Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/42—One nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/30—Halogen atoms or nitro radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/34—One oxygen atom
  • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical

Definitions

• This invention relates to a method for preparing 2-substituted 6-amino-5-chloro- 4-pyrimidinecarboxylate esters and to pyrrolidines useful as process intermediates in the method.
• the present invention relates to a method for preparing a compound of Formula 1,
• R 1 is cyclopropyl, 4-chlorophenyl or 4-bromophenyl; and R 2 is C1-C14 alkyl; comprising contacting a compound of Formula 2
• Another aspect of the present invention relates to the aforesaid method further comprising preparing the compound of Formula 2 by contacting a compound of Formula 3 with ammonia.
• Another aspect of the present invention relates to the aforesaid method further comprising preparing the compound of Formula 3 by contacting a compound of Formula 4
• dehydroxylating-chlorinating agent selected from phosphorus oxychloride and thionyl chloride in the presence of A ⁇ f-dimethylformamide.
• Another aspect of the present invention relates to the aforesaid method further comprising preparing the compound of Formula 4 by contacting a compound of Formula 5
• R is NH 2 , Cl or OH; X is H or Cl; R 1 is cyclopropyl, 4-chlorophenyl or
• R 2 is C1-C24 alkyl; provided that when R is NH2 or Cl, then X is Cl; which are useful as process intermediates in the aforedescribed method.
• compositions comprising, “comprising,” “includes,” “including,” “has,” “having” or any other variation thereof, are intended to cover a non-exclusive inclusion.
• a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.
• “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
• alkyl includes straight-chain or branched alkyl, such as, methyl, ethyl, ⁇ -propyl, /-propyl, or the different butyl, pentyl or hexyl isomers.
• Combining chemicals refers to contacting the chemicals with each other.
• Formula 6 embraces Formulae 3, 4 and 5. That is when R is NH2, and X is Cl, then Formula 6 is equivalent to Formula 3. When R is OH and X is Cl, then Formula 6 is equivalent to Formula 4. When R is OH and X is H, then Formula 6 is equivalent to Formula 5.
• references to Formulae 4 and 5 in the present disclosure and claims are to be construed to include all tautomers, including Formulae 4a and 5a, respectively.
• the nitrogen atom in the compounds of Formulae 2, 3 and 4 (including 4a) can be protonated, allowing said compounds to form acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
• Embodiments of the present invention include: Embodiment Al .
• Embodiment A2 A method for preparing a compound of Formula 1 wherein R 1 is 4-chlorophenyl or 4-bromophenyl.
• Embodiment A3 A method for preparing a compound of Formula 1 wherein R 2 is
• Embodiment A4 A method of Embodiment A3 wherein R 2 is C1-C3 alkyl. Embodiment A5. A method of Embodiment A4 wherein R 2 is methyl.
• Embodiment Bl A method for preparing the compound of Formula 1, comprising contacting a compound of Formula 2 with a persulfate oxidant in the presence of a strong sulfur- or phosphorus-containing mineral acid. Embodiment B2. A method of Embodiment Bl wherein the persulfate oxidant comprises an ammonium or alkali metal cation. Embodiment B3. A method of Embodiment B2 wherein the persulfate oxidant comprises ammonium persulfate. Embodiment B4. A method of Embodiment B2 wherein the persulfate oxidant comprises potassium persulfate.
• Embodiment B5 A method of Embodiment B2 wherein the persulfate oxidant comprises potassium peroxymonosulfate.
• Embodiment B 6 A method of Embodiment B2 wherein the persulfate oxidant comprises sodium persulfate.
• Embodiment B 7. A. method of Embodiment Bl wherein the molar ratio of the persulfate in the persulfate oxidant to the compound of Formula 2 is in a range of about 1 to about 3.
• Embodiment B8 A method of Embodiment B7 wherein the molar ratio is in a range of about 1.1 to about 2.2.
• Embodiment B9 A method of Embodiment B9 wherein the strong sulfur- or phosphorus-containing mineral acid is sulfuric acid.
• Embodiment BIl A method of Embodiment Bl wherein the molar ratio of the strong sulfur- or phosphorus-containing mineral acid to the compound of Formula 2 is in a range of about 1 to about 3.
• Embodiment B 12 A method of Embodiment BIl wherein the molar ratio is in a range of about 1.1 to about 2.2.
• Embodiment B 13 A method of Embodiment Bl wherein the contacting is performed in the presence of an oxidation resistant solvent.
• Embodiment B 14. A method of Embodiment B13 wherein the oxidation resistant solvent is an alkane nitrile-.
