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WO1994006737A1 - Procede de preparation de felbamate, 2-phenyl-3-propanediol et intermediaires - Google Patents

Procede de preparation de felbamate, 2-phenyl-3-propanediol et intermediaires Download PDF

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Publication number
WO1994006737A1
WO1994006737A1 PCT/US1993/008450 US9308450W WO9406737A1 WO 1994006737 A1 WO1994006737 A1 WO 1994006737A1 US 9308450 W US9308450 W US 9308450W WO 9406737 A1 WO9406737 A1 WO 9406737A1
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Prior art keywords
ppd
ester
phenyl
acid ester
alkyl
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PCT/US1993/008450
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Inventor
Derek Walker
Esther Babad
Chou-Hong Tann
David J. S. Tsai
Daw-Long Kwok
Kimberly Ann Belsky
Louie J. Herczeg
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Merck Sharp and Dohme LLC
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Schering Corp
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Priority to AU51593/93A priority Critical patent/AU5159393A/en
Priority to PCT/US1994/001587 priority patent/WO1994027941A1/fr
Priority to AU67653/94A priority patent/AU6765394A/en
Priority to MYPI94000482A priority patent/MY134492A/en
Publication of WO1994006737A1 publication Critical patent/WO1994006737A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
    • C07C29/12—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of mineral acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/26—Polyhydroxylic alcohols containing only six-membered aromatic rings as cyclic part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/022—Boron compounds without C-boron linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids

Definitions

  • Felbamate known as 2-phenyl-1 ,3-propanediol dicarbamate, shown below
  • CH CH H 2 OCONH 2 (l) is a potent antiepileptic compound useful for treating various types of epilepsy.
  • Felbamate is described in U.S. Patent 2,884,444 and 4,978,680.
  • the compound 2-phenyl-1 ,3-propanediol (PPD) is a valuable intermediate for preparing felbamate, but there are problems in commercial operation due to safety considerations during manufacturing, high expenses associated with its preparation, environmental and waste disposal problems, and generally low yields achieved by known processes.
  • PPD of formula (XVIII) can be converted to 2- phenyl-1 ,3-propanediol dicarbamate (felbamate) by methods, such as those described in U.S. Patent 4,868,327, 5,091 ,595 and B.J. Ludwig et al., J. Med. Chem., Vol. 12(3), 1969, pp. 462-472 using environmentally undesirable halogenated solvents such as chloroform and halogenated acids such as trifluoroacetic acid and trichloroacetic acid.
  • the present invention is directed toward a process for preparing 2- phenyl-1 ,3-propanediol (PPD), comprising: reacting a compound which is: i) the enolate salt of (VIII)
  • M is a cation, such as a metal of Groups I, II or III in the periodic table, titanium or ammonium;
  • R is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, arylalkyl, substituted arylalkyl, heterocyclic, heterocyclic alkyl, aryl or substituted aryl;
  • X, Y and Z independently represent H, -OH, -0-M+, -O-R 2 or -OCOR 2 where M is as defined hereinabove, R 2 is C-1 to C-6 alkyl; with an acid and a borohydride reducing agent in an amount effective to give PPD.
  • the present invention is directed toward a process for preparing 2-phenyl-1,3-propanediol (PPD-XVIII), comprising cleaving, optionally in the presence of an acid, a compound which is: v) a borate ester (XVI)
  • v-vi a mixture of v-vi); 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, R 2 is C-1 to C-6 alkyl, and with the proviso that in the borate ester (XVI), X and Y together can represent a diester of the formula:
  • borate ester (XVI), boric acid ester (XVII) or a mixture thereof can be cleaved by distillation or by extraction of the boron-moiety from the borate ester (XVI), boric acid ester (XVII) or mixture thereof.
  • the boron-moiety can be cleaved by transesterification and distillation of volatile borates formed therefrom.
  • the boron-moiety can be cleaved by extracting the borate ester (XVI), boric acid ester (XVII) or mixture thereof with water and a suitable organic solvent.
  • the present process further comprises the step of converting the 2-phenyl-1 ,3-propanediol (PPD) from any of the above intermediates, routes or processes to 2-phenyl-1 ,3-propanediol dicarbamate (felbamate).
