BACKGROUND Felbamate, known as 2-phenyl-1 ,3-propanediol dicarbamate, shown below

CH ₂ OCONH ₂

04 CH ^H ₂ OCONH ₂ ^(l) is a potent antiepileptic compound useful for treating various types of epilepsy. The compound 2-phenyl-1 ,3-propanediol (PPD) is a valuable intermediate for preparing felbamate. U.S. Patent 5,239,121 describes a process for preparing PPD by cleaving a borate ester using filtration and multiple aqueous extractions. Such filtration and multiple extraction procedures have the disadvantages of lengthening the time for processing the reaction mixture, of requiring high energy usage, of losing PPD to the aqueous layer during processing and of necessitating a complex workup to recover PPD from the mother liquors. This process leads to lower yields of the desired PPD intermediate and inconsistent purity.

U. S. Patents 4,982,016 and 5,091 ,595 teach the preparation of felbamate by urethane exchange or by a modified phosgene method. B.J. Ludwig et al., J. Med. Chem., Vol. 12(3), 1969, pp. 462-472 teach various procedures for converting diols to dicarbamates. There are problems associated with such known procedures. For example, Ludwig et al. utilize sodium cyanate in environmentally undesirable halogenated solvents such as chloroform and halogenated organic acids such as trifluoroacetic acid and trichloroacetic acid.

The above processes for making PPD and felbamate have many disadvantages in commercial operation due to safety considerations during manufacturing, generally low yields, high operational expenses, and environmental and waste disposal problems. In view of the above, it would be desirable to provide faster, simpler and more efficient processes for preparing PPD and felbamate.

SUMMARY OF THE INVENTION

In one embodiment, the present invention is directed toward a process for preparing 2-phenyl-1 ,3-propanediol (PPD), comprising cleaving a borate ester of PPD, a boric acid ester of PPD or a mixture thereof, with an anion exchange

resin in the presence of a suitable solvent to give PPD. The borate ester can be of the formula:

and the boric acid ester can be of the formula:

wherein M is a cation, such as a metal of Groups I, II or III in the periodic table, titanium or ammonium;

X and Y independently represent H, -OH, -0-M+, -O-R ² or -OCOR ² where M is as defined hereinabove and R ² is C-1 to C-6 alkyl. In the borate ester formula (XVI), X and Y together can also represent

thereby causing formula (XVI) to represent a diester. For boric acid ester (XVII), preferably Y is -OH.

Preferably the anion exchange resin is a strong anion exchange resin with a crosslinked, acrylic copolymer structure. Also preferred is that the solvent is water, a C-1 to C-6 alcohol or mixtures thereof.

Preferably, borate ester (XVI), boric acid ester (XVII) or a mixture thereof is treated with an acid, such as a strong acid, preferably an acid which is a strong cationic exchange resin (H+), prior to cleavage of the esters with the anion exchange resin.

The PPD thus prepared can be converted to felbamate using any of procedures (A), (B) or (C) described in our new process. As such, in another embodiment, the present invention is directed toward a process for preparing felbamate, by employing any one of the following procedures: (A) contacting 2-phenyl-1 ,3-propanediol (PPD) with isocyanic acid in the presence of another acid and a suitable solvent to give felbamate in a yield of about 80% or greater, whereby the isocyanic acid is prepared in the substantial absence of PPD; or

(B) contacting PPD with a cyanate and an acid in a non-halogenated solvent which can provide felbamate in a yield of about 80% or greater; or

(C) contacting PPD with chlorosulfonyl isocyanate in a suitable solvent.

In procedure (A), preferably the solvent is toluene and the other acid is an anhydrous hydrogen halide, such as hydrogen chloride or hydrogen bromide. In procedure (B), preferably the solvent is aceto nit rile and the acid is an anhydrous hydrogen halide such as hydrogen chloride or hydrogen bromide.