• Embodiment B 15. A method of Embodiment B 14 wherein the oxidation resistant solvent is acetonitrile or propionitrile.
• Embodiment Bl 6. A method of Embodiment B15 wherein the oxidation resistant solvent is acetonitrile.
• Embodiment B 17 A method of Embodiment Bl wherein the compound of Formula 2 is contacted with the persulfate oxidant at a temperature in a range of about 0 to about 40 0 C.
• Embodiment B 18. A method of Embodiment B17 wherein the temperature is in a range of about 25 to about 35 °C.
• Embodiment Cl A method of Embodiment Bl further comprising preparing the compound of Formula 2 by contacting a compound of Formula 3 with ammonia.
• Embodiment C2 A method of Embodiment Cl wherein the molar ratio of ammonia to the compound of Formula 3 is at least about 2. Embodiment C3. A method of Embodiment C2 wherein the molar ratio of ammonia to the compound of Formula 3 is in a range of about 2 to about 20. Embodiment C4. A method of Embodiment C3 wherein the molar ratio of ammonia to the compound of Formula 3 is in a range of about 5 to about 15. Embodiment C5. A method of Embodiment Cl wherein the contacting is performed in an non-acidic organic solvent
• Embodiment C6 A method of Embodiment C5 wherein the non-acidic organic solvent comprises an ether, alcohol or aromatic solvent.
• Embodiment C7 A method of Embodiment C6 wherein the non-acidic organic solvent comprises at least one of tetrahydrofuran, />-dioxane, methanol, ethanol,
• Embodiment C8 A method of Embodiment C7 wherein the non-acidic organic solvent comprises ethanol.
• Embodiment C9 A method of Embodiment Cl wherein the ammonia is at a pressure above atmospheric pressure.
• Embodiment ClO. A method of Embodiment C9 wherein the pressure above atmospheric pressure is between about 100 to about 1000 kPa.
• Embodiment Cl 1. A method of Embodiment ClO wherein the pressure above atmospheric pressure is between about 200 and about 500 kPa.
• Embodiment C12. A method of Embodiment Cl wherein the compound of Formula 3 is contacted with ammonia at a temperature in a range of about 0 to about 40 0 C and then the temperature is raised to a range of about 60 to about 100 °C.
• Embodiment Cl 3. A method of Embodiment C12 wherein the contacting is at a temperature in a range of about 10 to about 30 °C and then the temperature is raised to a range of about 70 to about 80 0 C.
• Embodiment Dl A method of Embodiment Cl further comprising preparing the compound of Formula 3 by contacting a compound of Formula 4 with a dehydroxylating-chlorinating agent selected from phosphorus oxychloride and thionyl chloride in the presence of iV,N-dimethylformamide.
• Embodiment D2 A method of Embodiment D 1 wherein the dehydroxylating- chlorinating agent is phosphorus oxychloride.
• Embodiment D3. A method of Embodiment Dl wherein the molar ratio of the dehydroxylat ⁇ ig-chlorinating agent to the compound of Formula 4 is in a range of about 1 to about 1.5.
• Embodiment D3 wherein the molar ratio of the dehydroxylating-chlorinating agent to the compound of Formula 4 is in a range of about 1.1 to about 1.3.
• Embodiment D5. A method of Embodiment Dl wherein the contacting is performed in an aprotic solvent.
• Embodiment D6. A method of Embodiment D5 wherein the aprotic solvent comprises at least one solvent selected from haloalkanes, haloalkenes, halobenzenes, toluene, xylenes and N,N-dimethylformamide.
• Embodiment D7 Embodiment D7.
• a method of Embodiment D6 wherein the aprotic solvent comprises at least one solvent selected from dichloromethane, 1,2-dichloroethane, chlorobenzene, toluene and ⁇ ,N-dimethylfo ⁇ namide.
• Embodiment D8 A method of Embodiment D7 wherein the aprotic solvent comprises toluene.
• Embodiment D9. A method of Embodiment Dl wherein the compound of Formula 4 is contacted with the dehydroxylating-chlorinating agent at a temperature in a range of about -5 to about 40 0 C.
• Embodiment DlO A method of Embodiment D9 wherein the compound of Formula 4 is contacted with the dehydroxylating-chlorinating agent at about ambient temperature.
• Embodiment El A method of Embodiment Dl further comprising preparing the compound of Formula 4 by contacting a compound of Formula 5 with a chlorinating agent.
