming the P-aminoalcohol products of this disclosure. It is to be noted that the reaction of the secondary amines with the epoxides is quite rapid at modest temperatures and as such, both semi-batch as well as continuous processes can be considered as modes of operation for the processes of this report. For Example, see Matthew W. Bedore, Nikolay Zaborenko, Klavs F. Jensen, and Timothy F. Jamison “Aminolysis of Epoxides in a Microreactor System: A Continuous Flow Approach to P-Amino Alcohols’’ Organic Process Research & Development 2010 14 (2), 432-440.

[0055] The reaction conditions and results Examples 1-10 along with the comparative example (Comp.) are presented in Table 2. These intermediate scale preparative examples are just sufficiently concentrated and large enough scale to monitor thermally by observing and comparing the reactor j acket temperature and the reaction temperature. However, theAttorney Docket No.: F1-8149-WO examples were also monitored for conversion by gas chromatography. Examples 11-15 are larger scale batch operations wherein the batch processes could be easily monitored thermally. These Examples are intended to demonstrate what an industrial scale process can look like from start to finish. Examples 16-23 are meant to model industrial scale processes that includes a) running at rates that are deemed on a larger scale to be heat transfer limited; b) direct recycle of the aqueous phase from run to run; c) direct recycle of unrecovered product and starting reagents recovered from distillation from run to run; d) recycle of solvents used in extraction of the aqueous phase; and e) recovery of the product with minimum use of drying agents if any. Examples 24-46, Tables 5-7, represent industrial processes wherein the aqueous phase is recycled directly or distilled after 3 to 8 runs to enhance product recovery and hence yield as was as to purge any heavier water-soluble coproducts for proper waste disposal.Examples 1-10 Intermediate Scale Preparative Processes.

[0056] The experimental details for the Comparative Example and Examples 1-10 are provided in Table 2 below. Details of three representative examples (Comp, and Ex. 3 and 6) are provided below. The reactor set up used herein for these Examples was a 2000 ml oil-jacketed (half jacket) creased reactor with a bottom drain valve and outfitted with overhead mechanical stirring. The reactor was further outfitted with a 250 ml addition funnel, thermowell with a thermal couple and a distillation head. The distillation head was configured such that all or a portion of the refluxing solvent could be returned to the reactor. The reactor was gently heated with a recirculating oil bath (heat only no refrigeration). Product recovery entailed small glassware with either a fractionation column or a short path vacuum distillation.

[0057] Comparative Example - Attempted Water Free Preparation of 2-(2-piperidino)- cyclohexanol. The 2000 ml reactor was charged with one liter of tetrahydrofuran (THF), 200 mg of zinc iodide, 100 ml of p-toluenesulfonic acid (PTSA) and 85.15 g (0.540 mole) piperidine and was heated to reflux. The addition funnel was charged with 47.5 g (0.484 mole) of cyclohexene oxide which was then added dropwise to the reaction medium. There was no evidence (no increase in reflux) of significant reaction taking place. The reaction mixture was then concentrated by distilling off about 75% of the THF. The reaction temperature was allowed to drop to 68°C and then cooled further to 50°C. The addition ofAttorney Docket No.: F1-8149-WO200 ml of water to the reaction mixture appeared to be exothermic. The reaction mixture was allowed to stir for several hours and then left to stand overnight. The reaction mixture was then combined with 300 ml of methylene chloride, stirred and the phases separated. The organic phase was dried with alumina, stripped of solvent and the residue distilled via short path distillation (BP 104°C 1-2 mmHg) to yield 63.5 g of 2-(2-piperidino)-cyclohexanol which fused as a solid mass upon standing.

[0058] Example 3 - Intermediate Scale Preparation of 2-(4-methylpiperazino)- cyclohexanol.

[0059] The 2000 ml reactor was charged with 500 ml of H2O, 54.68 g (0.546 mole) and 1- methylpiperazine. The introduction of the amine caused the reaction temperature to increase from 19°C to 27°C. The addition funnel was charged with 51.32 g (0.523 mole) of cyclohexene oxide which was then added in two portions causing the temperature to drop to 23°C. Anhydrous MgSC (2.0 g) was introduced and 28.0 °C oil was applied to the reactor allowing the reaction temperature to line out at 26.1 °C. The addition of 25 ml of THF caused the reaction temperature to rise to 26.9°C. The addition of 75 ml more THF caused the reaction temperature to reach 27.8°C. The reaction mixture was gently heated for a total of 280 minutes and then heated to reflux (80°C oil on jacket) for 120 minutes more and then left to cool to room temperature overnight. The THF was distilled off until the reaction mixture reached 87°C. The organic phase was diluted with methylene chloride and then concentrated in vacuo to yield 95 g of white crystalline solid. The solid was redissolved in THF and then distilled (short path) to yield 89.43 g (BP 110-111 °C. @ 0.2-0.3 mmHg vacuum) of clear colorless oil which on standing became a solid mass - 86% isolated yield.Example 6 - Intermediate Scale Preparation of l-(4-Morpholinyl)-2-propanol.

[0060] The 2000 ml reactor was charged with 250 ml of H2O, 74.01 g (0.8495 mole) and morpholine. The introduction of the amine caused the reaction temperature to increase from 19°C to 28°C. The addition funnel was charged with 47.02 g (0.8096 mole) of propylene oxide which was added dropsies over a period of 75 minutes. During the feed, the reactor was heated with 29°C oil on the jacket. The reaction temperature ranged from 31.0°C to a peak of 34.3°C at the end of the feed. After 20 additional minutes of mixing, the reaction temperature dropped to 32.8°C with the jacket temperature of 31.5°C. After a total of 3 hours after the start of the feed had elapsed, the reaction temperature was down to 28°C atAttorney Docket No.: F1-8149-WO which time 250 ml of diethyl ether was added along with 60 g of sodium chloride. After a period of 15 minutes of mixing the phases were separated. The aqueous phase was further extracted with 125 ml of diethyl ether and then with 130 ml of methylene chloride. The combined organic extracts were dried over potassium carbonate overnight in a freezer. The dried organic product mixture was filtered, washing the solids with 50 ml of methylene chloride. Solvent was removed by simple distillation. The residue was distilled at 46°C and 0. 1 mmHg vacuum to yield 97 g (83%) of a clear colorless liquid.Examples 11-15 Larger Scale Preparative Processes w / wo the Potential of Recycle of the Aqueous Phase.

[0061] The reactor typically used herein was a 5000 ml glycol-jacketed (heating and refrigeration) cylindrical lab reactor, and was outfitted with a baffle, thermometer, Friedrichs condenser and an 1 / 8” O.D. Teflon® feed line. The epoxide is fed to the reactor with time via peristaltic pump through the 1 / 8” O.D. PTFE tubing from either a 250 ml or a 500 ml graduated cylinder. To avoid exposure to either the secondary amine or the epoxide, all charges are made volumetrically from previously weighed reagent bottles - consequently there tends to be a little scatter in the amine / epoxide ratio from run to run. The mass of the reactants transferred to the reactor system was then determined by the weight difference of the respective reagent bottles.

[0062] For fractional distillation, a 1000 ml, or a 2000 ml or a 3000 ml distillation kettle was outfitted with a magnetic stirring bar, built-in subsurface thermal well and a fractionating distillation head. The reactor was heated with a two-piece zippered heating mantle. Generally, the top mantle was not heated and was only used as insulation. The receiver was a custom made narrow 2.0-liter graduated tank with a bottom drain valve. To assure homogeneity of the entire fraction, the product was first transferred to a 2.0-liter bottle, mixed and then divided in two equal mass portions to be bottled ( 1.0-liter oven-dried amber glass bottles) and capped.

[0063] Azeotropic drying was conducted using a six-liter hot-oil-jacketed creased round bottom flask with bottom drain valve. The flask was equipped with a thermometer, a large capacity Dean-Stark trap, and condenser.

[0064] Example 11 - Batch preparation of 2-(Dimethylamino)cyclohexanol. This example models refreshing dimethylamine concentration during the course of the reaction.Attorney Docket No.: F1-8149-WOAqueous dimethylamine (DMA) has the following approximate boiling points vs. wt.% DMA: 60 wt.%, ~ 38°C, 40 wt.%, ~ 52°C, 30 wt.%, ~ 59°C. 20 wt.%, 70°C, 10 wt.%, ~ 82°C. Example 11 starts with 23 wt.% aqueous DMA. but in effect runs as if it started with >27 wt.% (BP ~ 57°C) this is done as a matter of convenience when working at atmospheric pressure at temperatures near 55°C.