With regard to the production of PPD, one advantage of the present invention is that it provides a process for preparing PPD having consistently high purity and in higher yields than obtained using other known processes. Another advantage of the present invention is that it provides a process for preparing PPD having reduced chemical handling and disposal problems, thus minimizing impact upon the environment. Another advantage of the present process for preparing PPD is that the solvents and the resins employed can be reclaimed and reused, further minimizing impact upon the environment. Another advantage of the present invention is that it provides a method for preparing PPD from borate esters, boric acid esters or a mixture thereof, in significantly less time and in fewer steps than by using the extraction procedures taught in U.S. Patent 5,239,121. In particular, the use of an anion exchange resin allows for the concomitant cleavage of the borate esters, boric acid esters or a mixture thereof to PPD and a boron moiety, together with a convenient separation of the PPD from the boron moiety.

With regards to the production of felbamate, one advantage of the present invention is that it provides a process for preparing felbamate in higher yields than other known processes. Another advantage of the present invention is that it provides a process for preparing felbamate whose time for completion of the reaction is shorter or less compared with other known processes. Another advantage of the present invention is that it provides a process for preparing PPD and felbamate at lower cost and thus more economically, utilizing conventional process equipment for implementation on a large tonnage scale. Another advantage of the present invention is that it lends itself to high process throughput in a continuous process sequence suitable for the automated production of felbamate.

DETAILED DESCRIPTION OF THE INVENTION

When utilized herein the terms listed below, unless indicated otherwise, are defined as follows: alkyl - represents a straight chain saturated hydrocarbon moiety having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms, or a branched hydrocarbon moiety of 3 to 10 carbon atoms, preferably from 3 to 6, such as for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, decyl and the like; the term "substituted alkyl" refers to an alkyl moiety in which one or more of the hydrogen atoms can be substituted with halo, hydroxyl, alkyl, aryl or cycloalkyl; alkoxy - represents an alkyl moiety covalently bonded to an adjacent structure through an oxygen atom, such as for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like. cycloalkyl - represents a saturated carbocyclic ring containing from 3 to 7 carbon atoms, such as for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; the term "substituted cycloalkyl" refers to an cycloalkyl moiety in which one or more of the hydrogen atoms can be substituted with halo, hydroxyl, alkyl, aryl or cycloalkyl; alkenyl - represents a straight chain hydrocarbon moiety of two to 10 carbon atoms or a branched hydrocarbon moiety of three to 10 carbon atoms having at least one carbon-to-carbon double bond such as ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-methyl-1-butenyl, 1-hexenyl and the like; aryl - represents a carbocyclic moiety containing at least one benzenoid-type ring, with the aryl moiety having from 6 to 14 carbon atoms, with all available substitutable carbon atoms of the aryl moiety being intended as possible points of attachment, for example phenyl, naphthyl, indenyl, indanyl and the like; substituted aryl- refers to an aryl moiety substituted with one to three substituents independently selected from aryl, alkyl, alkoxy, halo, trifluoromethyl, cyano, nitro, amino, moπoalkylamino, dialkylamino, amido, -CONH2, phenoxy, hydroxy, protected hydroxy, hydroxyalkyl, protected hydroxyalkyl, mercapto or carboxy and salts or esters thereof; arylalkyl or substituted arylalkyl - refers to an aryl or substituted aryl moiety bonded to an adjacent structural element through an alkyl moiety, such as for example phenylmethyl, 2-chlorophenylethyl, 2-methoxyphenylethyl and the like;

chlorinated hydrocarbon - refers to a hydrocarbon in which one or more of the hydrogen atoms has been replaced by fluorine, chlorine, bromine or iodine. Representative chlorinated hydrocarbons include chloroform, carbon tetrachloride, chlorobenzene and trifiuoromethane. halo - represents fluoro, chloro, bromo or iodo; heterocyclic - represents a cyclic group having at least one O, S and/or N interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic group having from 2 to 14, preferably from 2 to 6 carbon atoms, for example 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 1 , 2- , 4- or 5-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3-, 5- or 6-[1 ,2,4-triazinyl], 3- or 5-[1 ,2,4-thiadazolyl], 2-, 3-, 4-, 5-, 6- or 7-benzofuranyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl and the like; heterocyclic alkyl - represents a heterocyclic moiety bonded to an adjacent structural element through an alkyl moiety; boron-moiety - refers to the moiety of borate ester of formula (XVI), boric acid ester of formula (XVII) or a mixture thereof containing a boron atom, whose cleavage or removal from the borate ester of formula (XVI), the boric acid ester of formula (XVII) or a mixture thereof gives PPD.

