STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0001] This invention was made with government NIH rapport under RCMI 2U54MDQ07595, IDeA 5 P20 GM103424-15, 3 P20 GM103424-15S1 and BUILD 5UL1GM118907,

5RL5GM118966, and 5TL4GM118968. The government has certain rights in the invention.

BACKGROUND [0002] 1. Field

[0003] Thepresentdisdosuterelatee to solution synthesis workup procedures, namely isolation of the heat-sensitive reaction products by solvent evaporation at an ambient or low temperature.

[0004] 2. Description of Related Art

[0005] Workup procedures of many solution-based synthesis protocol* commonly end with a solvent removal step. Atjueous solution-phase chemistry generates the least solvent waste and, unless the reaction product is oxygen-sensitive, water can be evaporated into the air or absorbed by a suitable desiccant Other solvents are typically removed by evaporation, followed by collection of the condensed solvent in a receiver. Relatively small amoonts of volatile solvent* with vapor pressures higher than the lowest pressure that the vacuum pomp is capable of providing can be evaporated at ambient temperature, with vapors condensed in a solvent trap chilled with an appropriate cryogen.fl-3] For larger volumes, rotary evaporators are commonly preferred: BOCHl guidelines suggest a standard water bath and condenser cooling water temperature set to 50 and 10 "C, respectively, while pressures are set foe specific solvents, at which it's the boiling point is 30 °C (Δ 20 °C rule).f4,5] In practice, few bench chemist* are comfortable with removing dimediylfixmamidc (DMF) (B.P. 30 °C at P - 43 tore) using a rotovap, because it is commonly paired with an oil-free diaphragm pump and such low pressure is difficult to achieve. Alteratively, raising the temperature of the heating bath usually requires using a beat-transfer liquid other than water, limits die lifetime of the seals used in the rotovap, and increases the possibility of product deeomposhioQ. [0006] In 2000 Cherian reported die concept of high-boding solvent removal v½ vacuum drying

« I method developed for drag formulations. {6] In this procedure, a h%h boiling solvent is removed from a solution of a pharmaceutical compound by adding a low boiling co-eohrcm end applying vacuum *t a temperature greater than the freezing point, bur lower than the boiling point of the solvent mixture. The concept of vacuum evaporation under centrifugal force was realized in die Vapcxtec V-10 evapotatoc.[7] The evaporator aces * high-speed (~6000 RPM) motor co spin a vial containing a sample, creating a thin film of solvent that can be readily evaporated from the heated vial, while die consequent centrifugal force prevents “bumping,’' Further devdopmenroothis system and inclusion of an additional external vacuum pomp was attained in ribe Bioeagp$ V-10 Touch, which «Bowed removal of higher-boiling solvents such aa dimethyl sulfoxide (DMSO) and N-methyi-2-pyriolkJooe (ΝΝΠ^.[8) A similar pdndpk is utilized in Genevac centrifugal evaporators. PI

[0007] High vacuum distillation, or molecular distillarion, is a techoiqac fiat purification of substance* with low volatility, having vapor pressures of Iff* torr or less, on a relatively emal scale. [3] The apparatus is desqpied ao that the distance from the surface of the evaporating fluid to the condenser is lent than (or comparable to) the mean face path of a molecule of distillate vapor. It is imperative for molecular distillation that residual non-condensable gas pressure a maintained at very tow vabes, which is achieved by mean* of a diffusion pump coupled with the fineerc-pump- thaw technique [10). High-vacuum solvent removal is often performed by distillation in a sealed system (FIG. 1) with die receiver cooled with liquid nitrogen while maintaining the temperature of another part of the apparatus with the solution being evaponeed, dose to ambient p0|.

[0006] In some cases, reaction solvent can be removed by extracting * with another solvent, provided that the targeted solute is insoluble in it [11]. Specific processes and apparatus have been designed for biomedical and synthetic product recovery applications [12-14).

[0009] Freeze drying (lyophiEzing) is a solvent evaporation technique at a temperature lower than die freezing point of the solution. In this method, a frozen solvent sublimes under conditions of dynamic vacuum and re-coodenses in the condenser chamber, thus providing conditions for isolation of the solutes with no exposure to hear and with reduced residual solvent content Freeze drier machines (lyophOizers) paired with vacuum pomps are used in this technology 115-171- [0010] In summary, there ½ a variety of solvent evaporation methods relying on specialized equipment for solving specific technological tasks. In particular, removal of high boiling point solvents remains a challenge requiring high-vacuum techniques, advanced equipment, and is associated with higher costs. There is no universal technology equally efficient in different systems, dins a need for further improvement exists.

2 BRIEF SUMMARY OF THE INVENTION

[0011] The present disclosure teaches a simple method of solvent removal in an evacuated, cloeed system at ambient or low (spontaneously dropped doe to evaporation endothermitity) temperature.

