Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D307/32—Oxygen atoms
  • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C327/00—Thiocarboxylic acids
  • C07C327/20—Esters of monothiocarboxylic acids
  • C07C327/22—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
  • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
  • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/06—Pyrimidine radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

• the invention relates to the art of organic chemistry. Specifically it relates to certain ⁇ , ⁇ -d fluoro- ⁇ -hydroxy thiol esters and processes to make them. ⁇ , ⁇ -D ⁇ fluoro- ⁇ -hydroxy thiol esters are useful as intermediates in organic syntheses of valuable pharmaceutical products.
• R 1 is selected from the group consisting of H, C1-C4 alkyl, substituted alkyl, including silyl alkyl, t ⁇ alkyl- silyl, aryl, substituted aryl, including silyl aryl
• R 2 is independently selected from alkyl and aryl groups
• Q is either S (for thiol esters) or 0 (for esters) .
• II (ID gemcitabine hydrochloride (II), a known anti-neoplastic agent .
• existing methods to make compounds of formula I where R 1 is S ⁇ R 3 R 4 R 5 , R 2 is R 6 , Q is S, and R 3 , R 4 , R 5 and R 6 are independently selected from C1-C4 alkyl and C5-C6 aryl groups are known in the art. See U.S. Patent 5,428,176 .
• the processes to make compounds of formula (I) as described in the '176 patent require a t ⁇ alkyl(or triaryl) silylhalide and the use of a catalyst.
• a first aspect of this invention is ⁇ , ⁇ -Difluoro- ⁇ - hydroxy thiol esters of formula (III) (III) wherein:
• R c and R ⁇ are independently selected from the group consisting of H, C3 . -C6 alkyl, substituted Ci-C ⁇ alkyl,
• R e is selected from the group consisting of Ci-Cirj alkyl, substituted C1.-C10 alkyl, aryl, substituted aryl, C3- C ⁇ cycloalkyi, C3-C8 cycloalkenyl, substituted C3-C8 cycloalkyi and substituted C3-C8 cycloalkenyl, Cg-Cio fused aromatic rings, and substituted Cg-Cio fused aromatic rings.
• a second aspect of this invention is a difluoroethanethioate compound of formula (IV) :
• R n is selected from the group consisting of C3-C8 cycloalkenyl and substituted C3-C8 cycloalkenyl.
• a third aspect of this invention is a process to make ⁇ , ⁇ -difluoro- ⁇ -hydroxy thiol esters of formula (IIIA), (IIIA) wherein:
• R 1 and R k are independently selected from the group consisting of H, Ci-Cg alkyl, substituted C -C ⁇ alkyl, S- tert-butyl difluorothioacet-2-yl, C3-C8 cycloalkyi, C3-C8 cycloalkenyl, substituted C3-C8 cycloalkyi, substituted C3-C8 cycloalkenyl, aryl, substituted aryl, 1 , 3-dioxolan-4-yl, substituted 1, 3-dioxolan-4-yl, C -C ⁇ o fused aromatic rings, substituted C ⁇ -Cio fused aromatic rings; or
• R 1 and R ⁇ together make up a ring selected from the group consisting of C3-C8 cycloalkyi, C3-C8 cycloalkenyl, substituted C3-C8 cycloalkyi, and substituted C3-C8 cycloalkenyl;
• R e is selected from the group consisting of C ⁇ -C ⁇ o alkyl, substituted C ⁇ -C ⁇ o alkyl, aryl, substituted aryl, C3-C8 cycloalkyi, C3-C8 cycloalkenyl, substituted C3-C8 cycloalkyi, and substituted C3-C8 cycloalkenyl, C ⁇ -Cio fused aromatic rings, and substituted Cg-Cio fused aromatic rings; comprising reacting a difluoroethanethioate of formula (IVA)
• a fourth aspect of this invention is a process to make gemcitabme hydrochloride, the improvement characterized m that the lactone intermediate, 2-deoxy-2 , 2-difluoro-D- erythro-pentofuranose-l-ulose-3 , 5-dibenzoate:
• alkyl by itself or as part of another substituent means a monovalent compound having the stated number of carbon atoms containing only carbon and hydrogen, and which my be straight or branched chain.