The present process and embodiments thereof are illustrated as follows.

anion I exchange] Step 1 Step 2 resin T Non in-situ HNCO

Felbamate

In the above illustration, M is a cation as defined previously, and can represent sodium, potassium, lithium, calcium, magnesium, zinc, aluminum, titanium or ammonium; R is alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclic, heterocyclic alkyl, and X, Y and R ² are as defined

previously. The wavy line "ΛΛΛΛ " in formula (VIII) indicates that the substituents can form either the cis or trans configurations about the double bond. The brackets [ ] indicate intermediates which are generally not, but could be isolated from the reaction mixture during the preparation of PPD. Ion exchange resins are synthetic resins containing chemically active groups that give the resin the property of combining with or exchanging ions between the resin and the ions in a solution. For example, a resin with active suifonic groups can be used to soften hard water by exchanging sodium ions for calcium ions present in hard water. Ion exchange resins are classified as anionic or cationic. An anion exchange resin has an affinity for negatively charged anions, ie. hydroxide or chloride, whereas a cation exchange resin has an affinity for positively charged cations, eg. sodium or calcium. Anion and cationic exchange resins can be further categorized as strong or weak. A strong anion or cation exchange resin tends to have a greater afffinity for an anion or cation, respectively, than does a weak anion or cation exchange resin. Strong anion exchange resins can preferably possess a quaternary ammonium group (-N+R10R11R12R13 x- where R™, R"* ¹ , R ² and R ¹ 3 are alkyl and X- is a counterion), whereas a weak anion exchange resin preferably possesses a tertiary amine. Anion exchange resins which can be employed in cleaving the borate ester, boric acid ester or mixtures thereof to PPD can include weak or strong anionic exchange resins. Cation exchange resins can also possess the suifonic acid group (-SO3H), or phosphoric (-H2PO3 or -H2PO2) whose proton is readily ionizable in water, as compared to more weakly ionizable groups, such as carboxyl or phenolic groups. One with ordinary skill in the art can determine the volume of resin needed to capture the cleaved boron moiety, by determining the amount of boron in the reaction mixture, the ionic exchange capacity of the anion exchange resin and the desired flow rate. Generally, resins with higher ionic exchange capacity are preferred over resins with a lower exchange capacity. One commercially available strong anion exchange resin is Amberlite® IRA- 958 (trademark of Rohm & Haas Co., Philadelphia, Pennsylvania, USA), characterized as a macroreticular, strongly basic anion exchange resin (OH- or hydroxide cycle) with a crosslinked, acrylic copolymer structure produced in the form of spherical particles. Another anion exchange resin is Amberlite® IRA- 743 resin, supplied as fully hydrated spherical particles. A commercially available strong cationic exchange resins is Amberlite® IR 120 Plus resin (H+

or hydrogen cycle), characterized as a high density, suifonic acid type ion exchange resin produced in the form of attrition resistant, spherical particles. In Step 1, a reaction mixture containing borate ester (XVI), boric acid ester (XVII), PPD or a mixture thereof in a solvent is passed through an anion exchange resin, followed by washings with a suitable solvent. Suitable solvents include water, C-1 to C-6 monoalcohols such as methanol, ethanol, propanol, butanol, pentanol and hexanol, diois such as ethylene glycol, ketones such as methyl isobutylketone (MIBK), ethers such as methyl tertiary butyl ether, water or a mixture of any of the above. Preferably the solvent is water, butanol or a mixture thereof, such as water saturated n-butanol. Water saturated n-butanol can be prepared by mixing about one volume of water with about three volumes of n-butanol and removing the excess water.