  • PPD 2-phenyl-1 ,3-propanediol
  • the enolate salt of formyl phenyl acetic acid ester (VIII) is prepared by contacting an ester of phenyl acetic acid (II) with an ester of formic acid (IV) in the presence of a base of the formula:
  • MA (VI) wherein M is a cation, such as a metal of Groups I, II or III in the periodic table, titanium or ammonium; and wherein A is an anion which enables MA to function as a base, to give the enolate salt of formylphenylacetic acid ester (VIII).
  • M is a cation, such as a metal of Groups I, II or III in the periodic table, titanium or ammonium
  • A is an anion which enables MA to function as a base, to give the enolate salt of formylphenylacetic acid ester (VIII).
  • the ester of phenylacetic acid (II) is methyl phenyl acetate
  • the base is sodium methoxide
  • the ester of formic acid (IV) is methyl formate.
  • the present invention is directed toward novel boron-containing intermediates such as tropate borate (XV), borate ester (XVI) and a boric acid ester (XVII).
  • the present invention is directed toward a process for preparing felbamate, comprising contacting 2-phenyl-1 ,3- propanediol with either a) a cyanate and dry, gaseous hydrogen chloride or bromide in a non- halogenated solvent which can provide felbamate in a yield of about 70% or greater in the reaction mixture; or b) chlorosulfonyl isocyanate in a suitable solvent.
  • the present invention is directed toward a process for preparing felbamate which comprises converting the hydroxy groups of PPD to -OCONH2 characterized in that the PPD used as a starting material is produced using any of the procedures described above.
  • the present invention has the advantage of providing a process for preparing felbamate and PPD having reduced chemical handling and disposal problems, thus minimizing impact upon the environment. And still yet another advantage of the present process is that the conversion of the starting materials and intermediates thereof to PPD can be accomplished at high process throughput in a continuous process sequence suitable for the automated production of both felbamate and PPD. Such high process throughput or automated production can significantly reduce manufacturing costs.
  • alkyl - represents a straight chain saturated hydrocarbon moiety having from 1 to 10, 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, hexoxy and the like.
  • cycloalkyl - represents a saturated carbocyciic 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 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 -
  • chlorinated hydrocarbons include chloroform, carbon tetrachloride, chlorobenzene and trifluoromethane.
  • halo - represents fluoro, chloro, bromo or iodo
  • heterocyclic - represents a cyclic group having at least one O, S and/or N interrupting a carbocyciic 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],
  • boron-moiety - refers to the moiety of borate ester (XVI), boric acid ester (XVII) or a mixture thereof containing a boron atom, whose cleavage or removal from the borate ester (XVI), boric acid ester (XVII) or a mixture thereof gives PPD .
  • M is a cation, such as a metal of Groups I, II or III in the periodic table such as sodium, potassium, lithium, calcium, magnesium, zinc or aluminum, or M is titanium or ammonium;
  • R is alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, arylalkyl, substituted arylalkyl, heterocyclic, heterocyclic alkyl, aryl, substituted aryl and X, Y and Z independently represent H, -OH, -0'M + , -O-R 2 or -OCOR 2 wherein M is as defined above, and R 2 is C-1 to C-6 alkyl.
  • the wavy line " * w " indicates that the substituents can form either the cis or trans configurations about the double bond.
  • the brackets ([ ]) indicate intermediates which are generally not,
  • the above process can be performed via several routes.
  • route A the enolate salt of formylphenylacetic acid ester (VIII) is contacted first with an acid and then with the borohydride reducing agent to give PPD.
  • Route B the enolate salt of formylphenylacetic acid ester (VIII) is contacted first with the borohydride reducing agent and then with acid to give PPD.
  • the enolate salt is methyl 2-formyl-2-phenyl acetate sodium salt.
  • Route C tropate (XIII) is contacted with borohydride, optionally in the presence of an acid, to give PPD.
  • borate esters (XVI) and boric acid esters (XVII) are cleaved, optionally in the presence of an acid, to give PPD.
  • the acid is sulfuric acid or acetic acid and the reducing agent is sodium borohydride or potassium borohydride.