[0012] The main principle of die disdoeed methods is the seme as in die solvent transfer systems, where the solvent evaporation h driven by the pressure gradient between a first chamber (<£, a distillation flask) and a second chamber («£, a receiving flask) in a dosed, evacuated system containing a minima] amount of residual non-condensable gas (FTG.l) [lOj. Typically, die content of residual non-condensable gas is brought to minimum by tedious ficee*e-pump-thaw technique and using a high-vacuum line with difiiisioaacturbomdecular pomp. The disclosed methods help to remove the non-condensable gas by using regular oil or even diaphragm pumps and idarivek brief initial pumping session». This can be accomplished if die pressure provided by the pomp ia lower than the vapor pressure of the solvent, and pumping is performed long enough so that the solvent vapor expels die non-condensable gas. Alternatively, if the solvent vapor pressure is lower than the pressure provided by die pump, a minute amount of inert co-solvent with a higher vapor pressure can be added. After initial pumping, the vacuum stopcock is doeed (F1G.1), and the system is isolated from the vacuum manifold (not shown). Once the receiver is dulled, the remaining traces of the vapor of the co-solvent condense, allowing die magnitude of the interna! vacuum to reach die ambient-temperature vapor pressure of the main solvent. Since the solvent vapor pressure in the chilled receiver is lower dun that in die distillation Bask, a condition of mass transfer is «ached and distillation takes place, provided that the surrounding medium (air or water bath) supplies thermal energy to the evaporating solution.

[0013] Co-solvents include, but are not limited to; low-polarity solvoics; hydrocarbons; chlorinated hydrocarbons; polar ptotic solvents; water; and alcohols. Preferred co-solvents are chemically compatible with the target substance being recovered. Preferred co-solvents may also have tow density and low miscibility with the main solvent ($o that die co-solvent stays on the top of the solution to be evaporated). Preferred co-solvents include, but a« not limited to: hydrocarbons such as petroleum edicts (benzines) with bofling point range 100-180 ^e C,iaooctane or decalin. [0014] The method is suitable for removing the solvents with a broad range of volatility, having normal (STP) boding points from 30 up to at least 202 ‘G (vapor pressures at least of 0.1 to 500 ton; higher boding point solvents am possible ID remove with longer experimental times) and is only limited from a volume standpoint by die size of the apparatus used The solvents that this method could be used for include but are not Kmioed to: water and other polar ptotic solvents Qndudii¾, but not limited to, alcohols such as methanol, ethanol, propanol, butanol; formic acid; and acetic add, far caamplc); polar aptotic solvents (including, but not limited to, N-methylpyrrolidooe; acetone; dimethylfofmamide; dimethyl acetamide; acetonitrile; mtmmethanc; dimethyl sulfoxide; and

3 propylene carbonate, fix example); end noo-polar solvents (including, but not limited to, hexane, benzene, toluene, tetraHn, dccalin, ethyl acetate; chloroform, 1,2-dichlarobenzene; ethers: 1,4- dkneane, tetnhydrofhran, gfyme, and digfyme, for example).

[0015] Particularly preferred solvents include (but are not limited to): vda; dimethyifbrmamide (DMP); tetxahydrofaran (THF); methanol, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide (DMSO), N-methyl-2-pynotidone (NMP), and 1,2-diclilorobenzene.

[0016] The solvent may further compdic a corrosive component selected 6xxn the group consisting of acids (including, but not limited to, hydrohaMc such as HF, HQ, HBr or HI; formic; acetic; ttifluoeoocetic; triflic; nitric; and aqua regie), aohitions containing NO, and NOG, add halides (SOQ¾ POO?, PCU, PBrs, acetyl chloride, benxoyl chloride; oxalyl chloride, ethyl chknoformate, ethyl chloiooxoacetate, methaneralfimykhlofide, and niAyl chloride), silicon tetrachloride, tin tetrachloride, titanium tetrachloride, chlorine, bromine, and boron trifluoride etheotc.

[0017] Furthermore, solution» containing volatile corrosive components (such as hydrogen halide) can be efficiently evaporated with minimal risk of damaging the hardware, because this method is realized in an al-fjhes or lined with corrosion-resisting film apparatus, without using a rotovap or any of its components, or a pump («£, a high-vacuum pump or oil pump) beyond an initial, «datively short evacuation stage- This method is recommended for general solution-phase synthesis routines in organic, biological, organometallic, and coordination chemistry on a basic or applied research and development scale.

[0018] Alternatively, restricting heat inflow from the surrounding? to the evaporation flask, can cause spontaneous freezing of the solution being evaporated, and can provide comfitionssimikr to freeze-drying [15-171. Compared to Jy used techniques, such as freeze-drying, the proposed method offers better protection fix heat- and air-sensitive substrates, and the benefits of more economical and shorter in time processes. A setup with the heat-insulated distillation Bask can afford a relatively tapid spontaneous freezing of the dikited aqueous solutions (hiring the initial pumping. This technique can help to recover water-free polymers and biopolymera in the form of a free- flowing fluffy solid, as compared to the liquid solution evaporation which usually results in the formation of a waxy product containing residual water.