Prior to treatment with the anion exchange resin, the reaction mixture can be acidified by treating it with a suitable acid. Suitable acids include inorganic acids, organic acids, cation exchange resins (H+) or a mixture thereof. Inorganic acids include hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, perchloric acid and the like. Organic acids include acetic, citric, formic, maleic, tartaric, methanesulfonic acid and arylsulfonic acids of the formula ArSOsH, wherein Ar is aryl or substituted aryl. Preferably the organic acids are non-halogenated. Also preferred is that the reaction mixture is acidified by passing it through a cation exchange resin, followed by washings with a suitable solvent, such as those described for use with the anion exchange resin.

Upon πearing depletion, cation or anion exchange resins can be regenerated to their desired form by following the recommendations of the manufacturer of the resin. For example, a used anionic exchange resin can be treated with a dilute solution of a base, eg. 4 bed volumes of 5% sodium hydroxide, followed by multiple washings with deionized water. A cation exchange resin can be regenerated by treating the used resin with a suitable acid, eg. 4 bed volumes of 10% sulfuric acid, followed by multiple rinses with deionized water.

Following cleavage of borate ester (XVI), boric acid ester (XVII) or a mixture thereof to PPD using an anion exchange resin as described in Step 1 , the PPD thus obtained can be converted to felbamate using either of the following procedures (A), (B) or (C). Alternatively, such procedures can be used to convert PPD prepared by any method, to felbamate.

For purposes of carrying out the present invention, the terms "isocyanic acid (HNCO)", "cyanic acid (HOCN)" or a mixture of the tautomers are regarded as interchangeable, as discussed in DJ. Belson and A.N. Strachan, Preparation and Properties of Isocyanic Acid, Chem. Soc. Reviews 11 , (1982), pp. 41-56. Similarly, the terms "isocyanate," "cyanate," or a mixture of the tautomers are also regarded as interchangeable. That is, isocyanic acid, cyanic acid, isocyanates and cyanates are all regarded as useful in practising the present invention for preparing felbamate from PPD.

In procedure (A) of Step 2, felbamate can be prepared, by contacting isocyanic acid with 2-phenyl-1 ,3-propanediol (PPD) in the presence of another acid and a suitable solvent to give felbamate in a yield of about 80% or greater, wherein the isocyanic acid is prepared in the substantial absence of PPD, ie. prepared separately. Isocyanic acid can be employed in amounts ranging from about 1.5 to about 3 moles of isocyanic acid per mole of PPD, preferably from about 1.8 to about 2.4 moles of isocyanic acid. Other acids which can be employed include inorganic or organic acids, such as those described hereinbefore. The amount of the other acid can range from about 0.03 to excess equivalents of acid per mole of PPD, preferably from about 0.05 to about 0.2 equivalents of acid. Suitable solvents which can be employed include but are not limited to N-dialkylacetamide(Cι-6alkyl); acetonitrile; dimethyl sufoxide (DMSO); toluene; xylenes such as o-, m- or p- xylene; ethers such as ethylene glycol dimethyl ether (DME, a monoglyme), bis-(2-methoxyethyl)ether (a diglyme), ethylene glycol diethyl ether, diethoxyethane (DEE) or mixtures of any of the above. Non-haiogenated solvents are preferred primarily for environmental reasons. The solvent, including that employed for preparation of the isocyanic acid, can range from about 3 to about 20 volumes of solvent per weight of PPD, preferably about 7 to about 14 volumes of solvent. The solvent should preferably contain no water, but small amounts of water can be tolerated. The reaction can be maintained at a temperature ranging from about 0°C to the boiling point of the solvent employed, preferably from about 20° to about 80°C. The felbamate in the reaction mixture can be recovered by filtration and purified by treatment with base, followed by recrystallization in water, an alcohol solvent or a mixture thereof. In procedure (A), isocyanic acid is prepared in the substantial absence of PPD and thus is prepared separate from the PPD. Isocyanic acid can be prepared separately from PPD by using any of the methods described in