[0065] Cyclohexene oxide, 235.33 g (242.6 ml, 2.40 mole, Aldrich) was charged to a 500 ml graduated cylinder feed reservoir. To the reactor was charged 232 g fresh tap water, and 313.6 g of 40 wt.% dimethylamine (DMA) in water (2.78 mole, 352 ml, Aldrich) to form a 23 wt.% DMA solution. The aqueous reaction mixture was warmed to 41.2°C with 45.0°C glycol on the jacket. A 178 ml portion of the cyclohexene oxide was fed over 80 min (2.23 ml / minute). The first 35 ml (16 minutes) caused the reaction temperature to reach 44.0°C with the 45.0°C jacket temperature. The jacket temperature was set to 50.0°C causing the reaction temperature to reach 50.9°C. After 80 minutes the cyclohexene oxide was interrupted and 334.36 g of 40 wt.% dimethylamine (DMA) in water (2.97 mole, 376 ml) was charged to the reactor. This restored the DMA concentration to 20-23 wt.% (relative to water and excluding product). Additional cyclohexene oxide, 255.92 g (263.8 ml. 2.40 mole) was charged to the 5000 ml graduated cylinder feed reservoir bring the volume to 325 ml.The reactor’s jacket temperature was increased to 55.0°C and the cyclohexene oxide feed was resumed once the reaction temperature reached 52.1 °C (115 minutes since the initial start of the cyclohexene feed). The cyclohexene oxide was fed at rate of 3.82 ml / min. After 30 minutes (145 minutes since the start) of the resumption of the feed the reaction temperature reached 56.2°C and a second phase separated from the aqueous reaction mixture. The jacket temperature was then set to 57.5°C with the reaction temperature lining out at 57.9°C. The feed was complete 210 minutes since the initial start of the cyclohexene oxide feed. After 30 minutes of stirring with a 57.5°C jacket temperature, the reaction temperature dropped to 57°C. The temperature setting of the glycol-jacket w as gradually increased to 75°C over a period of 36 minutes, during which time the reaction temperature reached 69.7°C.The two-phase reaction mixture was cooled to room temperature and was charged with 210 g of sodium chloride and 333 g of heptanes. The phases were separated, producingAttorney Docket No.: F1-8149-WO894 g of an aqueous phase and 998 g of an organic phase. The reactor was rinsed with 169 g of heptane which was combined with the organic phase.The organic phase was then fractionally distilled at atmospheric temperature to a pot temperature of 150°C. This operation produced 531 g of recovered solvent and 7.5 g of water. The contents of the distillation pot were allowed to cool to room temperature. The contents were then distilled under 20 mmHg vacuum. Initially 47.8 g of liquid was collected to an overhead temperature of 82°C. The main product phase 530 g (74% yield) was collected at 92.5-93.5 °C (20 mmHg) leaving behind 5.5 g of undistilled heavy ends (oligomers).

[0066] Example 12 - Batch preparation of 2-(l-Piperidinyl)cyclohexanol. Cyclohexene oxide, 484.9 g (500.0 ml, 4.94 mole, Aldrich) was charged to a 500 ml graduated cylinder feed reservoir. To the reactor was charged 1487 g fresh tap water, and 441. 14 g of piperidine (5.18 mole, 511.8 ml, Aldrich) to form a 23 wt.% piperidine in water solution. The aqueous reaction mixture was warmed to 52.5°C with 55.0°C glycol on the jacket. A 100 ml portion of the cyclohexene oxide was fed over 26 min (2.84 ml / minute) causing the reaction temperature to rise to 55.7°C - at this time a second phase separated from the aqueous reaction mixture. The cyclohexene feed was continued uninterrupted. After 50 minutes of feeding the reaction temperature reached 56.9°C with 55.0°C on the jacket. Between 70 minutes and 80 minutes of feeding the jacket temperature was gradually increased to 60°C. The feed was complete in 135 minutes at which point the reaction temperature reached 60.1 °C. After 15 minutes of mixing the reaction temperature decreased slightly to 59.8°C. accordingly the jacket temperature was increased to 75°C. The reaction mixture was allowed to stir for an additional 65 minutes (total reaction time was 220 minutes). The ending temperature was 73.1 °C.The two-phase reaction mixture was cooled to room temperature and was charged with 800 g of heptanes. The phases were separated, producing 1544 g of an aqueous phase and 1625 g of an organic phase. The reactor was rinsed with 169 g of heptane which was combined with the organic phase. The aqueous phase was extracted with 257 g of heptane. The combined organic phase was then fractionally distilled at atmospheric temperature to a pot temperature of 165°C. The contents of the distillation pot were allowed to cool to room temperature. The contents were then distilled under 7 mmHg vacuum to an overheadAttorney Docket No.: F1-8149-WO temperature of 125°C which provided 12.5 g of liquid. The main product phase 774 g (85.4% yield) was collected at 90 °C (1 mmHg) leaving behind 2.4 g of undistilled heavy ends (oligomers).

[0067] Example 13 - Batch preparation of l-(DimethyIamino)-2-butanol. 1,2- Epoxybutane, 272.8 g (329.1 ml, 3.78 mole, Aldrich) was charged to a 500 ml graduated cylinder feed reservoir. To the reactor was charged 400 g fresh tap water, and 1135.0 g of 40 wt.% dimethylamine (DMA) in water (10.07 mole, 1275.3 ml, Aldrich) to form a 30 wt.% DMA in water solution. The aqueous reaction mixture was warmed to 29.1 °C with 33.0°C glycol on the jacket. The 329.1 ml portion of the 1 ,2-epoxybutane was fed over 96 min (3.42 ml / minute). The first 80 ml (21 minutes) caused the reaction temperature to reach 37.8°C with the 33.0°C jacket temperature. The jacket temperature was reduced setting it at 28°C and the refrigeration on the recirculating bath was engaged to remove the excess heat. Accordingly, the reaction temperature equilibrated to 36.0°C. After 96 minutes the feed of 329.1 ml of 1,2-epoxybutane was completed. Additional 1,2-epoxybutane, 426.8 g (514.8 ml, 6.29 mole) was charged to the 5000 ml graduated cylinder feed reservoir, during this time (20 minutes) the reaction temperature dropped to 33.6°C. The additional 1,2- epoxybutane feed was completed in 155 minutes during which time the reaction temperature was maintained between 36.5 and 38.9 °C by adjusting the jacket temperature from 28 to 33 °C. After 10 minutes the reaction temperature had dropped to 35.2°C. Accordingly, the jacket temperature was set to 60°C and then 70°C. The final reaction temperature after 65 minutes was 64.9° C.The reaction mixture was cooled to 35°C to which was added 303 g of sodium chloride, 60 g of heptanes and 285 g of tetrahydrofuran (THF). The resulting two-phase mixture was stirred until most of the sodium chloride had dissolved. The phases were separated yielding 1338.3 g of an aqueous phase and 1427.6 g of an organic phase. The reactor was rinsed with 142.4 g of heptanes. The organic phase was combined with the heptane rinse and left to stand over 27 g of potassium carbonate. Overnight a substantial amount of the potassium carbonate had dissolved - 85 g of the aqueous slurry was removed leaving behind 1500 g of the organic phase. The organic phase was fractionally distilled to pot temperature of 140°C (overhead temperature of 105°C) to yield 843 g of distillate. The distillate formed two phases: 1) a lower phase having a mass of 444 g; and 2) an upper phaseAttorney Docket No.: F1-8149-WO having a mass of 399g. The lower phase was dried over 100 g of potassium carbonate to yield 285 g of an organic phase. The aqueous potassium carbonate was combined with the aqueous phase from the reaction mixture.The distillates were recombined with the material in the distillation pot and again distilled fractionally at atmospheric pressure. The solvent mixture was removed via distillation, distilling at an overhead temperature from 66 to 86 °C and a final pot temperature of 140°C. A total of 800 g of solvent was collected in the receiver. The product was then recovered by fractional distillation to yield 1000 ml of the product BP 95-97°C @ 160 mmHg vacuum, the vacuum was dropped to 60 mmHg and an additional amount of product was recovered. The total yield was 834 g (73.3%). The vacuum was then dropped to 0. 1 mmHg and 12.5 g of oligomeric material was taken overhead.

[0068] Example 14 - Batch preparation of l-Pyrrolidino-2-butanol. 1 ,2-Epoxybutane, 86.04 g (103.7 ml, 1.19 mole, Aldrich) was charged to a 250 ml graduated cylinder feed reservoir. To the reactor was charged 350 g fresh tap water, and 84.00 g of pyrrolidine (1.20 mole, 98.6 ml, Aldrich). The aqueous reaction mixture was warmed to 27.8°C with 28.0°C glycol on the jacket. 1,2-Epoxy butane was fed over 48 min (2. 16 ml / minute) at a rate such that the temperature was maintained at 30.9°C to 31.9°C. The reaction mixture remained homogenous (single phase) during the entire run. The gly col-jacket temperature was gradually increased to 50.0°C the reaction temperature peaked at 48.1 °C and then lined out at that temperature. After a total of 90 minutes of reaction time (time elapsed from the start of the feed), the temperature of the reaction mixture was lowered to 7°C. the mixture remained as a single phase. Solid sodium chloride, 80 g, was charged to the reactor. The aqueous mixture was extracted with 300 ml of a mixture of 200 ml diethyl ether and 100 ml of heptanes. The aqueous phase was then extracted two more times (2 x 150 ml diethyl ether). The combined organic extracts were dried overnight over 31 grams of anhydrous potassium carbonate.