[0019] Solutes suitable foe the disclosed methods include (but are not limited to): organic substances; inorganic substances; polymers; drugs and biological substances·

[0620] An apparatus suitable for performing the disclosed and claimed methods can be assembled in a variety of (Efferent configurations (aw, for example, FIGS. 2-4) in this disclosure. The cylindrical receiver shown in FIG. 2, was originally designed by V. D. Kbavruychenko in the early 1970$ (National Taras Shevchenko University of Kyiv, Ukraine), however die alternative apparatuses assembled using conventional pieces of glassware (FIGS.3 & 4) perform die same way. Although

4 the attached drawings demonstrate apparatus configurations at laboratory scale, using gjbsa, the skilled artisan wiD appreciate that these may be scaled up as necessary and materials other than gjasa used.

[0021] The important methodology considerations ate as follows The main principle of die described method is that the total pressure in each part of the apparatus most be equal to the vapor pressure of the solvent being distilled [lOj. In a typical apparatus (FIGS. 2-4), the evacuation port ½ located between the distiHatioa flask and the receiver. IF during setup die flask is chaqged with a solution, but the receiver is empty, evacuation would cause the non-condensable gas to be expelled by the solvent vapor ody from the distiHatioa flask, but not the receiver. It is imperative that a minute amount of the same or assisting co-solvent be added to the receiver before evacuation, so that the non-condenaable gu is removed from both sides of the apparatus. The amount of co- solvent (if used) can be estimated from the total volume of the apparatus; the pumping time can be determined empiricaly.

[0022] Absolutely essential to the success of this method is a leak-proof assembly of the apparatus. The skilled artisan will recognize that industrial volumes may be achieved with the methods described here by scaling up the apparatus to be used and by using materials («£, metal) suitable for the volumes and pressures required. To ensure this leak-proof condition ½ met, when using glass, al of die ground-glass joints and stopcock must be of the highest quality. Individually ground stopcocks (with numerically matching stopcock body and plug) and Schenk flasks with such stopcocks are available from many' glass companies, and each pair of inner /outer joints should be carefully matched, or individually ground. Similarly, these joints must all be greased with great care, using high-vacuum grease (silicone or hydrocarbon-based) and making sure that each joint and stopcock are completely transparent; a rotation test of each greased joint should be smooth and show no smeared air bubbles. The aame principle· of leak-proof assembly pertain to performance of the daimed methods at any scale, using any materials. A leak-proof assembly could also be achieved with a dedicated apparatus that does not require connecting joint» between a flask and a receiver, so long as the assembly can be charged, the product recovered, and the solvent removed (t&, drained)· [0623] Rapid stirring of the solution being evaporated is another important aspect An added benefit of high-RPM stirring is that if helps prevent violent solvent boding and bumping, which is especially common doting setup of the apparatus. Additionally, rapid stirring causes the surface area of the evaporating liquid to increase, which in turn, speeds up evaporation.

[0624] As a cryogen, liquid nitrogen ½ the mo« efficient, and the one to use for solvents with low vapor pressure. Preferably, a cryogenic liquid having a boiling point between -269°C and (PC, between -250°C and (PC, between -225°C and (PC, between -2(XPC and (PC, between -190°C and (PC, between -IfKPC and (PC, between -17(PC and (PC, between -160°C and (PC, between -15(PC and ⁽ PC, between -200°C and -ItPC, between -200°C and -20°C, between -200°C and -3<PC,

5 between -200°C end -40°C, between -200 ^® C and -50°C, between -200 ^® C and -60°C, between -200 ^® C and -70°C, between -200°C and -80°C, between -2O0°C and -90°C, between -200°C and - 100°C, between -175 ^® C and -125 ^e C is used. More preferably, a cryogenic liquid having a boding point below -150°C (-235°F) is used. Other suitable ccyqgens include, but are not limited to: crushed COj («*, either in a slurry oe not), ke (U, frozen HiO), and a refrigeration apparatus (<*, an active cooKqg system), for example.