• Embodiment E2 A method of Embodiment El wherein the chlorinating agent is selected from the group consisting of (a) a combination of elemental chlorine and an alkali metal salt of a carboxylic acid, and (b) sodium hypochlorite.
• Embodiment E3. A method of Embodiment E2 wherein the chlorinating agent is a combination of elemental chlorine and an alkali metal salt of a carboxylic acid.
• Embodiment E4. A method of Embodiment E3 wherein the wherein the contacting is performed in the presence of a carboxylic acid.
• Embodiment E5. A method of Embodiment E4 wherein the chlorinating agent is a combination of elemental chlorine, sodium acetate and acetic acid.
• Embodiment E6. A method of Embodiment E2 wherein the chlorinating agent is sodium hypochlorite.
• Embodiment E7. A method of Embodiment E6 wherein the contacting is performed in a solvent that comprises a mixture of water and at least one solvent selected from alcohols, carboxylic acids, haloalkanes, haloalkenes, halobenzenes, toluene and xylenes.
• Embodiment E8 A method of Embodiment E7 wherein the solvent comprises a mixture of water and toluene, methanol or acetic acid.
• Embodiment E9 A method of Embodiment El wherein the molar ratio of chlorinating agent to the compound of Formula 5 is in a range of about 0.98 to about 2.
• Embodiment ElO A method of Embodiment E3 wherein the molar ratio of elemental chlorine to the compound of Formula 5 is in a range of about 0.98 to about 1.00.
• Embodiment El 1. A method of Embodiment E3 wherein the molar ratio of the alkali metal salt of the carboxylic acid to the compound of Formula 5 is in a range of about 1 to about 1.2.
• Embodiment E12. A method of Embodiment El wherein the compound of Formula 5 is contacted with the chlorinating agent at a temperature in a range of about 20 to about 35 °C.
• Embodiment El 3 A method of Embodiment El 2 wherein the compound of Formula 5 is contacted with the chlorinating agent at a temperature in a range of about 25 to about 35 0 C.
• Embodiment Fl A compound of Formula 6 or a salt thereof wherein R is NH2, Cl or OH; X is H or Cl; R 1 is cyclopropyl, 4-chlorophenyl or 4-bromophenyl; and R 2 is C 1 -C 14 alkyl, provided that when R is NH 2 or Cl 5 then X is Cl.
• Embodiment F2. A compound of Embodiment F 1 wherein R is NH 2 .
• Embodiment F3. A compound of Embodiment Fl wherein R is Cl.
• Embodiment F4 A compound of Embodiment Fl wherein R is OH.
• Embodiment F5 A compound of Embodiment Fl wherein R is NH 2 , Cl or OH, and X is Cl.
• Embodiment F6 A compound of any one of Embodiments Fl to F5 wherein R 1 is cyclopropyl.
• Embodiment F7 A compound of any one of Embodiments Fl to F5 wherein R 1 is
• Embodiment F8 A compound of Embodiment F7 wherein R 1 is 4-chlorophenyl.
• Embodiment F9 A compound of Embodiment F7 wherein Rl is 4-bromophenyl.
• Embodiment FlO A compound of any one of Embodiments Fl to F5 wherein R 2 is
• Embodiment Fl 1 A compound of Embodiment FlO wherein R 2 is Cj- C3 alkyl.
• Embodiment F12. A compound of Embodiment FlO wherein R 2 is methyl.
• Persulfate oxidant refers to an oxidant containing persulfate.
• persulfate (alternatively spelled persulphate) ion is believed to have the chemical structural formula ⁇ OS(O) 2 OOS(O) 2 O 8 .
• reagents containing persulfate i.e. persulfate oxidants
• persulfate oxidants are generally salts, typically comprising ammonium or an alkali metal as the cation.
• commercially available persulfate oxidants include ammonium persulfate, potassium persulfate, potassium peroxymonosulfate (e.g., OXONE®) and sodium persulfate. Ammonium persulfate works particularly well for the present method.
• a strong sulfur- or phosphorus-containing mineral acid is used in the present method to promote the oxidation reaction.
• Strong sulfur- or phosphorus-containing mineral acids refers to acids containing sulfur or phosphorus but not carbon and having a pK a of less than 3.
• Examples of strong sulfur- or phosphorus-containing mineral acids include sulfur acid and phosphoric acid.
• Sulfuric acid which is available at low cost, works well for the present method. Both the persulfate and the acid are usually used in a molar ratio of in a range of about 1 (i.e. 1:1) to 3 (i.e. 3:1) relative to the substrate, with a molar ratio in a range of about 1.1 to 2.2 preferred.
