WO1993018021A1

WO1993018021A1 - Rare earth metal catalyzed oligomerization of alpha-hydroxycarboxylic acids and conversion to dimeric cyclic esters

Info

Publication number: WO1993018021A1
Application number: PCT/US1993/002299
Authority: WO
Inventors: Neville Everton Drysdale; Kang Lin; Thomas Walter Stambaugh
Original assignee: E.I. Du Pont De Nemours And Company
Priority date: 1992-03-13
Filing date: 1993-03-15
Publication date: 1993-09-16

Abstract

An improved process for catalytically preparing oligomers of alpha-hydroxycarboxylic acids by condensation polymerisation and catalytically producing the dimer cyclic acid esters by thermolysis of the oligomers involving the use of yttrium, lanthanum or other rare earth metal (atomic number 58 through 71) or process-compatible compound thereof as catalyst. The use of such catalysts leads to more manageable viscosities and lower toxicity.

Description

TITLE

RARE EARTH METAL CATALYZED OLIGOMERIZATION

OF ALPHA-HYDROXYCARBOXYLIC ACIDS

AND CONVERSION TO DIMERIC CYCLIC ESTERS

BACKGROPUND OF THE INVENTION 1 Field of the Invention:

This invention relates to an improved process for preparing oligomers of alpha-hydroxycarboxylic acids and their thermolysis to dimeric cyclic esters in the presence of a rare earth metal or a compound thereof.

More particularly, the invention relates to such a process as above for the preparation of lactic acid oligomers and their conversion to lactide.

2. Description of the Related Art: The oligomers of alpha-hydroxycarboxylic acids and the dimeric cyclic esters produced from them such as glycolide (l,4-dioxane-2,5-dione) and lactide (l,4-dioxane-3,6-dimethyl-2,5-dione), are intermediates to high molecular weight polyhydroxycarboxylic acids which are useful in biomedical and other applications because of their ability to be degraded biologically and hydrolytically to form physiologically and environmentally acceptable by-products.

The preparation of oligomers of alpha-hydroxycarboxylic acids, such as glycolic acid and lactic acid, and their thermolysis to dimeric cyclic esters, such as glycolide and lactide, are old and much studied processes. Both processes are known to have been carried out simply by heating at elevated temperatures and reduced pressures, but are more advantageously conducted in the presence of a catalyst.

Grater et al., U. S. Patent 1,095,205, discloses that the addition of small amounts of a suitable catalytic substance to a polylactyllactic acid (oligomer) derived from lactic acid facilitates the conversion to lactide and enables the reaction temperature to be lowered. Suitable Grater et al. substances include metal oxides such as zinc oxide, magnesium oxide and aluminum oxide; also, carbonates such as zinc carbonate and phosphates such as aluminum phosphate. Lowe, U. S. Patent 2,668,162, discloses the conversion of relatively low molecular weight polyglycolic acid to glycolide by heating with a catalytic amount of antimony trioxide, i.e. Sb2-θ3, at 270 to 285°C and 12 to 15 mm of Hg pressure. German Patent Application 1,083,275 describes the production of lactide in which the depolymerization (thermolysis) of an oligomeric polylactic acid to lactide is carried out in the presence of a metal or compound of a metal of Group IV, V or VJQI of the Periodic Table. Specifically exemplified catalysts are zinc oxide, lead oxide, stannous oxide, antimony oxide, ferrous lactate and ferric acetate.

U. S. Patent 3322,791 discloses the use of titanium tetraalkylates as catalysts for the production of lactide from lactic acid.

British Patent 1,108,720 discloses metals of Group IV of the Periodic Table or compounds thereof, e.g., lead (II) stearate as oligomerization and depolymerization catalysts.

German Patent Application 3,708,915 discloses that particularly suitable as catalysts for the production of optically active lactide from optically active lactic acid are tin powder or an organic tin compound derived from a carboxylic acid having up to 20 carbon atoms. Stannous (2-ethyIhexanoate) commonly referred to as stannous dioctoate is particularly preferred.

East German Patent 261,362 discloses the oligomerization of alpha-hydroxycarboxylic acids in the presence of antimony oxide or titanium tetrabutylate and the subsequent thermolysis of the oligomer in the presence of a manganese (II) salt, preferably manganese (II) acetate.