[0069] The organic extracts were decanted from the potassium carbonate, charged to a 1000 ml distillation kettle, and concentrated by fractional distillation collecting the first fraction (vapor temperature of 35°C to 50°C) and then the second fraction (vapor temperature 50°C to 99°C) until a pot temperature of 135°C was obtained. The pot temperature was cooled to 38°C as a vacuum was gradually applied down to 1.0 mmHg. The vacuum was adjusted toAttorney Docket No.: F1-8149-WO10 mmHg with increased heating and a small fraction (BP 80°C) w as collected. The vacuum was decreased to 5.0 mmHg and the product was collected at 68.2°C to 69.5°C. To ensure that a major portion of the minor isomer would be included in the product, the vacuum was set 1.0 mmHg and the product was distilled to dryness in the distillation kettle. A total of 138 g (80.8%) of product was collected comprising 1.45 area%, l-(2-pyrroline)-2-butanol; 97.48 area%, l-pyrrolidino-2-butanol; and 1.07 area%, 2-pyrrolidino- 1 -butanol.

[0070] Example 15 - Batch Preparation l-Piperidino-2-butanol. 1 ,2-Epoxybutane, 322.44 g (4.47 mole, 388.5 ml, Aldrich) was charged to a 500 ml graduated cylinder feed reservoir. To the reactor was charged 1500 g fresh tap water, and 373 g of piperidine (4.38 mole, 432.7 ml, Aldrich) - 20 wt.% piperidine in water. The aqueous reaction mixture was warmed to 37°C with 40.0°C glycol on the jacket. 1,2-Epoxy butane was fed over 144 min (2.7 ml / minute) at a rate such that the reaction temperature was maintained at 45.3°C to 49.0°C. After the first 38 minutes, wherein 100 ml of the epoxide had been fed the temperature was 40°C and 2 phases existed in the reactor. The glycol jacket temperature was gradually increased to 47.5°C. The reaction temperature peaked at 49°C and then lined out at 48.5°C after feeding a total of 228 mis of the epoxide (82 minutes of feeding). The feed was completed in a total of 144 minutes. At the end of the feed the reactor temperature was 48.4°C, 6 minutes after the end of the feed the temperature had dropped only to 48.2°C. The jacket temperature was increased to 60.0°C and the two-phase reaction mixture was stirred for another 30 minutes as the temperature rose to 57.4°C. Mixing was stopped and the reaction mixture was left to cool overnight (no mixing).

[0071] Mixing was reestablished and 700 ml of heptanes (mixture of isomers), was charged to the reactor. Mixing was interrupted and the phases separated. A rough-cut of 1432 g of the aqueous phase was collected. The organic phase was collected and transferred to a separatory funnel to make a fine-cut. Accordingly, an additional 74 g of aqueous phase and 1149.71 g of organic was collected. The combined aqueous phase (1509 g) was returned to the reactor and extracted with 367 g of diethyl ether. Separation of the phases produced 1553 g of aqueous solution and by material balance 278 g of diethyl ether was lost to the aqueous phase and some to the headspace. To the combined organic phase was charged 25 g of anhydrous potassium carbonate. Upon standing aqueous potassium carbonate formed (total weight of 60 g).Attorney Docket No.: F1-8149-WO

[0072] The dried organic phase was transferred to the 3000 ml distillation kettle. Solvent was removed at atmospheric pressure distilling to a pot temperature of 160°C. The distillation kettle was allowed to cool as a vacuum was gradually applied. The main cut, 588 g of 1 -piperidino-2-butanol was collected at 10 mmHg and boiling range of 88 to 90°C. A deep vacuum was applied and 53 g more was collected at 1.0 mmHg and 45°C. The combined sample provided 641 g 93% yield comprising l-piperidino-2-butanol, 98 wt%, and 2-piperidino-l -butanol. 2 wt%.

[0073] Examples 16-19 - Industrial Process Runs with Recycle for l-Piperidino-2- propanol (PiP).

[0074] Example 16. Propylene oxide, 209.9 g (3.61 mole, 252.89 ml, Aldrich) was charged to a 500 ml graduated cylinder feed reservoir. To the reactor was charged 1400 g fresh tap water, and 328.35 g of piperidine (3.86 mole. 380.92 ml. Aldrich). The aqueous reaction mixture warmed to 32°C from the heat of mixing. The glycol on the jacket was set to 27 5°C. Propylene oxide was fed over 120 min (2. 107 ml / minute) at a rate such that the temperature was maintained at 33.8°C to 36.0°C. The feed was completed in a total of 120 minutes. At the end of the feed the reactor temperature was 35.5°C. The jacket temperature was increased to 50.0°C and the two-phase reaction mixture was stirred for another 60 minutes as the temperature rose to 48.5°C. The phases were separated to the organic phase was dissolved in a mixture of 200 mis of methylcyclohexane and 500 mis of diethyl ether to which was added 15 g of anhydrous potassium carbonate. The aqueous phase, 1452 g, a portion of which was returned to the reactor for the next run.

[0075] Example 17. Propylene oxide, 237.03 g (4.08 mole, 285.58 ml, Aldrich) was charged to a 500 ml graduated cylinder feed reservoir. To the reactor was charged 1284 g recycle water from Example 16 and 170 g of fresh tap water. To the aqueous mixture was charged 369.81 g of piperidine (4.34 mole, 429.01 ml, Aldrich). The aqueous reaction mixture warmed to 28°C from the heat of solution of the piperidine in water. The propylene oxide was fed to the reactor (glycol jacket at 25°C) over a time of 120 minutes (2.38 ml / min). The reaction mixture was gradually heated to 48°C with 50°C on the glycol jacket. The solution was allowed to cool and was then combined sequentially with 400 g of methylcyclohexane and 500 g of diethyl ether. The phases were separated, and 1433 g of anAttorney Docket No.: F1-8149-WO aqueous phase was collected for recycling in the next run. The organic extract was combined with the organic phase of Example 16.

[0076] The combined organics from Example 16 and Example 17 were dried over an additional 15 g of potassium carbonate. After standing overnight the organic phase was separated from 60 g of aqueous potassium carbonate and then concentrated in the 3000 ml distillation kettle via fractional distillation. The first 800 ml of solvent was collected and then the next 400 ml until the pot temperature reached 125°C.

[0077] Example 18. Propylene oxide, 219.98 g (3.79 mole, 265.04 ml, Aldrich) was charged to a 500 ml graduated cylinder feed reservoir. To the reactor was charged 1433 g recycle water from Example 17 along with 67 g of fresh tap water. To the aqueous mixture was charged 306.00 g of piperidine (3.62 mole, 355.0 ml, Aldrich). The aqueous reaction mixture warmed to 28°C from the heat of solution of the amine and water. The propylene oxide was fed to the reactor (glycol jacket at 25°C) over a period of 113 minutes (2.35 ml / min). The reaction mixture was gradually heated to 48°C with 50°C on the jacket. The solution was allowed to cool. The aqueous phase was removed. To the organic phase was added 300 ml of methylcyclohexane recovered by distillation from the combined Examples16 and 17. The mixture was stirred and then allowed to settle. The aqueous phase that separated was combined with the first aqueous cut. The combined aqueous phase was returned to the reactor and extracted with 400 ml of recovered diethyl ether also from combined Examples 16 and 17. The organic phase was dried overnight over 40 g of potassium carbonate. The next day the organics were separated from the 80 g of aqueous potassium carbonate that formed. The organics were then combined with the previously solvent stripped (fractional distillation) concentrated organic phases from Examples 16 and17 as described in more detail below.

[0078] Product Recovery from Examples 16-18. The combined dried organic phases from Example 18 was added in portions via 2-liter addition funnel, to the concentrate obtained from solvent stripping of the combination of the reaction product streams from Example 16 and 17. This addition was conducted such that the low boiling solvent was distilled from the concentrate (600 mis with overhead vapor temperature range of 35°C to 45°C) as the product was fed maintaining a relatively constant level in the distillation kettle. Once the entire content from Example 18 had been charged the solvent was further removed by graduallyAttorney Docket No.: F1-8149-WO decreasing the vacuum to 320 mmHg. Further distillation produced 90.5 g of fraction with BP < 74°C at 10 mmHg (this was later added to the recovered organic phase obtained in - 178). GC-MS Analysis of this intermediate cut indicates it was comprised of 15.71 area% methylcyclohexane, 21.60 area% piperidine and 52.69 area% l-piperidino-2-propanol.

[0079] Further fractional distillation produced 1393 grams of 1 -piperidino-2-propanol (BP 74.4°C to 76.0°C at 10 mmHg). This fraction was collected in two portions. The first was comprised of 97.91 area% 1 -piperidino-2-propanol, and 2.09 area% 2-piperidino-l- propanol; and the second comprised of 2-piperidino-l -propanol 98.2 wt.% l-piperidino-2- propanol, 1.62 wt.% 2-piperidino-l-propanol. It is pointed out that both samples comprised trace levels of piperidine though the trace quantity in the second portion appeared to be lower than the first. After collecting the main product cut. the vacuum was gradually reduced to 1 mmHg. During this time the distillation temperature dropped to 46°C. This deep vacuum stripped produced 5.03 grams of pot bottoms and 24.6 g of a distillate comprised of (GC- MS) 84.63 area% l-piperidino-2-propanol and 15.37 area% 2-piperidino-l-propanol which is in good agreement with1HNMR analyses.