[0025] Most solvents will freeze in the receiver at tbe temperature of liquid nitrogen, which is not a prohlem if a relatively small amount of solvent is to be removed. When working with larger volumes, the solvent tends to freeze in tbe upper part of tbe receiver, plugging it and hampering further evaporation. This problem can be addressed by having a Dewar flask charged with a cryogen to ¼>½ of its opacity, so that only the lower part of the receiver» at the temperature of the cryogen. The upper part of the receiver, which ½ stil inside of the Dewar flask, also contributes to vapor condensation, but ½ less likely to accumulate frozen solvent and become dogged. As the diitiHarion progresses, more cryogen can be added or die Dewar flask repositioned higher, so as to submerse mom surface area of the receiver in cryogen (FIG. 5). A good indication that it is time » do so is when solvent begins to condense in the upper pan of the receiver. If the distillation is left unattended for an extended period of time and then found unfinished, the cryogen (liquid nitrogen) should not be refilled because the liquid solvent that ½ likdy to be present in tbe receiver in bulk amount, wifl freeze, possibly causing tbe receiver to burst This is especially tbe case if the frozen solvent baa a lower density than that of its liquid counterpart, as in die equilibrium between water and ice.

[0626] For evaporation of huge volumes of ceiativeiy volatile solvents, it may be beneficial to selecr cryogens so as to prevent freezing of die cSstilate. Otherwise die vapors, primarily condensing in the top part of the receiver (dose to the etyogen’s upper level), often make a drift and die lower part of die receiver remains empty through the test of the distillation process. For water (or aqueous HQ or HBr) removal, ke appears to be the cryogen of choice (FIG.6) became it is not cold enough to freeze the distilled solvent

[0027] Tbe solution being evaporated may be maintained at a temperature between about 15 ^® C and about 40°C, between about 20°C and about 40°C, between about 25°C and about 40°C, between about 15°C and about 35°C, between about 15°C and about 30°C, between about 15°C and about 25°C, between about 20°C and about 30°C, and preferably between about 22°C and about 25°C, and more preferably at a temperature sufficient that the solution being evaporated remains liquid·

[0026] The ambient temperature may be between about 15 ^® C and about 40°C, between about 20°C and about 40 ^® C, between about 25°C and about 40°C, between about 15°C and about 35 ^® C, between about 15°C and about 30°C, between about 15°C and about 25°C, between about 20°C

6 and about 3(PQ, and preferably between about 22*0 and about 25 ^® C, and more preferably at a temperature «nffirirnt that tire solution being evaporated remains liquid.

[0029] In an embodknent, the solvent remaining with die solute after performing a method of the instant disclosure, ½ from about 0.0% to about 4.5% about 0.0% to about 4.0% about 0.0% to about 3.5%, about 0.0% to about 3.0%, about 0.0% to about 2.5%, about 0.0% to about 2.0%, about 0.0% to about 1.5% about 0.0% to about 10% about 0.0% to about 0.5% about 0.1% to about 4.5% about 0.1% to about 4.0%, about 0.1% to about 3.5% about 0.1% to about 3 Λ% about 0.1% to about 23% about 0.1% to about 2 Λ% about 0.1% to about 1.5% about 0.1% to about 1.0% about 0.1% to about 03%, about 0.1% to about 0.4% about 0.1% to about 03%, about 0.1% to about 02% about 0.01% to about 03% about 0.01% to about 0.4% about 0.01% to about 03% about 0XM% to about 02% about 0.01% to about 0.1% about 0.05% to about 03% about 0.05% to about 0.4% about 0.05% to about 03% about 0.05% to about 02% and about 0.05% to about 0.1%

[0030] The following further embodiments ace provided:

[0031] 1. A method of removing at least one solvent from a mixture axnprising the at least solvent and a product, the method comprising: a) providing an apparatus comprising a first container, a second container, and a hollow tube, wherein: i) the first and second containers are fhiidkaDy connected to each other via die hollow tube; ii) the Efacst container, second container or Hollow tube further compose a stopcock; Hi) the first container contains the mixture comprising the at least one solvent and the product; and Hr) the second container contains the at least one solvent alone; b) opening the stopcock and applying a vacuum to the apparatus, via the stopcock, fix a time, then closing the stopcock; c) optionally warming the first container to a first temperature, for a first period; <l) coofii¾ the second container to a second temperature, far a second periodic) optionally recovering the product ficom the first container.

[0032] 2 The method of embodiment !, when» the at least one solvent is selected from the group «H«i«ting o£ dimethylformamide, dimcthyisitifoxide, dimethylacetamide, N-medqi-2- pynolidone, and a solvent with a normal boding point ranging from 150 to 210 °C [0033] 2 The method of any one of embodiments 1-2, wherein the mixture comprises at least one corrosive component selected from the group consisting o£ adds (optionally hydrohalic HF, HQ, HBr or HI, acetic, trifluoroacetic, nitric, and apt cegia), solutions mnwinii^

NO, and NOO, acid halides (opbooaBy SOClz. POCh, PCb, PBn, acetyl chloride, benzoyl chloride, oaaiyl chloride, ethyl ddorofbrmate, ediyl dikwooaoacetatc, methanesulfbnykhkmde, and triflyi chloride), silicon tetrachloride, tin tetrachloride, titanium tetrachloride, chlorine, bromine, and boron trifluoride dheeate.