• a compound of Formula 2 is contacted with the persulfate oxidant in the presence of a strong sulfur- or phosphorus-containing mineral acid and an oxidation resistant solvent.
• oxidation resistant solvent refers to solvents that resist oxidation, particularly by persulfate oxidants.
• the reaction of the present method works particularly well in alkane nitrile solvents, such as, but not limited to, acetonitrile or propi ⁇ nitrile. Acetonitrile gives excellent results and is preferred for reasons including cost and availability. .
• the reaction can be conducted in a temperature range of about 0 to about 40 °C, with the range of about 25 to about 35 °C preferred.
• Compounds of Formula 2 can be isolated by conventional methods such as dilution with water, extraction or crystallization and the like, all of which are well known to one skilled in the art. This method is illustrated in Example 7 below.
• alkoxy moieties in compounds of Formula 1 may undergo facile exchange (J. March, Advanced Organic Chemistry, 3rd Ed, Wiley). This transformation can be used to provide compounds of Formula 1 with different R 2 groups if desired. This method is illustrated in Example 8 below.
• Compounds of Formula 2 can be prepared by treatment of compounds of Formula 3 with ammonia, as illustrated in Scheme 2.
• the reaction generates hydrogen chloride as a byproduct, which binds with ammonia to form ammonium chloride salt.
• ammonia can be formed in situ by contact of ammonium salts such as ammonium chloride or ammonium sulfate with bases, the method is most simply and inexpensively conducted by using at least two molar equivalents of ammonia (one molar equivalent to form the compound of Formula 2 and the other molar equivalent to react with the hydrogen chloride formed). Larger amounts of ammonia increase the speed of reaction.
• the compounds of Formula 3 are thus contacted with ammonia, generally about 2 to about 20 molar equivalents with about 5 to about 15 molar equivalents being preferred, typically in a sealed vessel.
• This amination method is generally conducted in a solvent (i.e. amination solvent), which can comprise one or more of a wide variety of nonacidic organic solvents, for example, ether, alcohol or aromatic solvents.
• amination solvent can comprise tetrahydrofuran, j3-dioxane, methanol, ethanol, r ⁇ -propanol, isopropanol, r ⁇ -butanol, sec-butanol, toluene or xylenes, with ethanol being preferred.
• the reaction can be conducted between about 60 and about 100 0 C and at a pressure of about 100 to about 1000 kPa to provide an effective concentration of ammonia in the amination solvent.
• a preferred procedure involves adding the compound of Formula 3 to the amination solvent containing ammonia at a temperature in a range of about 0 to about 40 0 C (preferably about 10 to about 30 0 C) and then raising the temperature to a range of about 60 to about 100 °C (preferably about 70 to about 80 °C) to effect the reaction. After removal of the inorganic byproducts the product can be isolated by conventional techniques such as extraction, chromatography or crystallization. This method is illustrated by Example 6 below.
• a dehydroxylating-chlorinating agent such as thionyl chloride or more preferably phosphorus oxychloride, is added to a compound of Formula 4 in the presence of iV j iV-dimethylformamide.
• the transformation is usually carried out in at least one additional aprotic solvent such as, but not limited to, dichloromethane,
• the reaction can be conducted in a temperature range of about -5 to about 40 °C. After the initial addition of the chlorinating agent at about -5 to about 0 0 C, the reaction mixture is preferably warmed to about ambient temperature (e.g., about ⁇ 5-A0 °C). After the reaction is complete the reaction mixture is added to aqueous base to consume excess dehydroxylating-chlorinating agent and neutralize acidic byproducts, and the product is isolated by conventional procedures such as distillation, crystallization and the like. This method is illustrated by Example 5 below.
• Chlorination can be achieved in a number of ways, such as by chlorination with elemental chlorine or by use of a reagent such as sodium hypochlorite.
• a compatible solvent When chlorine is used, a compatible solvent must be employed, as well as a base to remove hydrogen chloride formed in the reaction.
• the base used with chlorine is an alkali metal carboxylate.
• the solvent used with the chlorinating agent comprising chlorine and an alkali metal carboxylate is typically a carboxylic acid, often the carboxylic acid corresponding to the alkali metal carboxylate. For reasons of cost and convenience, sodium acetate is a preferred alkali metal carboxylate and acetic acid is a preferred carboxylic acid for this method.
• the rate of chlorine addition and the temperature of the reaction mixture should be carefully controlled.
• the total amount of chlorine added should be as close to 1 molar equivalent relative to the compound of Formula 5 as practical. Typically the measured amount of chlorine corresponds to 1.00 molar equivalents, or very slightly less (e.g., 0.98 molar equivalents) to ensure that excess chlorine is not added.