[0080] Example 19. Propylene oxide, 239.2 g (4.12 mole, 288.2 ml, Aldrich) was charged to a 250 ml graduated cylinder feed reservoir. To the reactor was charged 1433 g of recycled water from the combination of Examples 18, the 60 g of piperidine / water recovered from concentration of Example 16 and 17. 342 g of piperidine (4.02 mole, 397 ml. Aldrich) and 130 g of fresh water. The aqueous reaction mixture was warmed to 28.3°C with 32.0°C glycol on the jacket. Propylene oxide was fed over 125 min (2.31 ml / minute) at a rate such the temperature was maintained at 35.5°C to 36.5°C without any apparent reflux of the PO reagent. The reaction continued to produce heat for 10 minutes after the completion of the feed. Once the temperature had dropped 0.5°C, the jacket temperature was increased to 42°C. Within 20 minutes, the temperature had reached 40.5°C showing no sign of an exotherm, thus the jacket temp was increased to 50°C. After 30 minutes (190 minutes since the start of the feed) the reactor temperature reached 48.2°C and the reaction was deemed complete. The glycol jacket was turned off and the mixing was stopped such that the two phases could separate. Mixing was resumed while 273 g of a recovered solvent mixture comprising diethyl ether and methylcyclohexane was pumped into the reactor slowly. WhenAttorney Docket No.: F1-8149-WO the temperature reached 40.8°C the mixing was interrupted, and the aqueous phase (1653 g) was removed along with 798 g of a turbid organic phase. The aqueous phase was returned to the reactor and combined / contacted with 143 g of recovered diethyl ether. The phases were separated to yield 1636 g aqueous and 153 g of an organic phase. The combined organic phase and second extract was dried overnight on 41 g of potassium carbonate to yield 89 g of aqueous potassium carbonate.

[0081] The combined organic phase was charged to the 2000 ml distillation kettle to be concentrated. The first fraction comprising mostly diethyl ether (overhead vapor temperature range of 35°C to 50°C, 760 mmHg) and a second fraction comprising diethyl ether and methyl cyclohexane (BP 50°C to 97°C, 760 mmHg) was collected. The higher boiling fraction also contained 5 g of water as a separate phase. The distillation was continued to a pot temperature of 166°C when 125 ml of heptanes was added to further remove water. The content of the distillation kettle was allowed to cool and then gradually placed under a vacuum of 10 mmHg. A 20.0 g fraction with a boiling range of 20°C to 72°C at 10 mmHg was collected. This fraction based on GC-MS analysis comprised 14.31 area% heptane; 14.62 area% methylcyclohexane; 28.61 area% piperidine; 0.33 area% N- methylpiperidine; and 42.12 area% l-piperidino-2-propanol.

[0082] The product fraction, 603 g having BP 72 to 75°C (@ 10 mmHg vacuum) was then obtained. This fraction based on GC-MS analysis comprised 0.81 area% piperidine; 97.25 area% l-piperidino-2-propanol and 1.94 area% 2-piperidino-l -proanol. These values compare well with1HNMR analysis: 0.45 wt.% piperidine; 98.17 wt.% l-piperidino-2- propanol; and 1.38 wt.% 2-piperidino-l -propanol. Upon completion of the distillation 3 g of bottoms (not analyzed) remained.

[0083] Examples 20-23: Industrial Process Runs with Recycle for l-piperidino-2- butanol (PsB).

[0084] Example 20. 1,2-Epoxy butane. 371.5 g (5.15 mole, 447.6 ml, Aldrich) was charged to a 500 ml graduated cylinder feed reservoir. To the reactor was charged 1500 g fresh tap water, and 425.5 g of piperidine (5.00 mole, 493.6 ml, Aldrich) to form a 22 wt.% piperidine in water solution. The aqueous reaction mixture was warmed to 38.6°C with 40.0°C glycol on the jacket. 1.2-Epoxybutane was fed over 209 min (2.142 ml / minute) at a rate such that the temperature was maintained at 42.1 °C to 49.0°C while the jacket temperature wasAttorney Docket No.: F1-8149-WO increased as the reaction rate appeared to slow with conversion. Accordingly, for the first 70 minutes of the epoxide feed the jacket temperature was maintained at 40°C. During this period the temperature rose from 38.6°C to a peak temperature of 42.1°C. When the temperature dropped slightly the jacket temperature was increased to 45 °C and the reaction temperature warmed to 44.8°C over a 15-minute period of feeding. After a total of 85 minutes of feeding the glycol jacket temperature was set to 47.5°C causing the reaction mixture to rise to 48.7°C during the next 80 minutes of feeding the epoxide. During the last 40 minutes of feeding the epoxide, the glycol jacket temperature was increased to 48.5°C causing the reaction mixture to rise to 49°C. Upon completion of the feed (204 minutes) and ride (5.0 minutes) the jacket temperature was set to 60.0°C causing the reactor temperature to rise to 57.4°C. The two-phase reaction mixture was stirred for a total of 50 minutes before charging 1000 ml of heptanes.

[0085] The heptanes diluted reaction mixture was left to stand overnight and equilibrate to room temperature. A perfect, emulsion free, phase boundary existed and both phases were water white. The phases were separated resulting in 1505 grams of an aqueous phase and 1392 g of an organic phase. The organic phase was charged wet to the 3000 ml distillation kettle and distilled to a pot temperature of 151°C. The heptane-water azeotrope was about 80°C. A total of 11g of water and 549.7 g of heptanes were collected.

[0086] Example 21. 1,2-Epoxy butane, 382.22 g (5.30 mole, 460.5 ml, Aldrich) was charged to a 500 ml graduated cylinder feed reservoir. To the reactor was charged 1505 g of recycled water from previous run (Example 20), and 436.53 g of piperidine (5.13mole, 506.4 ml, Aldrich). The aqueous reaction mixture was warmed to 37.4°C with 40.0°C glycol on the jacket. 1,2-Epoxybutane was fed over 190 min (2.424 ml / minute) at a rate such that the temperature was maintained at 41.3°C to 48.5°C while the jacket temperature was increased as the reaction rate appeared to slow with conversion in a manner similar to Example 20. At the end of the epoxide feed, the jacket temperature was increased to 60.0°C, the temperature of the reaction mixture rose to 58.4°C over a 35-minute period. This temperature was maintained for another 10 minutes before adding 800 ml of recycled solvent and 300 ml of fresh heptanes. Mixing was interrupted and 1465.6 grams of an aqueous phase and 1540 grams of an organic phase were recovered.Attorney Docket No.: F1-8149-WO

[0087] The wet organic phase from Example 21 was added in portions to the concentrate obtained from Example 20. As before the heptanes were distilled at atmospheric pressure but this time to a pot temperature of 160°C. This operation provided 17.7 g of water and 636 g of heptanes. The kettle was allowed to cool to 82°C and the solvent strip was continued at 90 mmHg with an overhead distillation temperature of 38°C to 40°C. A total of 124.04 grams of overhead material was collected as the pot temperature rose to 120°C. The heating mantle was turned off and the vacuum gradually dropped initially to 48 mmHg and then to 10 mmHg with a pot temperature of 90°C. This operation yielded another 46.03 g of overhead material.

[0088] After cooling over 36 hours, the distillation apparatus was placed under full vacuum (1.1 to 0.7 mmHg) and the product distilled at this high vacuum. Over the course of the distillation the pot temperature varied from 65.8°C to 70.3°C (it ran slightly higher 73.4° if the column became flooded and a back pressure developed). In general, the bottom of the column ranged from 56.8°C to 59°C depending on the vacuum. The top of the column (the boiling point of the product fraction) varied from 52.9°C to 56.6°C. A total 1452.74 g of distillate was obtained along with 1.4 g of still bottoms. The product was placed in a clean two-liter glass solvent bottle and well mixed to assure homogeneity. The material was then divided equally and placed in 1000 ml Sure Seal™ bottles and capped. Analyses (1HNMR) of the two divided samples demonstrated that they were comprised of l-piperidino-2- butanol. 97.95 wt%, 2-piperidino- 1 -butanol. 1.89 wt%; and l-piperidino-2-butanol, 97.94 wt%, 2-piperidino- 1 -butanol, 1.91 wt%.

[0089] GC analysis of trimethyl-silylated still bottoms showing higher butylene polyether oligomers as present. It would appear that oligomerization of 1,2-epoxybutane by addition to the desired product is only a minor side reaction even when the reagent is used in excess under this industrial scale process.

[0090] Example 22. 1 ,2-Epoxy butane, 374.91 g (5.20 mole, 451.7 ml, Aldrich) was charged to a 500 ml graduated cylinder feed reservoir. To the reactor was charged 1515.75 g recycled water from the previous run (including 28 grams of water collected from the distillate of Example 20 and Example 21), and 426.26 g of piperidine (5.01 mole, 494.5 ml, Aldrich). The aqueous reaction mixture was warmed to 39.8°C with 40.0°C glycol on theAttorney Docket No.: F1-8149-WO jacket. 1,2-Epoxy butane was fed over 166.7 min (2.710 ml / minute) at such a rate that the temperature was maintained at 40.7°C to 48.5°C while the jacket temperature was increased as the reaction rate appeared to slow with conversion in a manner similar to Example 20 and Example 21 . At the end of the epoxide feed, the jacket temperature was increased to 60.0°C consequently, the temperature of the reaction mixture rose to 58.3° over a 30-minute period. This temperature was maintained for another 5 minutes before adding 500 ml of recycled solvent and 141 ml of fresh heptanes. Mixing was interrupted and 1511.2 g aqueous and1214.9 g organic phases were recovered.