7 [0034] 5. The method of embodiment 1 , wherein the at Least one solvent is other thin tn organic solvent, and the at least one solvent is compatible with organic solvent, optionally water, alcohol, or ketone.

[0035] 6. The method of any one of embodiments 1-5, wherein the temperature of the evaporating solution e spontaneously lowered bdow freezing, and wherein the product being recovered is a polymer or a biopolymer.

[0036] 7. The method of embodiment 1, wherein the at least one solvent is selected from the group consisting of. polar protic solvents; polar aptotic solvent*; and ηαη-polar solvents.

[0037] 8. The method of any one of embodiments 1-8, wherein the produce is sefected ftom the group consisting of organk subtract^ inorgank substances; polymers; drugs; and biological substances.

[0038] 9. The method of any one of embodiments 1-8, wherein die product a a biopolymer, optionally a peptide or a protein.

[0039] 10. The method of any one of embodiments 1-9, wherein the pressure within the apparatus after the stopcock is dosed is between 500 ton and 0.1 tore.

[0040] 11. The method of any one of embodiments 1-10, wherein the first container is at a temperature, and further wherein the pressure within the apparatus after the stopcock is cloeed is equal to the vapor pressure of die at least one solvent at the temperature.

[0041] 12. The method ofany one of embodiments 1-11, wherein the second container is cooled with a cryogcn selected from the group consisting of: iiqaid dr)' ice (solid CC¼), a Uorry of dry ice and a further solvent, water ice, a salt-ice mixture, and an active coaling system.

[0042] 13. The method of any one of embodiments 1-12, wherein the time that the vacuum is applied is from about 1 minute to about 20 minutes.

[0043] 14. The method of any one of embodiments 1-13, wherein the first container is wanned fora second period, wherein the second period is from about 1 hour to about 14 hours.

[0044] 15. The method of any one of embodiments l-l 4 _¾ wherein the method is performed in an environment at a temperature, and further wherein the solvent has a vapor pressure of from 0.1 to 500 ton: at the temperature.

[0045] 16. The method of embodiment 10, wherein total pressure in the apparatus is equal to the vapor pressure of the solvent

[0046] 17. The method of any one of embodiments 1-16, wherein the first and second chambers further contain a volatile co-solvent selected from the group consisting of tow-polarity solvents; hydrocarbons; chlorinated hydrocarbons; polar protic solvents; water; and alcohols. [00*7] 18. The method ofany one of embodiments 1-17, wherein the difference between the first temperature and the second temperature is from about 25*C to about 225°C

8 [0048] 19. The method of any one of embodiments 1-18, wherein the second period is goatee than the 6ot period

[0040] 20. The method of any one of embodiments 1-19, wbesein the fiat container comprises a stirring means, and further wherein die contents of die fiat container are stirred via die stirring means.

[0050] 21. Use of an apparatus comprising a first container, a second container, and a hollow tube, to remove at least one solvent from a mixture comprising the at least one solvent and a product, wherein: i) the firm and second container» are fhndically-cotmected eo each other via the hoDow tube; ¾ the first container, second container or hollow mbe further comprise a stopcock; iii) the first container contains the mixture; and iv) the second container contains the at least one solvent alone.

[0051] 22. The use of embodiment 21, wherein the at least one solvent « selected from the group consisting o£ dimcdtylformamidc, dimethyiaoifoxide, dunethybeetamide, N-mcdxyl-2- pymolidone, and a solvent with a noraial boding point ranging from 150 to 210 ^® C [0052] 23. The use of any one of embodiments 21 -22, wherein the mixture comprises at least one corrosive component selected from the group consisting o£ adds (optionally hydrohalic HF, HQ, HBr or HI, formic, acetic, tiifluoroacetic, triflic, nitric, and aqua oga), solutions containing NO, and NOO, acid halides (optionaKy $OC½, POOs, PQs, PBn, acetyl chloride, benzoyi chloride, oaalyl chloride, ethyl ditaofbcmate, ethyl chlorooaoacetate, methanesulfbnyfchloride, and triflyi chloride), siticoa tetrachloride, tin tetrachloride, titanium tetrachloride, chlorine, bromine, and boron trifluoride ethecste.

[0053] 24. The use of any one of embodiments 21-23, wherein the at least one solvent is other than an organic solvent, and the at least one solvent is compatible with organic solvent, including water, alcohol, or ketone.

[0054] 25. The use of anyone of embodiments 21-24, wherein the product is a biopolymer, optionally a peptide or a protein.

[0055] 26. The use of any one of embodiments 21 -25, wherein the temperature of the evaporating solution e spontaneously lowered bdow freezing, and wherein the product being recovered is a polymer or a biopolymer.

[0056] 27. The use of any one of embodiments 21-26, wherein the at least one solvent is

•elected from the group consisting o£ polar ptotic solvents; polar aptotic solvents; and nan-polar solvents.