  • Tropate borates (XV), borate esters (XVI) and boric acid esters (XVII) useful for preparing PPD (XVIII) are provided in Tables 1 , 2 and 3, respectively. It should be appreciated that such compounds can also form the more complex polyborate esters. able 1. Tropate borates (XV)
  • PPD can be prepared by contacting the enolate salt of formyl phenyl acetic acid ester (VIII) with an acid and a borohydride reducing agent in an amount effective to reduce both the aldehyde and the ester moiety.
  • the reactants can be mixed in different orders of addition.
  • enolate salt (VIII) is contacted with a suitable acid to a form a product which can exist in an equilibrium of compounds (X), (XII) or (XIV), which can be isolated where desired.
  • enolate salt (VIII) can be admixed with a borohydride reducing agent prior to addition of the acid.
  • Acids which can be employed in the present process include any suitable mineral, organic acid or mixtures thereof.
  • Suitable mineral acids include sulfuric, hydrochloric, phosphoric, boric and the like.
  • Suitable organic acids include acetic, citric, formic, maleic, tartaric, methanesulfonic and the like.
  • the acid can be neat or admixed with an organic solvent or water.
  • the acids can be employed in amounts effective to protonate enolate salt (VIII). Such amounts can range from about equimolar to excess per mole of enolate salt (VIII), preferably from about equimolar to about two moles of acid.
  • Borohydrides which can be employed in the present process include sodium, potassium, lithium, calcium, zinc and magnesium borohydrides, preferably sodium or potassium, and modified borohydrides prepared by partial reaction of a borohydride with a protic solvent.
  • the borohydride reducing agent can be employed in amounts effective to reduce both the aldehyde and the ester moiety of either enolate salt (VIII), E-enol (X), Z-enol (XII) or formyl phenylacetic acid ester (XIV).
  • Such amounts can range from about equimolar to excess borohydride per mole of enolate salt (VIII), preferably from about 1.1 to about two moles borohydride, preferably from about 1.3 to about 1.7.
  • the term "excess" means an amount of borohydride in excess of the theoretical amount needed to reduce both the aldehyde and the ester moiety of either enolate salt (VIII) or aldehyde enol
  • the process can be carried out in a solvent compatible with the borohydride reducing agent.
  • solvents include protic solvents such as water, C-1 to C-10 alcohols including methanol, ethanol, propanol, isopropanol, butanol and the like.
  • Aprotic solvents such as tetrahydrofuran, toluene, ethers including methyl tertiary butyl ether and diethylether or esters of C-1 to C-5 carboxylic acids including formic, acetic and propionic. Mixtures of any of the above solvents can be employed.
  • 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 30°C. Also preferred is that the reactants are contacted at ambient pressures, although pressures greater than ambient can be employed.
  • the reactants can be contacted for a time sufficient to allow the desired completion of the reaction, such as from one to 24 hours or more, preferably from about 2 to 8 hours.
  • PPD can be converted to felbamate by transesterification with an appropriate ester carbamate.
  • PPD can also be converted to felbamate by reacting PPD with phosgene to form a bis chloroformate, or by reacting PPD with a phenyl chloro formate (Ph-OCOCI) to form a bis carbonate, followed by treatment with ammonia.
  • Ph-OCOCI phenyl chloro formate
  • PPD can be advantageously, and most economically, converted to felbamate via our new process which uses a cyanate and a strong acid in a non-halogenated solvent.
  • the reaction mixture can be maintained at a temperature ranging from about -20°C to the boiling point of the reaction mixture, preferably from about -15°C to about 50°C, more preferably about -10°C to about 40°C, most preferably about -5°C to about 35°C.
  • Suitable cyanates include cyanates and isocyanates of the formula: Tn+(NCO) n - (XXII) wherein T is hydrogen or a cation, such as a metal of Groups I, II or III in the periodic table, titanium or ammonium and n (the valency) can be an integer from 1 to 10, preferably n is 1 to 4.
  • Representative 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 ).
  • the amount of cyanate can range from about 2 to about 10 moles of cyanate per mole of PPD, preferably from about 2 to about 4 moles, more preferably from about 2 to about 2.5 moles of cyanate.
  • Suitable strong acids include inorganic acids and organic acids. Strong inorganic acids are hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, perchloric acid and mixtures thereof. Strong organic acids include methanesulfonic acid and arylsulfonic acids of the formula ArS03H, wherein Ar is aryl such as phenyl or substituted phenyl, including tolyl, nitrophenyl, xylyl, and the like.