Belson and Strachan, above. For example, isocyanic acid can be prepared by acidifying alkali isocyanates, such as by heating a mixture of KHSO4 and KNCO, by passing gaseous HCI over finely powdered NaNCO or by passing HCI gas into suspensions of alkali isocyanates in inert organic liquids. In another alternative method, isocyanic acid can be prepared by depolymerizing cyanuric acid using elevated temperatures. In another alternative method, isocyanic acid can be prepared by heating urea. Following its preparation, isocyanic acid or cyanic acid can be stored at low temperatures, ie. 0°C or below, to minimize decomposition losses. In procedure (B) of step 2, felbamate is prepared by contacting PPD with a cyanate and an acid in a non-halogenated solvent which can provide felbamate in a yield of about 80% or greater. In this procedure, isocyanic acid is prepared in-situ, ie. in the substantial presence of PPD. Suitable cyanates include sodium cyanate (NaOCN), potassium cyanate (KOCN), ammonium cyanate (NH4OCN), magnesium cyanate (Mg(OCN) ₂ ), aluminum cyanate

(AI(OCN) ₃ ) and titanium cyanate (Ti(OCN)4). Silylisocyanates (Si(NCO) ₄ ) may also be employed. Preferably the acid is a strong acid, such as those described hereinbefore, ie. hydrogen chloride, sulfuric acid and the like. In the order of addition of the reactants for Procedure (B), preferably the acid is added last. The amounts cyanate to be used can range from about 1.6 to about 5 moles of cyanate per mole of PPD, preferably from about 1.8 to about 2.5 moles of cyanate. The amount of acid employed can range from about 1.6 to about 5 moles of acid per mole of PPD, more preferably from about 1.8 to about 3 moles of acid. During contacting of the reactants, the reaction mixture can be maintained at a temperature ranging from about -20°C to the boiling point of the reaction mixture, preferably about -15° to about 80°C, more preferably from about -10°C to about 70°C. Non-halogenated solvents are preferred for both process efficiency and environmental reasons. Such non-halogenated solvents can include but are not limited to N,N-dialkyiacetamide(Cι-6alkyl); acetonitrile; dimethyl sufoxide (DMSO); acetone; toluene; ethers such as ethylene glycol dimethyl ether (DME, a monoglyme), bis-(2-methoxyethyl)ether (a diglyme), ethylene glycol diethyl ether and diethoxyethane (DEE). The amount of solvent can range from an amount effective to solubilize the PPD reactant to slightly or greatly excessive amounts and provide felbamate in a yield of about 80% or greater. The table below demonstrates the pronounced effect of the solvent upon yield of felbamate under comparable ratios of reactants in procedure (B).

in procedure (C) of step (2), felbamate can be prepared by contacting PPD with chlorosulfonyl isocyanate in a suitable solvent, or by using a blocked or masked isocyanate, ie. R ¹ NCO where R ¹⁴ is a readily removable protecting group, selected from a silyl group, e.g.

(CH ₃ ) ₃ Si-, (CH ₃ ) ₂ Si ^ _f CHaSi ^ , _S i^ or an acyl or sulphonyl isocyanate, including chlorosulphonyl isocyanate.

The following examples are representative of the manner in which the present invention can be practised and should not be construed as limiting the overall scope of the same.

Example 1. Preparation of PPD using ion exchange resins.