[0057] 28. The use of any one of embodiments 21-24 and 26-27, wherein the product is selected from the group consisting of. organic substances; inorganic substances; polymers; drugs; and biological substances.

9 [00503 29. The use of any one of embodiment 21 -28, wherein the pressure within the apparatus after die stopcock is dosed is between 500 torr and Cl 1 ton.

[00593 30. The use of any ooe of embodiments 21 -29, wherein die first container is at a temperature, and further wherein the pressure within the apparatus after the stopcock is dosed is equal to the vapor pressure of the at least one solvent at the temperature.

[00603 31. The use of any one of embodiments 21-30, wbetein the second container is cooled with a cryogen selected from die group consisting o£ liquid dry ice (solid CC¾, a slurry of dry ice and a further solvent, water ice, a salt-ice mixture, and an active cooling system.

[00613 32. The use of any one of embodiments 21-31, wbetein die time that the vacuum is applied is from about 1 minute to about 20 mmutes.

[00623 33. The use of any one of embodiments 21-32, wherein die first container is warmed fix a second period, wherein die second period ¼ from about 1 hour to about 14 hours.

[00653 34. The use of any ooe of embodiments 21 -33, wherein the use is performed in an environment at a temperature, and further wherein the solvent has a vapor pressure of from 0.1 to 500 ton at the temperature.

[00643 35. The use of any ooe of embodiments 21-34, wherein total pressure in the apparatus is equal to the vapor pressure of the solvent.

[00653 36. The use of any one of embodiments 21-35, wbetein the first and second chambers further contain a volatile co-solvent selected from the group consisting of: Vow-polarity solvents; hydrocarbons; chlorinated hydrocarbons; polar probe solvents; water; and alcohols.

[0066] 37. The use of any one of embodiments 21-36, wherein the difference between the first temperature and the second temperature is from about 25°C to about 225°G [0067] 38. The use of any one of embodiments 21-37, wherein die second period is greater than the first period

[0068] 39. The use of any one of embodiments 21-38, wherein the first container comprises a stirring means, and further wherein the contents of the first container are stirred via the stirring means.

BRIEF DESCRIPTION OF THE DRAWINGS

[00693 The patent or application Sic contains at least one drawing executed in color. Copies of this patenr or patent application publication with color dorwmg(e) will be provided by die Office upon request and payment of the necessity fee.

[00703 For Bather understanding of die nature; objects» and advantages of die present dtsdoaure; reference dioold be had to die following detailed description, reed in conjunction with the following drawings, wherein Kke reference numerals denote like dements.

[00713 FIG. 1 shows die scheme of ambient or low-tempeature vacuum distillatioa setup.

10 [0072] FIG. 2 draws a vacuum distillation apparatus with an air-free Schlenk distillation flask and a cylindrical receiver (which is shown as filled with frozen solvent).

[0073] FIG. 3 shows a vacuum disriBation apparatus useful for the daimed methods.

[0074] FIG.4 shows a vacuum distillation apparatus with a Schlenk disriBation flask and a bridge-connected receiver.

[0075] FIG. 5 shows a vacuum distillation setup with Bqrid nitrogen-chilled receiver.

[0076] FIG.6 shows a vacuum distillation setup with ice-drilled receiver.

[0077] FIG.7 shows a vacuum freeze-drying setup.

DETAILED DESCRIPTION

[007·] Before the subject disclosure is further described, it is robe understood that the disdoFure h nor limited to die particular embodiment* of the disclosure described below, as variations of the particular embodiments may be made and still fill within the scope of die appended claims. It is also to be underwood that the terminology employed is for the purpose of describing particular embodiments, and # not intended to be limiting. Instead, die scope of the present disclosure will be established by the appended daims.

[0079] In this specification and the appended claims, the singular forms “a,” “an," and "ribe” indude plural reference unless the context dearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the an to which thu disdosuir belongs.

[0080] REAGENTS & MATERIALS

[0081] Sdvems, polyethylene glycol- 1000 and benxophenone were purchased from ACROS Organics, AlftAcsar and Sigma-Aldrich and used without farther purification. Schlcnk and recovery flasks, and foe distillation bridge were purchased from ChcmgU» Inc The condcnser/recerver (40) from FIG.2 was ordered from the Chrmglats Custom Glass Shop. A LeyboldTrivac E2 rotary vane pomp was used fix evacuation of the demonstrated apparatus. NMR spectra were taken on a Broker Fourier 300 MH* instrument in CDClj.