  • the amount of the strong acid can range from about equimolar to about 2 moles of acid per mole of cyanate, preferably from about 1.05 to about 1.3 moles of acid.
  • the acid contains less than 50% water, more preferably less than 5%.
  • non- halogenated solvents include but are not limited to N- dialkylacetamide(C ⁇ - 6 alkyl); acetonitrile; dimethyl sufoxide (DMSO); 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 that effective to solubilize the PPD reactant to slightly or greatly excessive amounts and provide felbamate in a yield of about 70% or greater.
  • the yield of felbamate in the reaction mixture can be measured by HPLC or by any other suitable means. The table below demonstrates the pronounced effect of the solvent upon yield of felbamate under comparable ratios of reactants.
  • PPD can also be converted to felbamate with our new procedure using a blocked or masked isocyanate, ie. R 3 NCO where R 3 is a readily removable protecting group, selected from a silyl group, e.g.
  • felbamate can be converted from PPD which is still wet or moist with solvents, without the need to further process and dry the
  • reaction mixture is heated at 50-55° for 30 minutes and vacuum distilled to remove ethanol at a temperature of less than 60°C to give an in-solution yield of PPD of greater than 90%, based upon the enolate salt starting material.
  • the residual product is taken up in 200 mL of ethyl acetate, washed with 100 mL water, 100 mL saturated sodium bicarbonate and 100 mL saturated brine, dried over sodium sulfate and the solvent removed under vacuum.
  • the product can be further purified by charging crude felbamate (100 g) to a reaction flask, adding methanol (1.2 L, 12 volumes) and heating the product to reflux to effect solution. The hot solution is filtered and some of the methanol is stripped off to give a final volume of about 650 mL. The batch is cooled to ambient temperatures, cooled to 0-5°C for about 2 hours, the product is filtered, washed with methanol (100 mL, one volume) and dried between 30-60°C to give purified felbamate, (85% yield).
  • the ice bath is removed after complete addition of glacial acetic acid and the reaction mixture is stirred at room temperature until the sodium enolate has reacted, as determined by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the reaction mixture is warmed to 45°C until all the methyl tropate intermediate has reacted.
  • the reaction mixture is cooled to 10°C and water (250 mL) is slowly added. Caution is advised, since quenching excess sodium borohydride is exothermic and generated hydrogen gas may foam.
  • the pH is adjusted to 13 with 50% sodium hydroxide (40 mL) and isopropanol is atmospherically distilled at 81 °C. After distillation is complete, the slurry is cooled to 40°C and adjusted to pH to 4 with 6N sulfuric acid (290 mL).
  • the yield of PPD in solution, as determined by HPLC, is greater than 90%.
  • Tert-butyl methyl ether (200 mL) is charged to the reaction slurry, the resultant solution is transferred to a 2 liter separatory funnel. The layers are separated, the aqueous layer is washed with tert-butyl methyl ether (300 mL) and combined with the organic layer. Additional PPD can be recovered from the aqueous layer with multiple extractions of tert-butyl methyl ether. The combined organic layers are washed with 50% potassium carbonate solution (200 mL) and shaken until a precipitate of potassium carbonate forms. Water (60 mL) is added to dissolve most of the salts and the layers are separated. If needed, the pH of the aqueous layer is adjusted to 11 with 50% potassium carbonate solution.
  • the organic layers are concentrated to an oil by rotovap distillation and residual tert-butyl methyl ether is chased by adding toluene (50 mL) and concentrating the solution on high vacuum rotovap distillation.
  • the yield of the crude oil is 51 g, including residual toluene.
  • Toluene (100 mL) is charged to the crude oil, heated to 65°C and the hot toluene solution containing PPD is filtered.
  • the methyl 2-formyl-2-phenylacetate sodium salt (VIII) is protonated to a mixture of E-alpha-hydroxymethylene-phenylacetic acid methyl ester (X), Z-alpha-hydroxymethylene-phenylacetic acid methyl ester (XII) and formylphenylacetic acid methyl ester (XIV).
  • This mixture (X, XII and XIV) converts in-situ to methyl tropate borate (XV).