[0091] Example 23. 1,2-Epoxy butane, 374.21 g (5.19 mole. 450.9 ml, Aldrich) was charged to the 500 ml graduated cylinder feed reservoir. To the reactor was charged 1521.41 g recycled water from the previous Example 22, and 434.35 g of piperidine (5.10 mole.503.9 ml, Aldrich). The aqueous reaction mixture was warmed to 38.0°C with 40.0°C glycol on the jacket. 1,2-Epoxy butane was fed over 161.0 min (2.800 ml / minute) at a rate such that the temperature was maintained at 40.2°C to 48.7°C while the jacket temperature was increased as the reaction rate appeared to slow with conversion in a manner similar to Examples 20-22. At the end of the epoxide feed and after a 10-minute ride, the jacket temperature was increased to 60.0°C, as a result the temperature of the reaction mixture rose to 58.3° over a 40-minute period. The temperature was then dropped to 20°C (5°C glycol applied to the jacket). To the reaction mixture was added 450 ml of recycled solvent. Mixing was interrupted and 1521.5 g an aqueous phase and 1158.3 g of an organic phase were recovered.

[0092] To expedite product recovery for the campaign, while product was obtained from the combination of Examples 20 and 21 by fractional distillation, the combined organic phases (2400 g) and 200g of rinse solvent from Examples 22 and 23 were charged to the previously described 6-liter azeotropic drying equipment. The oil-jacket temperature was gradually raised to 155°C while 1200 ml of heptanes (845 g) and 42 g of water were taken overhead. This operation was conducted until a pot temperature of 138°C was obtained. Upon cooling overnight, 1754.21 grams of the concentrated product mixture was obtained.

[0093] The aqueous phase (1521.5 g) from Example 23 was returned to the synthesis reactor and combined with 217.6 g of solid sodium chloride and then extracted with 265 g of recycled heptanes. To this mixture was also added 42 g of azeotrope water from theAttorney Docket No.: F1-8149-WO operation described above. The organic phase was recovered and combined with the 1754.2 g portion of product concentrate described above. The mixture was returned to the azeotropic dry ing equipment and again heated to a pot temperature of 138°C. Upon cooling 1876.62 grams of material was collected and charged to the 3000 ml distillation kettle for further concentration. This heptane fraction was combined with later fractions and carefully redistilled as described further below.

[0094] The product concentrate was heated to a pot temperature of 139.9°C to distill the heptanes. The top of the column temperature was initially 93.1°C with the bottom of the column having a temperature of 113.9°C - the heptane coming overhead was still wet with free phase water present. The overhead temperature would vary, generally dropping to a lower temperature, as the pot temperature increased from 140°C to 158°C as more hydrated water was released from the product and azeotropically distilled with the heptanes. A total of 225.24 g of heptanes was collected as the overhead distillate. The crude undistilled product was left to cool overnight while nitrogen was passed through the distillation apparatus to remove any moisture.

[0095] Vacuum distillation of residual solvent was initially conducted at 125 mmHg to 112 mmHg with a pot temperature of 88 to 95 °C which produced 71.5 g of heptanes distilling between 25°C and 44°C. Further vacuum distillation of residual solvent was then conducted between 105 mmHg down to 55 mmHg with a pot temperature of 96°C to 100°C. This operation produced an additional 73.7 g of heptanes distilling between 44.0°C and 30.4°C. The vacuum was then incrementally lowered to 25 mmHg. During this time the overhead temperature ranged from 22.2°C to 18.9°C, the pot temperature increased from 95.3°C to 109. 1°C and the bottom of the column temperature increased from 38.0°C to 106.5°C. This produced 27.86 g of the distillation hard cut between solvent and product.

[0096] Final product recovery' was conducted by fractional distillation at 25 mmHg. A total of 1650 ml of product was distilled with an overhead temperature of 107.3°C to 108.3°C. During this time of product recovery, the bottom of the column ranged from 108.6°C to 109.4°C and the pot temperature ranged from 110.7°C to 111.0°C. The vacuum was incrementally lowered to 1 mmHg which produced another 125 ml of product. The total product, ca. 1775 ml, was collected as before in a 2.0-liter bottle to make homogenous. TheAttorney Docket No.: F1-8149-WO total product 1580.6 g was divided into two equal portions and sampled for analysis. Analyses ('HNMR) of the two divided samples were comprised of l-piperidino-2-butanol, 97.54 wt%, 2-piperidino-l -butanol, 2.02 wt%: and l-piperidino-2-butanol, 97.20 wt%, 2- piperidino-1 -butanol, 2.04 wt%.

[0097] Material Balance Data Results for Examples 16-23. Tables 3 and 4 provide the material balance data for the experiments described above. It should be clear that for Examples 16-19, in general an excess of piperidine was employed. Accordingly, the % yields reported are based on the limiting amount of propylene oxide employed. This series of runs clearly shows the improvements made in terms of yield of PiP when recycling the aqueous phase is employed. It should also be clear that for Examples 20 to 23, an excess of 1 ,2-epoxybutane was employed. Thus the % yields reported are based on piperidine as the limiting reagent. Again, the benefits of recycling the aqueous phase from run to run was demonstrated - though the benefit is perhaps not as significant likely because a decreased solubility of PsB in water.

[0098] It should be noted that the residual piperidine levels for the PiP compositions produced with limiting propylene oxide were generally on the order of 2100 to 4500 ppm. In contrast and comparison, the PsB compositions made with limiting piperidine had residual piperidine in the range of 400 to 800 ppm.

[0099] Examples 24-46: Extended Industrial Process Runs with Recycle for 1- piperidino-2-butanol (PsB) over Three Campaigns.

[0100] Example 24-31. Demonstrate even further scale up of the industrial process for forming 1 -piperidino-2-butanol to an 11 -molar scale. The Examples also demonstrate more concentrated (24 wt.% to 30 wt.%) piperidine reaction mixtures and consequently more concentrated (36 wt.% to 44 wt.% of the total mass) ending product content in the reactor. Example 24 uses a reaction mixture of fresh tap water. Examples 25-28 utilize direct recycle of the aqueous phase along with minimum amounts of fresh tap water to further scale up the process. After Example 28 but before its isolation, the aqueous phase was distilled to purge a portion of that phase and to recover a portion of the product via volatilization with steam. This recovered portion of product was added back to the product phase of Example 28. After product recovery of Example 28 the various heptanes phases were combined and distilled to yield more product. The purer fraction was combined with the product phase ofAttorney Docket No.: F1-8149-WOExample 29. At the successful completion of the campaign, ending with Example 31 , the combined aqueous phases solution (about 2700 g) was distilled to recover water (2338 g, 76% of the amount used as fresh tap water) for future use (used six months later to form the initial reaction mixture of Example 32). Again, during the distillation of the aqueous solution the first 25% of the overhead material produced two phases. The organic phase was combined with the organic phase from Example 41 for recovery. The overall yield for the 8 runs was 13.396 Kg, 97.9% yield. The process utilized about 3040 grams of water, 700 g of which was purged from the system for waste treatment (e.g. amine removal via ion exchange resin) and 2340 gram was available for future use in Example 32).

[0101] Example 24: 1,2-Epoxybutane, 738.01 g (10.23 mole, 889.17 ml, Aldrich) was charged to the 500 ml graduated cylinder feed reservoir in two separate portions. Fresh tap water (2550 g) and 871.91 g of piperidine (10.24 mole, 1011.5 ml, Aldrich) were charged to the reactor. The aqueous reaction mixture was warmed to 38.0°C with 40.0°C glycol on the jacket and then the jacket temperature was adjusted to 38.0°C. 1,2-Epoxybutane was fed over 160.0 min (5.557 ml / minute) at a rate such that the temperature was maintained at 42.1°C to 47.2°C while the jacket temperature was increased as the reaction rate appeared to slow with conversion in a manner similar to Examples 20-23. At the end of the epoxide feed and after a 10-minute ride, the jacket temperature was increased to 50.0°C and 60 minutes later to 60°C, as a result the temperature of the reaction mixture rose to 58.3° over a 100-minute period. The two-phase reaction mixture was left to stand and cool to room temperature overnight. The aqueous phase, 2579g was removed. To the stirred organic phase was added 766 g of heptanes. An additional 86 grams of water phase separated, was removed and combined with the recovered aqueous phase. The resulting organic phase (2312 g) was collected and transferred to the previously described 6-liter azeotropic drying equipment. The oil -jacket temperature was gradually raised to 170°C while heptanes and water were taken overhead. This operation was conducted until a pot temperature of 150°C was obtained. Upon cooling overnight, 1685 grams of the concentrated product mixture was obtained.