[0082] EXAMPLE 1. A 200 mL pear-shaped Schlenk flask was charged with a 10 mm stir bar, 50 mL of DMSO, and 03 mL of isooctane. The receiver (40) of the apparatus (10) was charged with 0.5 mL of isooctane, carefully greased, and attached to the Schlenk flask (20) containing DMSO. As the Schlenk flask (20) was hdd over a working magnetic sorter (60), die apparatus (10) was evacuated for 2-3 minutes via die stopcock (50) attached to the Schlenk flask (20). During pumping, the isooctane evaporated and its vapor expelled the residual air within foe apparatus (10). The stopcock (50) was dosed, and the system (10) was disconnected from the vacuum line (not shown) and arranged as shown in FIG. 5. A water bath (70) was filled with water, pte-waimed to 28 *C (to

11 supply thermal energy for evaporation and ro prevent the DMSO from freezing, and Schlenk flask (20) was partially submerged in the water bath (70). The water bath (70) was supported by a magnetic stirrer (60) which was set at high RPM. After about 5 minutes of stirring, the temperature between the water bath (70) and the solvent was assumed to have «ached equilibrium. A Dewar flask (80) charged with liquid nitrogen (~½ of Dewar flask volume), was adjusted to a position surrounding the receiver (40) and so that only the bottom of the receiver (40) was submerged in the cryogen within the Dewar flask (B0). Over the course of evaporation, die water bath (70) temperature was maintained between 27-28X and the receiver (40) was gradually immersed deeper into the Dewar flask (80). The solvent in the damnation flask (20) remained Bquid at all times and the distillation was complete after 105 minutes (the distillation flask (20) contained no residual solvent, and was empty).

[0083] EXAMPLE 2. A 200 mL pear-shaped Schlenk flask (20) was charged with a 10 mm stir bar and 50 mL of DMF. The receiver (40) of the apparatus 00) was charged wMi a5 mL of DMF, carefully greased, and attached to the Schlenk flask. (20) containing DMF. As the Schlenk flask (20) was held over a working magnetic stirrer (60), the apparatus 00) was evacuated for 4-5 minutes via the stopcock (50). During pumping, a portion of DMF evaporated and its vapor expelled the residual air within the apparatus (10). The stopcock (50) was dosed, Ae system (10) was disconnected from the vacuum line and arranged as shown in FIG.5. The water bath (7C) was filled wiA ambient-temperature water (to supply thermal energy for evaporation) and the magnetic stirrer (60) was set at high RPM. A Dewar flask (BO) charged wi A liquid nitrogen (~ Vi of its volume), was adjusted to a position so that only Ae bottom of the receiver (40) was submerged in the cryogen. Over the course of evaporation, Ae water baA (70) temperature spontaneously dropped to 17-18 «C, so minimal heat was applied to maintain its temperature at -~25 °C, while the receiver (40) was gradually immersed deeper into the Dewar flask (80)· The distillation was complete in 90 minutes (Ae distillation (20) flask was empty).

[OOB43 EXAMPLE 3. A 200 ml, pear-shaped Schlenk flask (20) was charged with a 10 mm stir bar, 50 mLofNMP, and 0J> mL of isooctane. The receiver (40) of Ae apparatus (10) was charged wi* 0.5 mL of isooctane, carefoBy greased, and attached to die Schlenk flask (20) containing NMP. As the Schlenk flask (20) was held over a working magnetic surer (60). die apparatus (10) was evacuated for 3-4 minute· via the stopcock (50). During pumping, the isooctane evaporated and its vapor capcDcd the residual air within the apparatus (10). The stopcock (50) was dosed, the system (1C) was disconnected from the vacuum line (not shown) and arranged as shown in FIG. 5. The water baA (70) was filled wiA ambient-temperature water (to supply thermal energy for evaporation) and die magnetic stirrer, was set at h¾h RPM. A Dewar flask (80) charged wiA liquid nitrogen (~½ of its volume), was adjusted to a position so that only the bottom of die receive (40)

12 was submerged in the ctyogen, Over Ac course of evaporation, the water bath (70) temperature spontaneously dropped to 19*C, as the receiver (40) wu gradually immersed deeper into die Dewar flask (80). The distillation was complete in 140 minutes (die distillation flask (20) was empty).

[00·$] EXAMPLE 4. A 200 mL pear-shaped Schlenk flask (20) was charged with a 10 mm stir bar and 50 mL of water. The round-bottomed flask receiver (40) was duuged with 03 mL of water, carefully greased, and attached to the Schlenk flask (20) through a distillation bridge (30). As the Schlenk Oask (20) with water was held overs working magnetic atiner (60), the apparatus (10) was evacuated ft» 5 minutes via the stopcock (50). During pumping, a portion of water evaporated and its vapor expelled the residual air within the apparatus (10). The stopcock (50) was dosed, the system (10) was disconnected from the vacuum line (not shown) and arranged as shown in FIG. 6. The water bath (70) temperature was set to 21-22 "C, the magnetic stirrer (60) was set at high RPM, and die ice bucket (90) was charged with ke. The distillation was complete in 3 hours (the distillation flask (20) was empty).