A cation exchange resin column (20 cm length by 2.5 cm diameter) is prepared by packing with 40 ml_ Amberlite® IR 120 (H ⁺ ) cation exchange resin, followed by displacing the water in the column with water saturated n- butanol. An anion exchange resin column (30 cm length by 3.0 cm diameter) is prepared by packing with 160 ml_ of Amberlite® IRA 958 (OH") anion exchange resin, followed by displacing the water in the column with water saturated n-butanol. An organic layer containing a mixture of borate ester (XVI), boric acid ester (XVII) or PPD (XVIII) is obtained as described in the Preparative Example. The organic layer (based upon 40 ml_ of methyl phenylacetate starting material) is passed through the cation exchange resin column at a flow rate of 6 to 10 mLJminute. The column is subsequently washed by passing through water saturated n-butanol (40 mL). The pH of the combined water saturated n-butanol effluents from the cation exchange resin column is about 2 to 3. The water saturated n-butanol effluents are then passed through the anion exchange column and the column is then washed with water saturated n-butanol (160 mL). The pH of the combined effluents from the anion exchange resin column is about 7 to 9. The effluents are

concentrated at 80° to 120°C under vacuum (27 inches Hg vacuum) to a thick oil. The oil is cooled to 40°C, charged with 200 mL of toluene and concentrated under vacuum to a final solution volume of 120 mL The solution is filtered at 55° to 60°C to remove insolubles. The reaction flask and the filter paper are washed with toluene (40 mL) at 55° to 60°C. The combined filtrates are slowly cooled to 10° to 25°C. The precipitated PPD is filtered, washed with toluene and dried in a vacuum oven with a nitrogen bleed, first at room temperature, then at 30°C to give 35.0 g of PPD (83% yield based upon methyl phenylacetate, +99% purity).

Example 2. Preparation of felbamate from PPD using a non in-situ preparation of isocyanic acid

Isocyanic acid (2.54 N) is prepared separately from PPD by reacting sodium cyanate (300 g, 4.43 moles) with hydrogen chloride (118 g, 3.23 moles) in toluene (900 mL) at 25°C for one hour and the reaction mixture is filtered. The solution of isocyanic acid (HNCO) in toluene is cooled to below

0°C prior to use.

To a 1 L three-neck round bottom flask equipped with a thermometer and mechanical stirrer are charged 2-phenyl-1 ,3-propaπediol (PPD) (50.0 g,

0.329 mole) and 200 mL of toluene. The solution is heated to 55°C and charged with a solution of anhydrous hydrogen chloride in toluene (0.4 N, 41 mL, 16.4 mmol). A portion of the cooled isocyanic acid solution (2.54 N, 272 mL, 0.691 mole) is slowly contacted with the reaction mixture at a flow rate of 4.5 mLΛπinute, and the reaction temperature is maintained at 60° to 65°C.

After all the isocyanic acid is charged, the progress of the reaction is analyzed by high performance liquid chromatography (HPLC). The reaction mixture is filtered after monitoring by HPLC indicates that the reaction is substantially

complete. The filter cake is washed with toluene (50 mL) and twice with water (50 mL each). The washed cake is transferred to a 1 L three-neck round bottom flask equipped with thermometer, condenser and mechanical stirrer. To the flask, methanol (400 mL) and water (225 mL) are charged. The mixture is heated to 65°C to give a solution and then slowly cooled to 40°C. The pH of the slurry is adjusted to 11.0 to 11.5 with 5% sodium hydroxide and the resultant heterogeneous slurry is agitated at 40°C until HPLC analysis indicates that an allophanate by-product is less than 0.1%. The slurry is then adjusted to pH 6 to 7.5 using aqueous sulfuric acid (6 N). The slurry is heated to 72° to 80°C and filtered to remove insolubles. The filtrate is maintained at 60° to 70°C, agitated for 5 minutes and the solution is slowly cooled to 5°C. After cooling, the resultant heterogeneous slurry is filtered. The wet filtered cake is washed twice with 100 mL of water and dried under vacuum with a nitrogen bleed at about 120°C to give 70.5 g (90% overall yield) of purified felbamate (+99% purity).

Example 3. Preparation of felbamate from PPD using an in-situ preparation of isocyanic acid.