[0102] Vacuum distillation of residual solvent was initially conducted at 125 mmHg until the pot temperature reached 140°C. The VARIAC ® transformer for heating mantle was turned off and the pressure in the distillation pot was gradually and incrementally decreasedAttorney Docket No.: F1-8149-WO to 25 mmHg. The recovered heptanes and any water were separated. The heptanes were then combined with recovered heptanes from the azeotropic distillation. All recovered water was combined with the recovered aqueous phase from the original reaction mixture for recycling.

[0103] Final product recovery was conducted by fractional distillation at 25 mmHg. A total of 1650 ml of product was distilled with an overhead temperature of 107.3°C to 108.3°C. During this time of product recovery, the bottom of the column ranged from 108.6°C to 109.4°C and the pot temperature ranged from 110.7°C to 111.0°C. The vacuum was incrementally lowered to 1 mmHg which produced another 100 ml of product. The total product, ca. 1750 ml was collected as before in a 2.0-liter bottle to make it homogenous. The total product 1502.0 g combined with 1529.03 g of product from Example 25. The materials were blended and then sampled for analysis. Analyses (GC) : l-piperidino-2- butanol, 97.11 wt.%, 2-piperidino-l -butanol, 1.68 wt.%; and piperidine was not detected (detection limit of 500 ppm). Combined yield of 90.8%.

[0104] Examples 25-28: These Examples demonstrate recycle of the aqueous phase over four runs after the all-fresh run of Example 24. During the course of these runs 4469.84 g total of piperidine was reacted with 3284.93 g of 1 ,2-epoxy butane while only bringing in 440 more grams of water to simply maintain an initial piperidine content of about 24.3 wt.% and a final product content of about 37.2 wt.%. The details of reactor charges, water recover}', solvent and product recovery are presented in Table 5. For clarity a brief description of Example 28 is provided. Example 28-31 serves as the general procedure used in Examples 32-39 and 40-46 wherein only one distillation of the recovered aqueous recycle material was conducted at the end of the respective campaigns.

[0105] Example 28: Accordingly, the combined aqueous phases (3038 g) from Example 27 were returned to the synthesis reactor. A new reaction mixture was formed by the addition of 936.12 g (10.99 mole, 1086.0 ml, Aldrich). As was described in Example 24, 1 ,2-Epoxy butane 808.93 g (11.22 mole, 974.62 ml, Aldrich) was fed over 175.0 min (5.569 ml / minute) at a rate such that the temperature was maintained at 41.7°C to 44.7°C using a jacket temperature from 36.0°C to 42.0°C. At the end of the feed and over the course of the next 125 minutes the jacket temperature was gradually increased from 44°C to 60°C. The reaction mixture slowly increased form 44.6°C to 58.2°C, during which time there was littleAttorney Docket No.: F1-8149-WO or no evidence of further reaction. The two-phase reaction mixture was left to stand and cool to room temperature overnight. The aqueous phase, 3000 g was removed. To the stirred organic phase was added 700 g of heptanes. An additional 29 grams of water phase separated, was removed and combined with the recovered aqueous phase.

[0106] The recovered and combined aqueous phases used in Examples 24-28 were distilled to yield 2712 g of distilled water and about 350 g of aqueous bottoms that was purged as waste. During the distillation of the first 500 to 600 ml of water a second phase, an organic phase formed in the distillate. This organic phase was combined with 500 ml of heptanes and then combined with the product phase from Example 28. The recovered distilled aqueous phase was used to form the reaction mixture of Example 29. This represents an alternative means of secondary product recovery wherein the product volatilizes with steam in lieu of salting the product out at the end of a campaign.

[0107] The resulting organic phase of Example 28 and the organic phase obtained from distillation of the aqueous phased of Ex. 24-28 was collected and transferred to the previously described 6-liter azeotropic drying equipment. The oil-jacket temperature was gradually increased to 175°C while heptanes and water were taken overhead. This operation was conducted until a pot temperature of 155°C was obtained. Upon cooling overnight, 2184 grams of the concentrated product mixture was obtained. Distillation of the product as described above yielded 1899.0 g of product. Analyses (GC): l-piperidino-2-butanol, 97.65 wt.%, 2-piperidino-l -butanol, 1.60 wt.%; and piperidine was not detected (detection limit of 500 ppm). The combined yield for Examples 24-28 was 8443.44 g (96.8%).

[0108] The miscellaneous recovered heptanes fractions were combined and fractionally distilled to yield two product fractions. The first fraction (about 7 g) boiling just below the product boiling point had analyses (GC) l-piperidino-2-butanol. 91.15 wt.%, 2-piperidino- 1 -butanol, 0.82 wt.%; and 1 .03 wt .% piperidine. The second fraction (58 g) having boiling point equivalent to the desired product had analyses (GC) l-piperidino-2-butanol, 97.33 wt.%, 2-piperidino-l -butanol, 1.17 wt.%; and piperidine was not detected. This second fraction was blended with the organic phase obtained from Example 29.

[0109] Example 29 The distilled aqueous mixture (2712 g) from Example 28 was returned to the synthesis reactor. A new reaction mixture was formed by the addition of 938.0 g (11.02 mole, 1088.2 ml, Aldrich). As was described in Example 24, 1,2-EpoxybutaneAttorney Docket No.: F1-8149-WO838.00 g (11.62 mole, 974.62 ml, Aldrich) was fed over 175.0 min (5.769 ml / minute) at a rate such that the temperature was maintained at 39.9°C to 44.7°C using ajacket temperature from 36.0°C to 42.0°C. At the end of the feed and over the course of the next 117 minutes the jacket temperature was gradually increased from 44°C to 60°C. The reaction mixture slowly increased form 44.7°C to 58.4°C, during which time there was little or no evidence of further reaction. The two-phase reaction mixture was left to stand and cool to room temperature overnight. The aqueous phase, 2670 g, was removed. To the stirred organic phase was added 650 g of heptanes. An additional 35 grams of water phase separated, was removed and combined with the recovered aqueous phase.

[0110] The resulting organic phase of Example 29, 2500 g (also comprising the 58 g of product from heptane distillation) was collected and transferred to the previously described 6-liter azeotropic drying equipment. The oil-jacket temperature was gradually increased to 175°C while heptanes and water were taken overhead. This operation was conducted until a pot temperature of 159°C was obtained. Upon cooling overnight, 1831 grams of concentrated product mixture was obtained. Distillation of the product as described above yielded 1710.6 g of product. Analyses (GC) : l-piperidino-2-butanol, 97.79 wt.%, 2- piperidino-1 -butanol, 1.58 wt.%,' and piperidine was not detected (detection limit of 500 ppm). The combined yield for Examples 24-29 was 10457.93 g (97.1%).

[0111] Example 31 The recovered aqueous mixture (2712 g) from Example 30 was returned to the synthesis reactor. A new reaction mixture comprising 29.3 wt.% piperidine was formed by the addition of 871.9 g (10.24 mole, 1011.3 ml, Aldrich). As was described in Example 24, 1,2-Epoxybutane 775.00 g (10.75 mole, 933.73 ml, Aldrich) was fed over 170.0 min (5.493 ml / minute) at a rate such that the temperature was maintained at 38.6°C to 44.8°C using a jacket temperature from 36.5°C to 40.0°C. At the end of the feed and over the course of the next 60 minutes the jacket temperature was gradually increased from 44°C to 60°C. The reaction mixture slowly increased form 44.7°C to 58.8°C, during which time there was little or no evidence of further reaction. The two-phase reaction mixture was left to stand and cool to room temperature overnight. The aqueous phase, 250 g, was removed. To the stirred organic phase was added 501 g of heptanes. An additional 34 grams of a water phase separated, was removed and combined with the recovered aqueous phase.Attorney Docket No.: F1-8149-WO

[0112] The recovered and combined aqueous phases used in Examples 29-31 were distilled to yield 2338 g of distilled water and about 350 g of aqueous bottoms that was purged as waste. During the distillation of the first 575 ml of water a second phase, an organic phase formed in the distillate. This organic phase was combined with 500 ml of heptanes and then combined with the product phase from Example 31. The recovered distilled aqueous set aside for future use.

[0113] The resulting organic phase of Example 31, 2236 g was combined with the organic phase from the aqueous phase distillation / recovery. The combined solution was transferred to the previously described 6-liter azeotropic drying equipment. The oil-jacket temperature was gradually raised to 175°C while heptanes and water were taken overhead. This operation was conducted until a pot temperature of 159°C was obtained. Upon cooling overnight. 2236 grams of the concentrated product mixture was obtained. Given Example 31 was the last in the series of the campaign, extra care was taken to minimize the size of the initial cut vs. the final product cut. Accordingly, 8.0 grams of a forecut was obtained boiling between 102°C and 107°C at 25 mmHg vacuum. Analysis of this sample was as follows: (GC) 1-piperidino- 2-butanol, 95.72 wt.%, 2-piperidino-l -butanol, 0.01 wt.%; and 2.40 wt.% piperidine. Distillation of the product as described above yielded 1680.46 g of product. Analyses (GC) : l-piperidino-2-butanol, 97.46 wt.%, 2-piperidino-l-butanol, 1.54 wt.%; and piperidine was not detected (detection limit of 500 ppm). The combined yield for Examples 24-29 was 10457.93 g (97.1%).