  • the temperature is maintained at -15°C to -10°C. Nitrogen gas is used to blanket the exothermic reaction, which evolves hydrogen gas.
  • the reaction mixture is gently agitated for one hour.
  • the reaction mixture is warmed to about 9°C and agitated overnight.
  • the methyl tropate borate (XV) is further converted to the borate esters (XVI) of PPD by reaction with the borohydrides present in the reaction mixture.
  • Water (16 liters) is charged to the reaction mixture containing a mixture of borate esters (XVI) and the pH is adjusted between about 4.8 and 5.2 with concentrated hydrochloric acid to give a mixture of boric acid esters (XVII) and PPD (XVIII), as determined by proton nuclear magnetic resonance (NMR) spectral analysis.
  • the reaction mixture is azeotropically distilled to remove the isopropanol and water, and the concentrated mixture is cooled to 20°C.
  • the concentrated mixture containing 2-phenyl- 1 ,3-propanediol or PPD (XVIII) and boric acid esters (XVII) is extracted with three, 32 liter portions of methyl tert-butyl ether.
  • the combined methyl tert-butyl ether extracts are washed with two, 32 liter portions of aqueous potassium carbonate (40%) to further convert the boric acid esters (XVII) to PPD (XVIII).
  • the organic layer is again washed with aqueous potassium carbonate.
  • the combined aqueous potassium carbonate washes are back extracted with methyl tert-butyl ether.
  • the combined organic layer containing PPD (XVIII), is concentrated to a volume of about 8 liters to which toluene (56 liters) is added.
  • the mixture is distilled to remove residual tert-butyl ether and water.
  • the concentrated mixture is filtered at 60°C, then cooled at 5°C.
  • the precipitated PPD is filtered, washed with chilled toluene and dried in a vacuum oven with a nitrogen bleed at 30°C to give 6.4 kilograms (76% yield, +99% purity) of 2-phenyl-1 ,3-propane diol (PPD-XVIII). Recovery of PPD from the mother liquors increases the yield.
  • the mixture is cooled to 0° to 5°C.
  • Sodium borohydride (0.38 g, 0.01 mole) is charged in several portions at 0° to 5°C. Nitrogen gas is used to blanket the exothermic reaction, which evolves hydrogen gas.
  • the reaction mixture is stirred at 0° to 5°C for 15 minutes.
  • the reaction mixture is concentrated with rotovap at 18°C to produce 1.08 g (96% yield) of the title tropate borate (XV), a solid.
  • acetic acid 2.7 mL, 0.047 mole is slowly charged to the reaction mixture to produce a mixture of borate esters (XVI).
  • the reaction temperature is maintained at -5° to 0°C. Nitrogen gas is used to blanket the exothermic reaction, which evolves hydrogen gas.
  • isopropanol (20 mL) is charged to the thick reaction mixture at 5° to 10°C.
  • Water (50 mL) is charged to the reaction mixture containing a mixture of borate esters (XVI).
  • the pH is adjusted to 7.2 with 6N sulfuric acid (5.5 mL) to give a mixture of boric acid ester (XVII) and PPD (XVIII).
  • the reaction mixture is azeotropically distilled to remove isopropanol and water.
  • the concentrated mixture is cooled to 45°C and extracted with n-butanol (30 mL) at 40° to 45°C. After phases separation, the aqueous layer is extracted again with n-butanol (20 mL).
  • boric acid ester (XVII, 17.8 g, 0.10 mole), methanol (53.4 mL) and sulfuric acid (0.1 mL). The mixture is heated to azeotropically distill methanol and trimethyl borate. During the distillation, boric acid ester (XVII) is slowly converted to PPD (XVIII). The distillation is repeated until boric acid ester is converted to >95% PPD, based upon analysis by 1 H-NMR. Toluene (89.0 mL) is added and the mixture is distilled to a final volume of about 70 mL to remove residual methanol. The concentrated mixture is cooled at 10-15°C to crystallize the PPD (XVIII). The mixture is filtered, washed with toluene and dried in a vacuum oven with a nitrogen bleed at 30°C to give 14.99 g (98% yield) of PPD (XVIII).
  • reaction mixture is cooled to -5 to 0°C and slowly added to a precooled (-5-0°C) mixture of 160 mL water and 40 mL of 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 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 200 mL 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.