• the term is exemplified by compounds containing from 1 to 10 carbon atoms, such as, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl (t-butyl) , n-pentyl, iso-pentyl, n-hexyl, isohexyl, heptyl, octyl, nonyl and decyl; "C1-C4 alkyl” refers to alkyl compound of from 1-4 carbon atoms. "C1.-C6 alkyl” refers to alkyl compounds of from 1-6 carbon atoms. “C1-C10" alkyl refers to alkyl compounds of from 1-10 carbon atoms.
• substituted means one to three hydrogens on the structure have been replaced with a like number of moieties independently selected from the group consisting of bromo, chloro, lodo, fluoro, C ⁇ -C ⁇ rj alkyl, Ci-C ⁇ alkoxy, -COOH, ammo or hydroxyl, with the proviso that any substituted structure must be so configured that it is sterically feasible, affords a stable structure and is capable of reacting as described herein.
• C1-C6 alkoxy refers to monovalent structures of the formula -O- (C ⁇ -C6 alkyl) .
• Alkoxy includes, but is not limited to, methoxy (-OCH3), ethoxy (-OCH2CH3), propoxy (-OCH2CH2CH3) , butoxy(-OCH2CH2CH2CH3 ) , pentoxy (-OCH2CH2CH2CH3) and hexoxy(-OCH2CH2CH2CH2CH2CH2CH3) .
• a ring must contain one or more groups of atoms in a cyclic array that contains clouds of delocalized ⁇ electrons above and below the plane of the atoms; furthermore, the ⁇ clouds must contain a total of (4q+2) ⁇ electrons, where q is any positive integer.
• aryl refers to: any 5 or 6 membered aromatic ring that will afford a stable structure containing all carbon atoms; or containing carbon atoms and: one or two nitrogen atoms; one sulfur atom; one oxygen atom; one nitrogen and one sulfur atom; one oxygen atom and one sulfur atom; or one nitrogen and one oxygen atom.
• the 5-membered ring has one or two double bonds and the 6-membered ring has two or three double bonds. Examples of aryl structures are:
• C -C10 fused aromatic rings refers to two fused aromatic rings that have at least six and at most ten carbon atoms in the rings. Fused aromatic rings are monovalent, with the bond to the rest of the structure being attached to any available ring carbon. Fused aromatic rings are carbocyclic or contain from one to four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
• Fused aromatic rings are configured as follows: when there are six carbon atoms present in the rings, there are at least four heteroatoms m the rings and all of these heteroatoms are nitrogen; when there are seven carbon atoms present in the rings, there are at least three heteroatoms present in the rings, only one of which may be sulfur; when there are eight carbon atoms present in the rings there are at least two heteroatoms, which may be the same or different, present in the rings; when there are n ne carbon atoms in the ring, there may or may not be one heteroatom in one of the rings; and when there are ten carbon atoms in the rings there are no heteroatoms in the rings.
• Examples of some "C6 ⁇ C ⁇ o fused aromatic rings" include, but are not limited to, the following structures:
• the solid bond that becomes a dotted line bond present in the above structures indicates that the bond can be attached to any available carbon in any ring that the solid-dotted line intersects.
• C3-C8 cycloalkyi refers to saturated carbocyclic ring structures containing from 3 to 8 carbon atoms.
• Examples of some “C3-C.8 cycloalkyi” rings include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• C3-C8 cycloalkenyl refers to carbocyclic ring structures containing from 3 to 8 carbon atoms and one double bond.
• C3-C8 cycloalkenyl rings examples include, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
• halo refers to bromo, iodo, fluoro and chloro.
• Preferred ⁇ , ⁇ -Difluoro- ⁇ -hydroxy thiol esters compounds of Formula (III) are selected from the group consisting of:
• Preferred difluoroethanethioate compounds of formula (IV) are selected from the group consisting of:
• S-cyclohexen-4-yl difluoroethanethioate S-cyclohepten-1-yl difluoroethanethioate; S-cyclohepten-3-yl difluoroethanethioate; S-cyclohepten-4-yl difluoroethanethioate; S-cyclohepten-5-yl difluoroethanethioate; S-cycloocten-1-yl difluoroethanethioate, • S-cycloocten-3-yl difluoroethanethioate; S-cycloocten-4-yl difluoroethanethioate and S-cycloocten-5-yl difluoroethanethioate.