[0114] The use of excess epoxy butane only increased the quantity of heavy ends present in the distillation kettle. The product is stable under nitrogen even at 160° with a jacket temperature of 175°C under a stream of nitrogen in the headspace. However, this did not remove all the water from the product as is needed for the application as a polar modifier ligand for hydrogen mediated anionic polymerization. In every case moisture distilled over head with the residual heptanes (typically 8 to 10 wt.% of the solution prior to fractional distillation) during the fractional distillation. One of ordinary skill in the art would understand and appreciate that the application of a subsurface inert atmosphere sparge might allow for the removal of the last of the water. A sparging operation together with the other teachings of this disclosure might afford a l-piperidino-2-butanol industrial production process wherein the product would not require distillation.Attorney Docket No.: F1-8149-WO

[0115] Examples 32-39 and Examples 40-46 demonstrate even further scale up of the industrial process for forming l-piperidino-2-butanol on 10 to 11-molar scale. The processes were run similarly to Examples 24-31 except recovery of the aqueous phase for future recycling via distillation was conducted at the end of the two campaigns. The Examples also demonstrate 22 wt.% to 25 wt.%) piperidine reaction mixtures and consequently more concentrated (34 wt.% to 39 wt.% as a percentage of the entire mass) ending product content in the reactor. The purpose of conducting these experiments (in addition to making product) was to demonstrate the use of recovered distilled water during the entirety of an eight or seven run campaign. Accordingly, 2.33 Kg of recovered distilled water from Examples 24-31 of Table 5 was used in forming the reaction mixtures of Examples 32-39 of Table 6. During the course of these Examples 0.58 Kg of fresh tap water was introduced as necessary mainly to rinse vessels and lines. As a consequence, a total of 12.27 Kg of l-piperidino-2-butanol was prepared in a total of 2.91 kg of water, 80% of which was recycled from a previous campaign after having been stored for 6 months. At the end of the 8-run campaign 2.90 Kg of recovered water was distilled to yield 2.60 Kg of distilled water. The l-piperidino-2-butanol that steam distilled with the first 600 ml of water was collected and added to the heptane solution from Example 39 for product recovery. The undistilled bottoms from the distillation operation were disposed of for proper waste treatment.

[0116] The 2.60 Kg of recovered distilled water from Examples 32-39 was used in forming the reaction mixtures for Examples 40-46 (Table 7). Accordingly, the aqueous reaction mixture of Example 40 comprised 2.60 Kg of distilled water and 0.13 Kg of extraneous water recovered from the final product isolation operations of Examples 32-39. During the course of the seven Examples of this campaign, and additional 0.15 Kg of fresh water was introduced. Thus. 11.2 Kg of l-piperidino-2-butanol was formed with a total of 2.88 Kg of water. At the end of the campaign 2.84 Kg of recovered water was distilled to recover 2.38 Kg of water for a future campaign. As before, the 1 -piperidino-2-butanol that steam distilled with the first 600 ml of water was collected and added to the heptane solution from Example 46 for product recovery. The undistilled bottoms from the distillation operation were disposed of for proper waste treatment.Attorney Docket No.: F1-8149-WO

[0117] The 1 -piperidino-2-butanol of Examples 32-39 and 40-46 were each blended to form 4 samples (a total of 8). The analyses regarding the assay of l-piperidino-2-butanol and 2- piperidino-1 -butanol were identical to earlier samples. Notably however the residual piperidine was determined by1HNMR to range from 28 to 85 ppm - and average of 55 ppm and standard deviation of 17 ppm. Moisture analysis (KF) demonstrated water contents in the range of 79 to 162 ppm, with the average of 120 ppm with a standard deviation of 30 PPm

[0118] Summary Examples 24-46: The sum or the averages (as is appropriate for instruction) of the solvent and reagent charges as well as the product and solvent recovery are presented in the final column of Table 7. It is important to appreciate that a total of 36.9 Kg (97.2% yield) of 1 -piperidino-2-butanol as produced from 17.5 Kg of 1 ,2-epoxy butane and 20.5 Kg of piperidine in reaction media formed from a total of 3.76 kg of fresh water.Table 1 : Log P of amines, epoxides and of selected P-aminoalcohols formed therefromComponent Propylene Oxide 1,2-epoxybutane 1,2-epoxyhexene Cyclopentene oxide Cyclohexene oxideLogP 0.030 0.68 1.950 0.68 1.24Attorney Docket No.: F1-8149-WOTable 2: Small Scale PreparationsExample Amino-alcohol Amine (mole) oxide (mole)HSolvent Phasesv v’Comp. 2-(l-Piperidinyl)cyclohexanol THF water one Piperidine 0.540 cyclohexene 0.484Ex. 1 2-(l-Pyrrolidinyl)cyclohexanol THF water two Pyrrolidine 0.638 cyclohexene 0.633Ex. 2 2-(4-methylpiperazino)-cyclohexanol THF water one 1 -Methylpiperazine 0.546 cyclohexene 0.523Ex. 3 l-(4-Methyl-l-piperazinyl)-2-propanol water one 1 -Methylpiperazine 0.479 propylene 0.479Ex. 4 l-(l-Pyrrolidinyl)-2-propanol water one Pyrrolidine 0.544 propylene 0.546Ex.5 l-(Dimethylamino)-2-butanol water one Dimethylamine 1.292 butylene 1.050Ex. 6 l-(4-Morpholinyl)-2-propanol water one Morpholine 0.850 propylene 0.810Ex. 7 l-(4-Morpholinyl)-2-butanol water one Morpholine 0.875 butylene 0.857Ex. 8 2-(4-Morpholinyl)cyclohexanol water one Morpholine 0.574 cyclohexene 0.564Ex. 9 l-piperidino-2-butanol water two Piperidine 1.347 butylene 1.288Ex. 10l-piperidino-2-propanol water two Piperidine 0.664 propylene 0.654Example Amine wt.% in water Rxn Temp °C FW Theory yield % yield BP (°C) Vac (mmHg)Atorney Docket No.: F1-8149-WOTable 3Sum or Ave.Example No.ofEx. 16-19Atorney Docket No.: F1-8149-WOAtorney Docket No.: F1-8149-WOTable 5Example No. 24 25 26 27 28 29 30 31 24-31Time of feed (min) 160 165 175 180 175 175 170 170 1370Average feed rate (g 5.56 5.81 5.78 5.63 5.57 5.77 5.41 5.49 5.63Oxirane 1,2-EpoxybutaneVolume, Liter 0.89 0.96 1.01 1.01 0.98 1.01 0.92 0.93 7.71 amt, g 738 796 839 841 809 838 764 775 6400 moles 10.2 11.0 11.6 11.7 11.2 11.6 10.6 10.888.8Amine Piperidine volume, Liter 1.01 1.09 1.15 1.15 1.09 1.09 1.01 1.01 8.593 amt, g 872 937 990 990 936 938 872 872 7407 mole 10.2 11.0 11.6 11.6 11.0 11.0 10.2 10.2 87.0Pip / EPOXB1.00 1.00 1.00 1.00 0.98 0.95 0.97 0.95 0.98Water Fresh Recycle Distilled RecycleTotal, Kg 2.55 2.92 3.03 3.02 3.04 2.76 2.76 2.10 3.04 recycle water, Kg 0.00 2.58 2.96 3.00 3.04 2.76 2.71 2.10 2.34Fresh water, Kg 2.55 0.34 0.08 0.02 0.00 0.00 0.05 0.00 3.04Est. Reactor vol., Liter 4.45 4.96 5.19 5.18 5.10 4.82 4.78 4.03 12.62Fresh Amine wt.% at start 25.5 24.3 24.6 24.7 23.6 25.4 24.0 29.3 70.6Product wt.% at end 38.7 37.2 37.6 37.7 36.3 38.5 36.8 43.4 81.6Aqueous phase end, Kg i 2.58 2.80 3.00 2.94 3.00 2.67 2.65 2.05 NAHeptane, g 766 957 698 711 700 650 773 501 NAMaterial Balance, Kg 2.35 2.81 2.56 262 2.48 2.52 2.52 2.20 16.90Recov. organic w / solv., Kg 2.31 2.51 2.60 2.67 2.51 2.50 2.47 2.24 19.79Crude after solv. strip, Kg 1.66 1.81 1.93 1.99 2.18 1.83 1.71 1.86 14.97Distilled Yield, Kg 1.50 1.53 1.75 1.77 1.90 1.71 1.56 1.68 13.40Yield % 90.8 96.1 104.3 100.7 97.9Atorney Docket No.: F1-8149-WOTable 6Example No. 32 33 34 35 36 37 38 39 32-39Time of feed (min)151 143 147 151 146 146 146 139 1168 Average feed rate (g / min) 5.79 6.14 6.00 6.00 6.05 6.00 6.00 6.00 6.00 Oxirane 1,2-EpoxybutaneTotal, Kg 2.72 2.84 2.71 2.64 2.71 2.80 2.83 2.90 2.909 recycle water, Kg 2.33 2.84 2.69 2.62 2.70 2.77 2.77 2.82 2.333 Fresh water, Kg 0.38 0.00 0.02 0.01 0.01 0.02 0.06 0.07 0.58Est. Reactor vol., Liter 4.60 4.72 4.59 4.58 2.73 4.68 4.70 4.72 11.73 Fresh Amine wt.% at start 24.1 23.3 24.2 25.3 24.3 23.5 23.3 22.0 70.3 Product wt.% at end 37.0 35.9 37.1 38.5 37.2 36.2 35.9 34.2 81.4 Aqueous phase end, Kg 2.85 2.69 2.56 2.60 2.70 2.70 2.76 2.83 21.69 Heptane, g 667 744 700 724 658 597 594 600 5284Material Balance, Kg 2.13 2.48 2.44 2.40 2.27 2.28 2.24 2.18 18.42 Recov. organic w / solv., Kg 2.13 2.45 2.41 2.380 2.28 2.25 2.22 2.15 18.27 Crude after solv. strip, Kg 1.54 1.72 1.78 1.75 1.73 1.740 1.75 1.62 13.64 Distilled Yield, Kg 2.93 9.34 12.27Yield % 92.1 98.0 96.6Atorney Docket No.: F1-8149-WOTable 7*Kilograms (Kg)Attorney Docket No.: F1-8149-WOEMBODIMENTS