  • the reaction mixture is monitored by HPLC for completion. The reaction mixture is warmed to 10 to 15°C.
  • reaction mixture is then maintained at 10 to 15°C until monitoring of the reaction mixture by HPLC indicates a conversion of methyl tropate to 2-phenyl-1 ,3- propanediol (PPD), leaving ⁇ 3% unreacted methyl tropate.
  • HPLC 2-phenyl-1 ,3- propanediol
  • the reaction mixture is slowly warmed to 25°C, 320 mL water is slowly added, the temperature is maintained at 25°C and agitated for 5 minutes.
  • the pH is adjusted to about 7.2 with concentrated sulfuric acid ( ⁇ 6.5 mL) and the temperature of the mixture is raised to 40°C.
  • the aqueous layer is extracted again with 80 mL n-butanol (solution yield of PPD is ⁇ 90%).
  • the combined butanol extracts are charged with 80 mL water and the pH is adjusted to about 2.2 with concentrated sulfuric acid ( ⁇ 1 mL) to give a mixture of boric acid esters and PPD.
  • the organic layer is washed with 40 mL water.
  • the n-butanol layer is concentrated to give an oil containing a mixture of boric acid esters and PPD.
  • Methanol 160 mL is charged to the oil, concentrated, and distillation of 160 mL methanol is repeated.
  • the filter cake is charged to 3.4 L of water, the pH of the mixture is adjusted to 2-2.5 with 2 N hydrochloric acid and the mixture is gently refluxed at 100°C for 5 hours. After cooling, the resultant heterogeneous solution is filtered. The wet cake is washed with two washings of 0.5 liter water and dried under vacuum with a nitrogen bleed at 100°C to give 214 g (90% overall yield) of purified felbamate (>99% purity).
  • 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 MX (VI) to give the enolate salt of formyl phenyl acetic acid ester (VIII):
  • R is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, aralkyl, substituted aralkyl, heterocyclic, heterocyclic alkyl, aryl or substituted aryl;
  • R 1 can represent the same values as R or another group capable of forming a leaving group R 1 0-, e.g., trimethylsilyl;
  • M is a cation, such as a metal of Groups I, II or III in the periodic table, titanium or ammonium;
  • A is an anion which enables MX to function as a base, i.e., a hydride, alkoxide, amide or like moiety.
  • R and R 1 are methyl and MX is sodium methoxide.
  • the process can be carried out under conditions effective to yield the enolate salt of formylphenylacetic acid ester (VIII), such as described in Chemical Abstract 75(a): 63435q.
  • the process for preparing the enolate salt (VIII) can be carried out neat or in the presence of any suitable organic solvent.
  • suitable organic solvents include aprotic solvents inert to the base used such as hydrocarbons, such as toluene, benzene and xylenes, or ethers such as diethylether, methyl tertiary butyl ether and the like. Where a base is employed, however, it is not essential that the base is soluble in the organic solvent.
  • 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.
  • Preparative Example 1 Methyl 2-formyl-2-phenyl acetate sodium salt
  • Sodium methoxide (32.4 g, 0.6 mole) is added to 300 mL toluene. Small amounts of methanol and water are removed by azeotropic distillation. The mixture is cooled to 40-45°C and contacted with methyl phenyl acetate (45.1 g, 0.3 mole). The mixture is stirred for about 10 minutes at 45-50°C and methyl formate (19.8 g, 0.33 moles) is added. The temperature of the exothermic reaction is maintained at a temperature less than or equal to 50°C by the rate of addition of methyl formate. As the reaction progresses a heavy precipitate forms.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de felbamate et d'un intermédiaire clé, le 2-phényl-1,3-propanediol (PPD). On peut préparer du PPD par mise en contact (i) du sel d'énolate d'ester d'acide formylphénylique (VIII), (ii) d'un E-énole (X), d'un Z-énole (XII) ou d'un ester d'acide formylphénylacétique (XIV), (iii) d'un tropate (XIII), (iv) d'un borate de tropate (XV) ou de leurs mélanges avec un acide et un agent réducteur d'hydrure de bore en quantité efficace pour obtenir du PPD. Dans un autre mode de réalisation, on peut également préparer du PPD par dédoublement, éventuellement en présence d'un acide, (v) d'un ester de borate (XVI), (vi) d'un ester d'acide borique (XVII) ou de leurs mélanges. On peut préparer le felbamate à partir de PPD à l'état sec ou humide par réaction avec soit (a) un cyanate et un acide fort dans un solvant non halogéné, soit (b) un isocyanate de chlorosulfonyle dans un solvant approprié.