[0006] EXAMPLE 5. A 100 mL pear-shaped Schlenk flask (20) was charged with a 10 mm stir bar, l.OQOgof bcnaophcnonc, 20mLof DMSO, and 0-5 mL of isooctane. The receiver (40) of the apparatus (10) was duuged with 0.5 mLofisooctane, carefully gmased, and attached to the Schlenk flask (20) containing the benaophenooe solution. The system (10) was evacuated for ~2 minutes via die stopcock (50), disconnected from the vacuum line (not shown), and arranged as shown in FIG. 5. The water hath (70) was filled with ambient-temperature water and die magnetic stirrer (60), was set at high RPM. A Dewar flask (80) charged with liquid nitrogen (~½ of its volume), was adjusted to s position so that only the bottom of die receiver (40) was submerged in the ciyogen. Over the course of evaporation, the water bath (70) temperature spontaneously dropped to 22 "C, and it was readjusted co 25-26 *C Most of die solvent evaporated in ~50 minutes, but the experiment was continued for additional 35 minutes. Gravimetric control showed that 12% of the bensophenone sample evaporated. The recovered benzophenone contained no residual solvent as determined by *H NMR and had a melting point range of 47-47.5 ’XL

[0007] EXAMPLE 6. A 100 mL pear-shaped Schlenk flask (20) was charged with a 10 mm star bat; 1.000 g of benzophenone, 20 mL of NMP, and 0.5 mLofisooctane. The receiver (40) of the apparatus (10) was charged with 05 mL of booctane, carefully greased, and attached to the Schlenk flask (20) containing the benzophenone solution. The system (10) was evacuated for ~2 minutes via the stopcock (50), disconnected from the vacuum line (not shown) and arranged as shown in FIG.

5. The water bath (70) was filled with ambient- temperature water and the magnetic stirrer, was set at high RPM. A Dewar flask (80) charged with liquid nitrogen (~¼ of its volume), was adjusted to a position so that only the bottom of the receiver (40) was submerged in the ctyogen. Over the course of evaporation, the water bath (70) temperature was maintained at 24-26 ’XL Most of the solvent

13 evaporated m ~50 minutes, but the experiment was continued far additional 35 minutes. The recovered beraophenone sample contained 4 mol% of residual solvent by *H NMR (22 wt%) and had a melting point range of 41-45 *C.

[0088] EXAMPLE?. A IWmL pear-shaped tmjvety flask (20) was chatged with a 10 mm stir bat; 690 mg of polyethylene glycol 1000 and 10 mL of water. The receiver (40) of the apparatus (10) was chatged with 0.5 mL of water, carefully greased, and attached to the distillation flask (20) containing the polyethylene glycol solution. A K-typc thermocouple (not shown) was taped to die flask (20) bottom, the flask (20) was wrapped by beat-insuhting blanket (100), the magnetic stirrer (60), was set at high RFM and the system (10) was evacuated far 15 minute». By die end of pumping the entice solution was frozen. The evacuation stopcock (50) was dosed, the system (10) was disconnected from the vacuum line (not shown), and assembled as shown in FIG.7. A Dewar flask (8(¾ chatged with liquid nitrogen (~ ¾ of its volume), was adjusted to a position so that most of the receiver (40) was submerged in the ctyqgen. The lowest tempersture of the outside bottom surface of the flask (20) was measured to be -17 °C

[0089] After 7 hours the system (10) was taken apart and the gravimetric control showed 1.45% sample weight depression (final mass was 10 tqg lower than initial) which is most tikdy attributed to water being present in the original sample. The recovered polymer had a fluffy texture. In the control experiment, the same sample was «-dissolved in 10 mL of water and freeze-dried under the same conditions. Ibe sample weight depression was found 0.29%, the number which borders with the accuracy limitation of this method. Thus, in the control test performed with the same polymer at ambient temperature (Le., as shown in FIG.2) the water evaporation was incomplete even after an extended period of 14 hours (5% to 7% of water remained), and the polymer was recovered in the farm of a waxy mass. In contrast; when water was removed from the polymer via die methods of the imtant disclosure, polymer was «covered as a flufly-texfured solid with 0.07-0.2 %water.

[0090] All «ferenccs died in this specification ate herein incorporated by reference as though each reference was specifically and individually indicated to be incorporated by reference. The citation of any reference is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such reference by virtue of prior invention.

[0091] It will be understood that each of the dement* described above, or two or more together may aho find * useful application in other types of methods differing from the type described above. Without further analysis, the foregoing will so fully reveal the gist of die present disclosure that others can, by applying current knowledge, readily adapt if for various applications without ¹ omitting features that, from the standpoint of prior art, fitiriy constitute essential characteristics of the generic or specific aspects of due disclosure set forth in the appended claims. The foregoing embodiments

14 are presented by way of example only; the scope of the present disclosure is to be limited only by the following claims.

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