C. CHgOH CH 1)NaOCN/CH ₃ CN

' CH.oOnH ² > ^HCI < ^9as > , * ^■

Felbamate To a 4 L three-neck round bottom flask equipped with a thermometer and mechanical stirrer are charged 2-phenyl-1 ,3-propanediol (PPD) (152.19 g, 1.0 mole) and 760 mL of acetonitrile. The mixture is stirred at room temperature (20°C). Sodium cyanate (149.15 g, 2.29 mole) is charged and the mixture is cooled to -5°C. Hydrogen chloride gas is bubbled into the mixture at a rate of 1300 cubic centimeters (cc)/minute for 30 minutes until about 95 g (2.6 moles) of HCI gas is delivered into the mixture. The exothermic reaction is maintained below 35°C with an ice bath. Analysis of the reaction mixture by HPLC indicates a yield or conversion > 95% of 2-phenyl-1 ,3-propanediol (XVIII) to

felbamate (I), leaving less than 2% of monocarbamate alcohol (XX). The reaction is quenched by adding the mixture to 1.5 L of water. The resultant slurry is neutralized to a pH between 4 and 6 using 10% sodium hydroxide. The mixture is heated to 80°C until a clear solution is obtained. The hot solution is filtered and cooled to 10°C, forming a heterogeneous slurry. The heterogeneous slurry is filtered. The filtered cake is slurried in 3.4 L of water and the pH of the mixture is adjusted to 2-2.5 with 2 N hydrochloric acid. The mixture is gently refluxed at 100°C for 5 hours. After cooling, the resultant heterogeneous slurry is filtered. The wet cake is washed twice with water (0.5 L each) and dried under vacuum with a nitrogen bleed at 100°C to give 214 g (90% overall yield) of purified felbamate (+99% purity).

Ex nate

To a suspension of PPD (3.04 g, 0.02 mole) in 21 mL of toluene is added dropwise, at 10°C to 25°C, a solution of chlorosulfonyl isocyanate (CSI) (5.78 g, 0.04 moles) in 9 mL of toluene. The mixture is stirred at ambient temperature for two hours. Water (25 mL) is added dropwise while maintaining the temperature below 50°C. The reaction mixture is stirred for 30 minutes, heated to 50°C for 20 minutes, cooled to ambient temperature and filtered to give 4.6 g of crude precipitated felbamate (96% yield ).

Preparation of Starting Materials

In the illustration below, the enolate salt of formyl phenyl acetic acid ester (VIII) can be prepared by contacting a phenyl acetic acid ester (II) with a formic acid ester (IV) in the presence of base MA (VI) to give the enolate salt of formyl phenyl acetic acid ester (VIII):

(IV) wherein R is as defined hereinbefore;

R ¹ can represent any of the values as R or another group capable of forming a leaving group R ¹ 0- _f e.g., trimethylsilyl; M is a cation as described hereinbefore; and

A is an anion which enables MA to function as a base, i.e., a hydride, alkoxide, amide or like moiety. Preferably R and R ¹ are methyl and MA is sodium methoxide.

The process for preparing the enolate salt (VIII) can be carried out neat or in the presence of any suitable organic solvent. Such solvents include aprotic solvents inert to the base used such as hydrocarbons, including toluene, benzene and xylenes, or ethers such as diethylether, methyl tertiary butyl ether and the like. Suitable bases include hydroxides of the alkali and alkaline earth metals such as sodium hydroxide, potassium hydroxide and calcium hydroxide; hydrides such as sodium or potassium hydride; sodium methoxide; and potassium t-butoxide.

In Preparative step (a), enolate salt (VIII) can be contacted with a suitable acid to a form a product which can exist in an equilibrium of E-enol (X), Z-enol (XII), formyl phenyl acetic acid ester (XIV) or a mixture of any of the above. Suitable acids include any suitable inorganic acid, organic acid or a mixture thereof. The acid can be neat or admixed with an organic solvent or water. The acid can be employed in amounts effective to protonate enolate salt (VIII). Such amounts can range from about equimolarto excess moles of acid per mole of enolate salt (VIII), preferably from about equimolarto about two moles of acid.