• the rate of chlorine addition should be such that the temperature of the reaction can be maintained in the range about 20 to about 35 °C, preferably in the range of about 25 to about 35 °C.
• the quantity of the base e.g., alkali metal carboxylate, should be sufficient to absorb the hydrogen chloride generated, and typically is about 1 to about 1.2 molar equivalents. This method is illustrated by Example 4 below.
• chlorination solvents such as alcohols, carboxylic acids, haloalkanes, halobenzenes and unhalogenated aromatic hydrocarbons (e.g., toluene, xylenes).
• Preferred solvents include toluene, methanol and acetic acid.
• the reaction is conducted at ambient temperature (e.g., about 20-35 °C).
• Compounds of Formula 5 can be prepared by combination of a carboximidamide hydrochloride of Formula 7, an ester of a dialkoxy acetate of Formula 8, an ester of acetic acid of Formula 9, and an alkali metal alkoxide base as shown in Scheme 5.
• Compounds of Formula 8 and Formula 9 are added to an alkali metal alkoxide (i.e. MOR 2 ) such as sodium or potassium methoxide, ethoxide, 1-propoxide, 2-propoxide or t-butoxide in a suitable solvent such as toluene, chlorobenzene or heptane.
• MOR 2 alkali metal alkoxide
• the alcohol (R 2 OH) formed is removed by distillation.
• a sufficient excess of the compound of Formula 9 must be used such that at least one molar equivalent relative to the compound of Formula 8 remains available for the reaction after the alcohol R 2 OH is removed by distillation, possibly involving azeotropes comprising R 2 OH, the Formula 9 compound and/or solvent.
• This step provides the sodium salt of the Claisen condensation product of the compounds of Formula 8 and Formula 9 as an intermediate, which is then condensed with the carboximidamide of Formula 7. Preparation of the Claisen condensation product is illustrated by Example 2 below.
• Example 3 Methods for the preparation of amidines of Formula 7 and their salts are well known in the art; see, for example, J. Chem. Soc. 1950, 1603 and Japanese patent publication JP 2004/359609. A method of preparation is illustrated by Example 1 below.
• Ethyl cyclopropanecarboximidate monohydrochloride (40.5 g 0.27 mol) was added portionwise to a saturated solution of ammonia in ethanol (50 mL). A further portion of ethanol (33 mL) was added. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in ethanol to give the title composition (83 mL).
• Example 2 A portion (-40.4 mL) of the ethanol solution of cyclopropanecarboximidamide monohydrochloride as prepared in Example 1 was added to a portion (-210 mL) of the solution of the sodium salt of ethyl 4,4-diethoxy-3-oxobutanoate as prepared in Example 2. The mixture was allowed to stir overnight at room temperature. The mixture was boiled for about 2 h and then allowed to cool to room temperature. The mixture was evaporated under reduced pressure, and the residue was redissolved in toluene (200 mL). A solution of ammonium chloride (0.68 g, 12.7 mmol) in water (30 mL) was added. After stirring for 10 minutes, the aqueous phase was removed. The organic phase was dried and evaporated to leave the product as pale yellow solid (27.27 g, 88 % yield). Product recrystallized from hexanes melted at 111.5-112.0 °C.
• Ethanol 190 mL was saturated with ammonia.
• 4,5-Dichloro-2-cyclopropyl- 6-(diethoxymethyl)pyrimidine i.e. the product of Example 5
• the mixture was warmed to 75 °C, and the pressure was maintained at 40 psi (276 kPa). After 8 h at this temperature and pressure the mixture was allowed to cool to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and then filtered.
• the filtrate was evaporated under reduced pressure, and the residue was taken up in hexanes to crystallize the product as an off-white solid (19.97 g, 85 % yield).
• the product recrystallized from hexanes had a melting point of 104.5-109.5 °C.
• 6-(diethoxymethyl)-4-pyrimidinamine i.e. the product of Example 6) (2.71 g, 10 mmol) in acetonitrile (27.5 mL) at room temperature. The temperature rose to 35 °C. When the mixture had cooled to 29 °C ammonium persulfate (0.5 g, 2.21 mmol) was added in one portion. After stirring for 20 h at room temperature the mixture was poured into saturated aqueous sodium bicarbonate solution (100 mL). The mixture was extracted with ethyl acetate (2 x 70 mL). The combined extracts were dried and evaporated to leave the product as an off-white solid (1.32 g, 55 % yield). Product purified by chromatography on silica gel

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