SUMMARY OF THE INVENTION

The divalent tin carboxylates of the art, notably stannous octoate, have been found herein suitable catalysts for the production of lactide and other cyclic esters since the same material may be used in both the oligomerization and depolymerization steps. However it has now been discovered that the tin catalysts suffer the drawback that they produce relatively viscous oligomers, and the viscosity of the molten state tends to increase with time. This would be disadvantageous in commercial use where it may be necessary to hold the ohgomer molten at elevated temperatures for an extended period of time before feeding it to the depolymerization step. Further, the more viscous the oligomer, the slower/poorer is the transfer of heat into it in the depolymerization step, and the slower/poorer is the mass transfer of the cyclic ester product out of the depolymerization mass. The result is a less efficient overall process. Also, viscous oligomers produce even more viscous "heels" of unconverted oligomer in the depolymerization step. These "heels" are slow draining which tends to limit the overall production rate. Also, they are inefficiently converted to the desired cyclic ester when it is attempted to increase process productivity by recycling them to the depolymerization reactor. Accordingly, they either have to be subjected to a wasteful hydrolysis step for the recovery of the residual hydroxycarboxylic acid values or discarded altogether. Another drawback of many of the prior art catalysts is that metals such as antimony and lead are toxic and require special handling and procedures for their safe disposal.

In view of the above, the present invention provides an improved process involving the use of a catalytically effective amount of a rare earth metal or process-compatible compound thereof.

In one aspect of the invention, the catalyzed process is a process for oligomerizing the alpha-hydroxycarboxylic compound. In another aspect, the catalyzed process is a process for depolymerizing the depolymerizable oligomer to a dimeric cyclic ester. In still another aspect, the invention process comprises sequential oligomerization and depolymerization steps conducted in the presence of the novel lanthanoid catalytic substance. In other embodiments, the alpha-hydroxy compound is the acid, preferably glycolic or lactic acid, more preferably is lactic acid, in particular L-lactic acid.

By a rare earth (or lanthanoid) metal is meant, for purposes of this invention, yittrium, lanthanum or other metal having an atomic number of from 58 through 71 as defined by Rose and Rose, The Condensed Chemical Dictionary, 7th Ed., Reinbold Publishing Corporation, New York, at pages 309-310.

By a process-compatible compound of lanthanum or other rare earth metal is meant a compound of such metal wherein the constituent groups attached to the metal moiety are so constituted that they are compatible with the other components of the reaction system and do not interfere with the intended transformations. The compounds may be pre-formed derivatives of the metals or may be formed in situ, for example, by reaction of the metal with an alpha-hydroxycarboxylic acid starting material. Preferred catalytic metals include lanthanum and mixtures thereof with other rare earth metals having atomic number 58 through 64, i.e. encompassing lanthanum through gadolinium. The catalysts of this invention offer several advantages over the art. They are generally regarded as non-toxic. They produce fluid (relatively low viscosity) reaction masses, whether oligomerization or depolymerization, which permits their ready removal from the reaction zone and helps maintain high product throughput, of particular advantage in continuous operations. Also, the oHgomers show reduced tendencies to undergo increase in viscosity on being held molten at elevated temperatures for prolonged periods of time prior to being fed to the depolymerization zone for conversion to cyclic ester. This is important since, in general, the less viscous the ohgomer, the faster and more easily it is converted to cyclic ester and the less viscous is the residual (unconverted) oligomeric mass that remains as reaction heel. The uncracked heels produced in accordance with the present invention are sufficiently fluid and operationally active to be recycled to the depolymerization step for the production of additionally quantities of the desired cyclic ester. In contrast, the highly viscous heels produced with prior art catalysts, stannous carboxylates, for example, yield little or no additional quantities of cyclic ester under substantially sύnilar conditions.

It is an object of this invention to eUminate or minimize the various drawbacks associated with the use of the oligomerization and depolymerization catalysts of the art. Another object is to provide new and improved oligomerization and depolymerization processes involving non-toxic catalysts and showing significantly reduced tendencies to produce viscous oligomers and intractable depolymerization heels.

Still another object is to provide such a catalyzed process that enables the depolymerization heels to be recycled to the depolymerization step for further conversion into cyclic ester with attendant increase in process productivity.

DETAILED DESCRIPTION OF THE INVENTION The lanthanum (lanthanoid) catalysts of this invention include yttrium, lanthanum, other rare earth metals having an atomic number of 58 to 71 and mixtures thereof, including commercially available mixtures such as bastnaesite and didymium oxide, especially the latter, which is obtained from monazite sand and consists essentially of oxides of lanthanum, praseodymium, neodymium, samarium, yttrium, cerium and gadoliriurn. Lanthanum and the other lanthanoids may be employed as the free metals, in view of their reactivity with water and acids, or as process-compatible compounds thereof. Representative compatible compounds are the hydroxides, oxides, carbonates, nitrates, sulfates, halides and carboxylates, preferably the hydroxides, oxides, carbonates and carboxylates, more preferably the carboxylates, notably such carboxylates as the acetates and their homologs, oxalates, benzoates, glycolates, lactates, citrates and other hydroxycarboxylates. The compounds of lanthanum (La) and didymium (sometimes given the "atomic" designation Di) are preferred, in particular their carboxylates. It is to be understood that, whatever the initial composition of the rare earth compound employed, the actual composition present during the oligomerization and depolymerization reactions may well vary with time, in view of the likelihood of substituent exchanges taking place around the metal moiety, but is most likely a carboxylate derived from monomeric and/or ohgomeric hydroxycarboxylic components present in the reaction mass at any given moment of time.