In Preparative step (b), the E-enol (X), Z-enol (XII), formyl phenyl acetic acid ester (XIV) or a mixture of any of the above can be reduced with a borohydride reducing agent to borate esters (XVI) of PPD, boric acid esters (XVII) of PPD or a mixture thereof for use in Step 1. Suitable borohydride reducing agents which can be employed include sodium, potassium, lithium,

calcium, zinc and magnesium borohydrides, and modified borohydrides prepared by partial reaction of a borohydride with a protic or aprotic solvent. The borohydride reducing agent can be employed in amounts ranging from about equimolar to excess borohydride per mole of enolate salt (VIII), E-enol (X), Z-enol (XII), formyl phenyl acetic acid esters (XIV) or a mixture of any of the above, preferably from about 0.7 to about two moles borohydride, preferably from about 1.0 to about 1.7.

The reaction can be carried out in a suitable solvent. Such solvents include protic solvents such as water, C-1 to C-10 alcohols including methanol, ethanol, propanol, isopropanol, butanol and the like. Aprotic solvents include tetrahydrofuran, toluene, ethers including methyl tertiarybutyl ether and diethylether or esters of C-1 to C-5 carboxylic acids including formic, acetic, propionic or mixtures of any of the above solvents. The amount of solvent should be sufficient to provide a mixable slurry of the reactants. The reaction can be carried out at temperatures ranging from about

-40°C to the boiling point of the solvent employed, preferably from about -20° to about 40°C, more preferably from about -15°C to about 20°C.

Preparative Example Sodium methoxide (24 g, 0.422 moles) is added to 140 mL of toluene under a nitrogen atmosphere, followed by addition of methyl phenylacetate (40 mL, 0.278 moles). The mixture is warmed to 40° to 45°C and methyl formate (27 mL, 0.427 moles) is added while maintaining the reaction at 40° to 50°C. Following addition of methyl formate, the reaction mixture is agitated at 40° to 50°C for 30 minutes. A second charge of sodium methoxide (4 g, 0.070 moles) is added to the reaction mixture and the mixture is agitated at 40° to 50°C for 30 minutes. At the end of 30 minutes, analysis of the reaction mixture by HPLC indicates a conversion of methyl phenylacetate to methyl 2-formyl-2-phenyl acetate sodium salt (>95%, based upon disappearance of methyl phenylacetate starting material), leaving <3% of unreacted methyl phenylacetate. The reaction mixture is cooled to -5° to 0°C and slowly added to a precooled (-5° to 0°C) mixture of 160 mL water and 40 mL of water saturated n-butanol. The reaction vessel is rinsed with 40 mL toluene and added to the quenched mixture. The reaction mixture is maintained at -5° to 2°C. The aqueous phase containing methyl 2-formyl-2-phenylacetate sodium salt is rapidly added to a precooled (-5 to 0°C) mixture of 120 mL of water saturated n-butanol and 32 mL (0.559 mole) of glacial acetic acid. The organic

phase containing the protonated enolate is slowly added to a mixture of 120 mL of water saturated n-butanol and NaBH ₄ (16 g, 0.422 moles) at -5° to 0°C, while maintaining the temperature of the exothermic reaction at -5° to 5°C. At the end of the addition, the reaction is monitored by HPLC for the substantial absence of the enols. The reaction mixture is warmed to 10° to 15°C and maintained at this temperature until monitoring by HPLC indicates the reaction is substantially complete. The reaction mixture is slowly warmed to 25°C, 160 mL water is slowly added, the temperature is maintained at 25°C and agitated for 5 minutes. The pH is adjusted to about 7.5 to 8.0 with concentrated sulfuric acid (-6.5 mL) and the temperature of the mixture is raised to 40° to 50°C. After phase separation, an organic layer containing a mixture of borate ester (XVI), boric acid ester (XVII) or PPD is treated with ion exchange resins as described in Example 1.