• the first step in the process of the present invention to make the ⁇ , ⁇ -difluoro- ⁇ -hydroxy thiol esters of the present invention is the synthesis of a difluoroethanethioate of Formula (IVA) .
• a preferred method to synthesize a difluoroethanethioate of Formula (IVA) is as follows:
• Step 1 At a temperature of between about 20°C and about 100°C, under a suitable inert atmosphere such as nitrogen, argon or neon, add difluoroacetic acid or difluoroacetic anhydride dropwise to a solution of chloride containing compound in an aprotic solvent .
• the chloride containing compound may be any compound that will, under suitable conditions, release chloride to form an acid chloride.
• Suitable chloride containing compounds include oxaloyl chloride, thionyl chloride, phosgene, phosphorous oxychloride, phosphorous trichloride and phosphorous pentachloride.
• the preferred chloride containing compound is oxaloyl chloride.
• Any aprotic solvent may be used; for example: acetonitrile, tetrahydrofuran, dichloromethane, toluene, glyme and xylene are all useful.
• a preferred aprotic solvent is acetonitrile.
• the temperature selected depends upon the choice of chloride containing compound and solvent with about 25°C being suitable when oxaloyl chloride in acetonitrile is used. From the beginning of the reaction, and at any time thereafter, a catalytic amount of a suitable Lewis acid catalyst may be added.
• a suitable Lewis acid catalyst is cobalt (II) chloride. The use of a catalyst in this process is optional .
• Step 2 Allow the reactants of step 1 to react from between one and ten hours.
• the overall reaction time is dependent upon temperature with the higher temperatures having the faster reaction times.
• R e is tert-butyl
• the suitable thiol is 2-methyl-2-propanethiol.
• a "sufficient amount" is at least one molar equivalent based upon the difluoro starting material.
• Step 3 Stir reaction mixture for a sufficient amount of time.
• a sufficient amount of time could be any time up to 24 hours.
• the temperature of the reaction mixture can be anywhere between about 20°C and about 100°C with 25°C being the preferred reaction temperature.
• Step 4 Perform a standard workup using standard techniques.
• One such workup is as follows: Pour the reaction mixture over a suitable water immiscible solvent such as diethyl ether (Et2 ⁇ ) and then wash with a suitable basic aqueous solution such as saturated sodium bicarbonate (NaHC03) in water.
• a suitable water immiscible solvent such as diethyl ether (Et2 ⁇ )
• a suitable basic aqueous solution such as saturated sodium bicarbonate (NaHC03) in water.
• the reaction mixture divides into two layers with the desired product contained in the organic layer.
• the mostly aqueous layer containing the undesired material is separated and discarded in an environmentally sound manner.
• the layer containing the desired product is dried over a suitable drying reagent such as sodium sulfate ( a2S04) .
• a2S04 sodium sulfate
• the substituted difluoroethanethioate may be kept either at room temperature or, more preferred, kept in a refrigerator at a temperature below 25°C until it is needed.
• the substituted difluoroethanethioate (IVA) is used to begin the process to make the ⁇ , ⁇ -difluoro- ⁇ -hydroxy thiol esters (IIIA) of the instant invention.
• the preferred substituted difluoroethanethioate for the synthesis of gemcitabme hydrochloride is S-tert butyl difluoroethanethioate.
• One synthetic route to ⁇ , ⁇ -d ⁇ fluoro- ⁇ -hydroxy thiol esters is to react a substituted difluoroethanethioate (IV) with a second reactant selected from the group consisting of aldehydes, ketones, acid halides and esters m a solvent and in the presence of a strong base; with the proviso that the process is conducted in the absence of a catalyst and the absence of a silyl containing compound.