The catalyst is employed in catalytically effective amounts, which can vary widely depending upon the particular feed material (e.g. hydroxycarboxylic acid, ester or amine salt as defined) and the reaction conditions. The optimum catalytically-effective amounts are readily determined through trial runs. For example, with lanthanum acetate as the catalyst, its quantity is generally such that the reaction mass contains from about 0.01 to about 5% by weight, more usually from about 0.5 to 3% by weight The oligomerizable hydroxycarboxylic acid composition may be an alpha-hydroxycarboxylic acid, an ester of an alpha-hydroxycarboxylic acid or a heat-dissociable nitrogen base salt thereof. Accordingly, the invention includes converting an oligomerizable alpha-hydroxycarboxylic acid composition having the formula I, below, to an ohgomer having the formula π, below: n HOCR₁R₂C0₂X → H(OCR₁R₂CO)_nOX + (n-1) HOX (1)

I π

where; n is an integer of 2 to 50; X is independently H, R^ or a cationic group HA R- , R^ and R, are independently H or a C^ to C₆ hydrocarbyl radical; and A is a volatile nitrogen base. Preferably, R_j, R2 and R^, when other than H in the above formula, are alkyl groups. More preferably, R_j and R2 are H or methyl, as in glycolic acid

and lactic acid (R=H,

Preferably, the cationic group is derived from a nitrogen base such as ammonia or alkyl amine, and preferably is ammonia or a tertiary amine such as trimethylamine, triethylamine, memyldiethylamine, tripropylamine, tributylamine or the like. Preferably, n is not greater than about 20, more preferably not greater than about 12. The value of n defines the average number of monomenc units in the ohgomer, the value n-1 the average degree of polymerization.

It should be further appreciated and understood that for purposes of this invention low molecular weight oHgomers having formula II may be used as starting material and in such case the average value of n will increase as the condensation polymerization proceeds with formation of a mole of HOX for every new oHgomer molecule produced, e.g.:

2 H^CR^CO^OH -* HζOCR^CO^OH + HOH

HOCR^O^H + HζOCR^CO^OH -^HCOCR^CO^OH + HOH

It is to be understood that when starting material I is a heat-dissociable amine salt,, i.e., X=HA, then ohgomer II would have the formula HCOCR_jR^CO) OH, i.e., X=H, and the by-products would correspond to HLO and the nitrogen base, A. Correspondingly, when the starting material I is an alkyl ester, X in oHgomer π is an alkyl group, and the by-product, HOX, is the alcohol, ROH. Preferably, X is H throughout, for reasons of economy, and by-product HOX is water. Whatever the starting material, X is so constituted that condensation by-product, HOX, whether water, alcohol or a nitrogen base, is more volatile than the oligomer, and distills away from it during the course of the reaction. The oligomerization and depolymerization embodiments of the invention may be conducted batchwise or in a semi-continuous or continuous manner in accordance with any of such processes disclosed in the art. In general, in the catalyzed oHgomerization process, a hydroxycarboxylic starting material, as described above, containing an oUgomerizing concentration of a lanthanoid catalyst, as defined above, is heated at temperatures and pressures effective to produce an ohgomer along with by-product HOX, per equation

(1) above, under conditions for the removal of HOX from the reaction mass.

Suitable temperatures for oHgomerization generally range upwards from an initial 20° to 30°C up to about 230°C depending on the particular hydroxycarboxylic compound employed and the degree of polymerization/condensation desired. For example, for the production of L- or D-lactic acid oligomer, the temperature is usually in the range from about 20° through about 185°C and, for glycolic acid oHgomer from about 20° through 210°C.