[0119] Additionally or alternately, the disclosure can include one or more of the following embodiments.

[0120] Embodiment 1. A method for preparing a P-aminoalcohol of Formula I,The method comprises (a) forming a reaction solution of 10-40 wt% of an HNR3R4amine in an aqueous solution; (b) feeding an epoxide of Formula II to the reaction solution to produce a reaction mixture;(c) Controlling the temperature of the reaction mixture during the feeding in step b) to a temperature range of about 20° C to about 80° C; and (d) purifying the reaction mixture to obtain the P-aminoalcohol.

[0121] Embodiment 2. The method of any one or more of the previous embodiments, wherein the molar ratio of amine to epoxide is between 1 : 1.1 and 1.1 : 1; between 1 : 1.07 and 1.07: 1 ; or between 1: 1.05 and 1.05: 1.

[0122] Embodiment 3. The method of any one or more of the previous embodiments, wherein purifying the reaction mixture in step d) further comprises forming an organic layer comprising the P-aminoalcohol and an aqueous layer from the reaction mixture wherein a salt is optionally added to decrease the aqueous solubility of the P-aminoalcohol and separating the two layers.

[0123] Embodiment 4. The method of any one or more of the previous embodiments, wherein the aqueous layer is recycled as the reaction solution in step a.

[0124] Embodiment 5. The method of any one or more of the previous embodiments, wherein the temperature of step c) is about 30 to 60 °C.

[0125] Embodiment 6. The method of any one or more of the previous embodiments, wherein the forming an organic layer and an aqueous layer comprises cooling the reaction mixture and either separating out a neat organic layer or adding an organic solvent to generate the organic layer.Attorney Docket No.: F1-8149-WO

[0126] Embodiment 7. The method of any one or more of the previous embodiments, wherein the organic solvent comprises an ether, alkyl ester, dialkyl carbonate, alkane, or cycloalkane, and combinations thereof.

[0127] Embodiment 8. The method of any one or more of the previous embodiments, wherein the salt that is optionally added is one or more of non-oxidative aqueous soluble salts of sodium, and / or potassium, and / or magnesium, and / or calcium.

[0128] Embodiment 9. The method of any one or more of the previous embodiments, wherein R1and R2are each independently H or Ci to C4 alkyl, provided at least one of R1and R2is not H, or R1and R2together with the two connecting carbons for a Q to Cs carbocyclic ring; R3and R4are each independently a Ci to C3 alkyl or R3and R4together along with the nitrogen form a 5- or 6- member heterocyclic alkyl that optionally contains O or N-R5, where R5is a Ci to C3 alkyl.

[0129] Embodiment 10. The method of any one or more of the previous embodiments, wherein R2is H.

[0130] Embodiment 11. The method of any one or more of the previous embodiments, R1is methyl or ethyl and R2is H.

[0131] Embodiment 12. The method of any one or more of the previous embodiments, wherein R3and R4together with the nitrogen form a 5- or 6- member heterocyclic alkyl that is piperidinyl, pyrrolidinyl, morpholinyl, or piperazinyl.

[0132] Embodiment 13. The method of any one or more of the previous embodiments, wherein R1is methyl or ethyl, R2is H, and R3and R4together along with the nitrogen form a 5- or 6- member heterocyclic alkyl that is piperidinyl, pyrrolidinyl, morpholinyl, or piperazinyl.

[0133] Embodiment 14. The method of any one or more of the previous embodiments, wherein R3and R4are both Cl alkyl.

[0134] Embodiment 15. The method of any one or more of the previous embodiments, wherein R1is methyl or ethyl, R2is H, and R3and R4are both Cl alkyl.

[0135] It is to be understood that the embodiments and claims disclosed herein are not limited in their application to the details of construction and arrangement of the components set forth in the description and illustrated in the drawings. Rather, the description and the drawings provide examples of the embodiments envisioned. The embodiments and claims disclosed herein are further capable of other embodiments and of being practiced and carried out inAttorney Docket No.: F1-8149-WO various ways. Also, it is to be understood that the phraseology and terminology employed herein are for the purposes of description and should not be regarded as limiting the claims.

[0136] Accordingly, those skilled in the art will appreciate that the conception upon which the application and claims are based can be readily utilized as a basis for the design of other structures, methods, and systems for carrying out the several purposes of the embodiments and claims presented in this application. It is important, therefore, that the claims be regarded as including such equivalent constructions.

Claims

Attorney DocketNo.: F1-8149-WOCLAIMSWe claim:

1. An industrial scale method for preparing a p-aminoalcohol of Formula I,whereinR1and R2are each independently H or Ci to C4 alkyl, provided at least one of R1and R2is not H. or R1and R2together with the two connecting carbons for a C5 to Cs carbocyclic ring; R3and R4are each independently a Ci to C3 alkyl or R3and R4together along with the nitrogen form a 5- or 6- member heterocyclic alkyl that optionally contains O or N-R5, where R5is a Ci to C3 alkyl, the method comprising, a) Forming a reaction solution of 10-40 wt% of an HNR3R4amine in an aqueous solution; b) Feeding an epoxide of Formula II to the reaction solution to produce a reaction mixture;c) Controlling the temperature of the reaction mixture during the feeding in step b) to a temperature range of about 20° C to about 80° C; and d) Purifying the reaction mixture to obtain the P-aminoalcoholWherein the molar ratio of amine to epoxide is between 1 : 1.1 and 1.1: 1.

2. The industrial scale method of Claim 1, wherein purifying the reaction mixture in step d) further comprises forming an organic layer comprising the P-aminoalcohol and an aqueous layer from the reaction mixture wherein a salt is optionally added to decrease the aqueous solubility of the P-aminoalcohol, and separating the two layers.

3. The industrial scale method of Claim 2, where the aqueous layer is recycled as the reaction solution in step a).Attorney DocketNo.: F1-8149-WO4. The industrial scale method of Claim 1. wherein the molar ratio of amino to epoxide is between 1: 1.05 and 1.05: 1.

5. The industrial scale method of Claim 1, wherein R2is H.

6. The industrial scale method of Claim 1. wherein R1is methyl or ethyl and R2is H.

7. The industrial scale method of Claim 1, wherein R3and R4together along with the nitrogen form a 5- or 6- member heterocyclic alkyl that is piperidinyl, pyrrolidinyl, morpholinyl, or piperazinyl.

8. The industrial scale method of Claim 1, wherein R1is methyl or ethyl, R2is H, and R3and R4together along with the nitrogen form a 5- or 6- member heterocyclic alkyl that is piperidinyl, pyrrolidinyl, morpholinyl, or piperazinyl.

9. The industrial scale method of Claim 1, wherein R3and R4are both Cl alkyd.

10. The industrial scale method of Claim 1, wherein R1is methyl or ethyl, R2is H, and R3and R4are both Cl alkyl.

11. The industrial scale method of Claim 1 , wherein the temperature of step c) is about 30 to 60 °C.

12. The industrial scale method of Claim 2, wherein the forming an organic layer and an aqueous layer comprises cooling the reaction mixture and either separating out a neat organic layer or adding an organic solvent to generate the organic layer.

13. The industrial scale method of Claim 12. wherein the organic solvent comprises an ether, alky 1 ester, dialkyl carbonate, alkane, or cycloalkane, and combinations thereof.Attorney DocketNo.: F1-8149-WO14. The industrial scale method of Claim 12, wherein the salt that is optionally added is one or more of non-oxidative aqueous soluble salts of sodium, and / or potassium, and / or magnesium, and / or calcium.

15. The industrial scale method of Claim 12, wherein aqueous phase is first distilled to recover a portion of the p-aminoalcohol that remained dissolved in said aqueous phase, the recovered P-aminoalcohol is combined with the recovered organic layer for further purification, the distilled water is recycled in a subsequent batch and the unrecovered undistilled bottoms are purged as waste.

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