• the aldehyde or ketone is of formula (V) :
• R a and R are independently selected from the group consisting of H, C ⁇ -C6 alkyl, substituted C ⁇ -C6 alkyl, C3-C8 cycloalkyi, substituted C3-C8 cycloalkyi, C3-C8 cycloalkenyl, substituted C3-C8 cycloalkenyl, aryl, substituted aryl, 1,3- d ⁇ oxolan-4-yl, substituted 1, 3-d ⁇ oxolan-4-yl, C -C10 fused aromatic rings and substituted C6-C10 fused aromatic rings, or R a and R together make up a ring selected from the group consisting of C3-C8 cycloalkyi, substituted C3-C8 cycloalkyi, C3-C8 cycloalkenyl and substituted C3-C8 cycloalkenyl.
• the acid halides are of formula (VI)
• esters are of formula (VII!
• R f and R9 are independently R e , where R e has the same definition as before.
• aldehydes ketones, acid halides and esters are as follows.
• the synthesis involves reacting a difluoroethanethioate (IVA) with a second reactant (of formula V, VI or VII) m a solvent, in the presence of a strong base; with the proviso that the process is conducted in the absence of a catalyst and in the absence of a silyl containing compound.
• IVA difluoroethanethioate
• second reactant of formula V, VI or VII
• the preferred order of addition or reagents is to first add the substituted difluoroethanethioate to the solvent, then add the strong base and allow the three components to react for a sufficient length of time before adding the second reactant to the reaction mixture.
• this synthesis is preferably conducted under a suitable inert atmosphere such as nitrogen, argon or neon.
• Suitable solvents for the synthesis include hydrocarbons, nitriles and ethers. These solvents include, but are not limited to, toluene, xylene, glyme, tetrahydrofuran, acetonitrile, hexane, heptane, diethyl ether and many other solvents of the general class. The most preferred solvent for this reaction is toluene.
• the strong base is any suitable strong base such as amides, alkoxides and hydrides. Suitable strong bases include lithium diisopropylamide (LDA) , lithium hexamethylsilazide, triethylamine, pyridme and n-butyl lithium.
• LDA lithium diisopropylamide
• the preferred solvent is LDA.
• the sufficient length of time for the substituted difluoroethanethioate, solvent and strong base to react is anywhere between about thirty seconds and about 1 hour. A preferred length of time is about 2 minutes. if desirable, the reaction mixture is capable of being stabilized at this point, preferably by keeping it at a temperature below 25°C, and held indefinitely until needed.
• the temperature of the substituted difluoro- ethanethioate/solvent mixture is lowered to between at least about -100°C and about 25°C prior to the addition of the strong base.
• the preferred temperature is about -78°C.
• the reaction is allowed to precede at about the same temperature for between about five minutes and about 24 hours.
• the reaction mixture may be warmed to about room temperature (about 25°C) .
• the reaction can be quenched by addition of a suitable quenching agent, such as, phosphate buffer.
• a suitable quenching agent such as, phosphate buffer.
• ⁇ , ⁇ -difluoro- ⁇ -hydroxy thiol esters of the claimed invention can be useful as intermediates in organic syntheses of valuable pharmaceutical products.
• nucleosides including pharmaceutically acceptable salts of nucleosides, with said nucleosides, and pharmaceutically acceptable salts of said nucleosides, having utility as pharmaceutical products.
• nucleoside is gemcitabme hydrochloride:
• Example 2 General Process to Make ⁇ , ⁇ -difluoro- ⁇ -hydroxy thiol esters using S-tert butyl difluoroethanethioate as a starting material
• S-tert butyl difluoroethanethioate (VIII) (0.152 mL, 1.00 mmol) from Example 1 in toluene (10 mL) at -78 °C was added dropwise over 1 min LDA (0.550 mL of 2.0 M solution m heptane/THF/ethylbenzene, 1.10 mmol) .

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• 1996
  • 1996-12-09 CA CA002239891A patent/CA2239891A1/en not_active Abandoned
  • 1996-12-09 JP JP9522225A patent/JP2000501738A/ja active Pending
  • 1996-12-09 AU AU12896/97A patent/AU1289697A/en not_active Abandoned
  • 1996-12-09 EP EP19960308899 patent/EP0779275A2/en not_active Withdrawn
  • 1996-12-09 WO PCT/US1996/019867 patent/WO1997021719A1/en not_active Ceased

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