The oligomerization process can be carried out under sub-atmospheric to atmospheric pressures consistent with the vapor pressures of the volatile by-products and the oHgomers being recovered at the operating (polymerizing) temperature. For example, it is convenient to initiate the oHgomerization reaction at ambient temperatures and pressure and gradually raise the temperature as indicated above and gradually decrease the pressure, e.g. to 1 to 20 mm of Hg, such that by-product(s), e.g. H O, is (are) volatilized and removed as distillate, as more fully disclosed and taught, for example, in U.S. Patents 1,095,205, 2,668,162 and 3,597,450, which are incorporated herein by reference for such purposes. Alternatively, the by-product HOX (e.g. 1^.0) may be removed in a stream of N₂ or other inert gas at ambient pressures, as more fully disclosed and taught, for example, in U.S. Patents 4,727,163, 4,835,293 and 5,023,349, which are also incorporated herein by reference. Heating of the oHgomers produced by any of the above methods wherein, however, the catalyst is a lanthanum or other rare earth metal compound described above may be continued to convert them to the corresponding dimeric cyclic esters, that is, cyclic esters having the formula:

C C-Ri o* \> ₂

where R-. and R2 have the significance ascribed above. The concentration of catalyst employed in the oHgomerization step is normally sufficient for the depolymerization step as well although if desired the concentration may be augmented by the addition of a further charge of the same or different lanthanum or other rare earth metal compound.

The depolymerization conditions in terms of temperature, pressure and reaction mode can vary widely, as described in the art, with continuous operation preferred. In general, the temperature of the depolymerization mass is in the range of about 180° to 270°C depending on the chemical constitution of the ohgomer and the cychc ester being produced. For the preparation of lactide from ohgomeric lactic acid, the temperature is normally in the 190° to 230°C range, preferably in the 200° to 220°C range. Somewhat higher temperatures, in the 220°-250°C, are normally employed for preparing glycolide from ohgomeric glycohc acid.

The reaction pressure may vary widely from subatmospheric to atmospheric pressure and above, and the mode of operation can vary from batch to continuous, as disclosed in U.S. Patents 1,095,205, 2,668,162, 3,597,450, 4,727,163, 4,835,293 and 5,023349 referenced and incorporated above. The catalysts of this invention may also be employed in the process of European Patent AppUcation 0264 926 A2 wherein the depolymerization of a polyhydroxycarboxyHc acid (ohgomer) to a dimeric cyclic ester is conducted under reduced pressure and forced feed in an extruder having an increased temperature gradient along its length, a vapor port at its end for the volatile cychc ester and a drain for the unconverted oHgomeric reaction heel. The catalyst of this invention may also be used in the thin film depolymerization of oHgomers of alpha-hydroxycarboxylic acids to dimeric cychc esters desribed in copending patent apphcation U. S. serial number 07/734,977, filed July 25, 1991. The foUowing examples are intended to illustrate, not Hmit, the scope of the appended claims. Unless specified otherwise, the materials described are reagent grade, temperatures are in degrees Celsius and pressures in pounds per square inch (psi).

EXAMPLE 1 OLIGOMERIZATION OF L-LACTIC ACID

Fifteen grams of lanthanum acetate hydrate, (CH3< >2)3L -xH2θ where x is less than 2, are added to 2000 grams of 88% L-lactic acid containing less than 1% D-lactic acid, and the mixture is warmed to 50° with stirring and held for 1 hour. The mixture is then added to a 2 Hter distiUation flask surmounted by a 3-inch diameter 5-sieve tray Oldershaw column and gradually heated to 185° over a 2 hour period. During this heat-up period, water distills and is removed overhead, (optionally, N₂ gas is sparged through the lactic acid solution during heat-up to aid in water removal). After water ceases distilling, the ohgomeric material in the flask is held at 185° for another hour, then analyzed for its degree of polymerization by titration with 0.1 N sodium methoxide in methanol containing phenolphthalein indicator, and is found to have an average value of n equal to 11, where n is defined in equation (1) above.

The oUgomer is a readily pourable fluid, and retains its high degree of fluidity on being held molten for extended periods of time at 185°.

EXAMPLE 2 DEPOLYMERIZATION TO L-LACTIDE

The reactor for this step is a heated 3-inch diameter 5-sieve tray glass Oldershaw column surmounting a 2 Hter flask heated at 200° to prevent depolymerization residue from sohdifying. The column is equipped with an electrically-heated mantle whose heating temperature is controlled by means of a thermocouple situated at the third tray from the top of the column. The flask is fitted with an inlet for N₂ gas. Cracking of the ohgomer to lactide is effected by pumping the molten (185°) oUgomer of Example 1 to the top tray of the column, which is heated to 210° as measured at the third tray. The ohgomer feed rate is adjusted to allow the entire Example 1 charge to be fed over a period of about 3 hours. During this time, N₂ gas, preheated to about 200° is fed to the column via the flask at a rate of 22.4 gr /min countercurrent to the downfiow of the oligomer. The oligomer cracks as it moves down the heated column and lactide and other volatile products of cracking are vaporized and swept out of the column in the N₂ gas flow. Unvaporized material exits the column at its lower end and accumulates as heel in the unheated flask.