PCT/US1993/008450 1992-09-18 1993-09-14 Procede de preparation de felbamate, 2-phenyl-3-propanediol et intermediaires Ceased WO1994006737A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU51593/93A AU5159393A (en) 1992-09-18 1993-09-14 Process for preparing felbamate, 2-phenyl-1,3-propanediol and intermediates
PCT/US1994/001587 WO1994027941A1 (fr) 1993-05-25 1994-02-18 Procede de preparation du felbamate et de ses intermediaires
AU67653/94A AU6765394A (en) 1993-05-25 1994-02-18 Process for preparing felbamate and intermediates thereto
MYPI94000482A MY134492A (en) 1993-05-25 1994-03-01 Process for preparing felbamate and intermediates thereto

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US94731292A 1992-09-18 1992-09-18
US07/947,312 1992-09-18
US6507593A 1993-05-25 1993-05-25
US08/065,075 1993-05-25

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1156798A4 (fr) * 1999-02-09 2002-07-17 Univ Virginia Composes derives du felbamate
WO2005074531A3 (fr) * 2004-01-30 2007-01-18 Semequip Inc Procedes de synthese de borohydrure et boranes enrichis de maniere isotope
US7884227B2 (en) 2007-10-26 2011-02-08 Navinta Llc Felbamate with improved bulk density
US9233898B2 (en) 2010-09-07 2016-01-12 Taro Pharmaceutical Industries Ltd. Process for the preparation of 2-phenyl-1,3-propanediol
WO2021233976A1 (fr) 2020-05-19 2021-11-25 Consorzio Interuniversitario Nazionale Per La Reattivita' Chimica E La Catalisi Procédé de synthèse d'oméga-hydroxy-uréthanes, d'alpha-oméga-diuréthanes et d'oligo (poly)uréthanes exempts d'isocyanate

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104151340B (zh) * 2014-07-30 2017-01-18 河南师范大学 一种二吡唑基硼酸盐‑k[(c3n2h3)2bc8h14]的制备方法

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US5091595A (en) * 1989-06-07 1992-02-25 Choi Young M Reduction of diethyl phenylmalonate to 2-phenyl-1,3-propanediol
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1156798A4 (fr) * 1999-02-09 2002-07-17 Univ Virginia Composes derives du felbamate
US6599935B2 (en) 1999-02-09 2003-07-29 University Of Virginia Patent Foundation Felbamate derived compounds
US6759402B2 (en) 1999-02-09 2004-07-06 University Of Virginia Patent Foundation Cyclic felbamate derived compounds
WO2005074531A3 (fr) * 2004-01-30 2007-01-18 Semequip Inc Procedes de synthese de borohydrure et boranes enrichis de maniere isotope
US7641879B2 (en) 2004-01-30 2010-01-05 Semequip Inc. Methods of synthesis of isotopically enriched borohydride and methods of synthesis of isotopically enriched boranes
US8084007B2 (en) 2004-01-30 2011-12-27 Semequip Inc. Methods of synthesis of isotropically enriched borohydride and methods of synthesis of isotropically enriched boranes
US7884227B2 (en) 2007-10-26 2011-02-08 Navinta Llc Felbamate with improved bulk density
US9233898B2 (en) 2010-09-07 2016-01-12 Taro Pharmaceutical Industries Ltd. Process for the preparation of 2-phenyl-1,3-propanediol
WO2021233976A1 (fr) 2020-05-19 2021-11-25 Consorzio Interuniversitario Nazionale Per La Reattivita' Chimica E La Catalisi Procédé de synthèse d'oméga-hydroxy-uréthanes, d'alpha-oméga-diuréthanes et d'oligo (poly)uréthanes exempts d'isocyanate

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CN1092759A (zh) 1994-09-28
AU5159393A (en) 1994-04-12

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