The gas stream exiting the column at its top end is passed through a 1000 gm body of methyl isobutyl ketone (MIBK) as scrubbing solvent contained in a 2 Hter receiver. The gas leaves the scrubbing flask and is vented after first passing through cold traps cooled at about -80°C with soHd C0₂.

Upon completion of the run, the MIBK solution is cooled to about 5°, held at that temperature for about 16 hours and filtered to recover 501 gms of the L-lactide product. Evaporation of the filtrate yields an additional 285 grams of somewhat less pure L-lactide. The 786 grams total amount of lactide corresponds to a yield of 56%. In yield and quahty the L-lactide product is comparable to that of the product obtained using stannous octoate as the catalyst.

The heel of unconverted ohgomer coUected at the bottom of the column is relatively fluid and is recyclable to the cracking column for the production of additional quantities of lactide. This is in marked contrast to the highly viscous heels obtained using stannous octoate as the catalyst, which heels on being recycled to the depolymerization column yield Uttle or no additional lactide.

Having thus described and exemplified the invention with a certain degree of particularity, it should be appreciated that the foUowing claims are not to be so limited but are to be afforded a scope commensurate with the wording of each element of the claim and equivalents thereof.

Claims

CLAIMS:

1. In a catalyzed process for oligomerizing an oUgomerizable alpha-hydroxycarboxyHc acid, or an ester of an alpha- hydroxycarboxyHc acid or a heat-dissociable amine salt thereof, which involves mamtaining the hydroxycarboxyHc acid containing compositon in the presence of a catalytically-effective amount of an oHgomerization catalyst for a time and at a temperature and pressure sufficient to produce an ohgomer and volatile by-product by condensation polymerization followed by separation and recovery of the ohgomer from the by-product,, wherein the improvement comprises; employing as the catalyst at least one of a rare earth metal or a process-compatible compound thereof.

2. The process of Claim 1 wherein the oUgomerizable compound is an alpha-hydroxycarboxylic acid.

3. The process of Claim 2 wherein the hydroxycarboxyHc acid is lactic acid.

4. The process of Claim 3 wherein the catalyst consists essentially of a lanthanum compound.

5. The process of Claim 4 wherein the lanthanum compound is a carboxylate.

6. In a catalyzed process for depolymerizing an oUgomer of an alpha-hydroxycarboxylic acid to the corresponding dimeric cycUc ester and a reaction residue, which involves mamtaining the oUgomer in the presence of a catalytically-effective amount of a depolymerization catalyst for a time and at a temperature and pressure sufficient to convert a portion of the ohgomer to the dimeric cycHc ester foUowed by the separation and recovery of the dimeric cychc ester, wherein the improvement comprises; employing as the depolymerization catalyst at least one of a rare earth metal or a process-compatible compound thereof.

7. The process of Claim 6 further comprising the step of recoverying an ohgomeric residue and recycling said residue for further cataUytic depolymerization thus yielding additional quantity of the dimeric cycUc ester.

5

8. The process of Claim 6 wherein the depolymerizable compound is an oUgomer of an alpha-hydroxycarboxyUc acid.

9. The process of Claim 8 wherein the hydroxycarboxyHc acid is 10 lactic acid and the cychc ester is lactide.

10. The process of Claim 6 wherein the catalyst consists essentially of a lanthanum compound.

^•w?^ 15 11. The process of Claim 10 wherein the lanthanum compound is a carboxylate.

12. In the sequential process for producing a dimeric cycUc ester of an alpha-hydroxycarboxylic acid which process involves the steps of

20 oHgomerizing an oUgomerizable alpha-hydroxycarboxyUc acid composition in the presence of a catalytically effective amount of an oHgomerization catalyst and then depolymerizing the oUgomer containing the catalyst under depolymerization conditions to produce the corresponding dimeric cychc ester, wherein the improvement

25 comprises; employing as the catalyst at least one of a rare earth metal or a process-compatible compound thereof.

13. The process of Claim 12 wherein the oUgomerizable compound is an alpha-hydroxycarboxyhc acid.

30

14. The process of Claim 13 wherein the hydroxycarboxyHc acid is lactic acid and the dimeric cychc ester is lactide.

15. The process of Claim 12 wherein the catalyst is a rare earth 35 metal compound consisting essentially of a lanthanum compound.

16. The process of Claim 15 wherein the lanthanum compound is a carboxylate.