GB2356862A - Chlorination of hydroxymethylfurans with thionyl chloride and diisopropylethylamine - Google Patents

Abstract

Chloromethylfurans of general formula (II), in which Z is an optionally substituted 5- to 7-membered carbocylic or nitrogen-containing heterocyclic ring which includes the two carbon atoms of the adjacent furan ring, R<SP>1</SP> is a standard substituent and R<SP>2</SP> and R<SP>3</SP> are hydrogen, C<SB>1</SB>-C<SB>4</SB> alkyl or halogenated C<SB>1</SB>-C<SB>4</SB> alkyl, are prepared by reacting the corresponding hydroxymethylfuran with thionyl chloride and diisopropylethylamine. Use of diisopropylethylamine produces chloromethylfurans in higher yields and of greater purity than those produced using other proton scavengers such as pyridine, triethylamine and diisopropylamine. The chloromethylfuran may be 2-chloromethylbenzofuran. The chloromethylfurans may be used as intermediates in the synthesis of HIV protease inhibitors which are useful for treating HIV infections and AIDS.

Description

20' 2356862 TITI-E OF THE INVENTION PROCESS FOR PREPARING CHLOROALKYL

FURANS

FIELD OF THE INVENTION

The present invention relates to processes for preparing 2-chloromethylfurans by chlorination of the corresponding 2hydroxymethylfurans.

The 2-chloromethylfurans can be employed as intermediates in the production of HIV protease inhibitors, which are useful in the treatment of infection by MV and in the treatments of AIDS and ARC.

References are made throughout this application to various published documents in order to more fully describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference in their entireties.

BACKGROUNI) OF TEE INVENTION A retrovirus designated human immunodeficiency virus (IHE[V) is the etiological agent of a complex disease that includes progressive destruction of the immune system (AIDS) and degeneration of the central and peripheral nervous system. Recently, a number of EffV protease inhibitor compounds have been disclosed as being useful in the treatment of infection by IIIV and in the treatment of AIDS. Among them are the compounds described in US 5646148, including compounds which may be described as benzofuranylmethylated and pyridofuranylmethylated derivatives of the following penultimate, referred to herein as Compound 4:

HN OH H PH 0 NHC(CH3)3 0 4 In particular, the compound N-(2(R)-hydroxy-I(S)-indanyl)-2(R)- phenylmethyl-4(S)hydroxy-5-(I-(4-(2-benzo[b]furanylmethyl)-2(S)-N-(t-butylcarboxamido)20'-9 piperazinyl))pentaneamide, disclosed in Example 3 of US 5646148 and referred to herein as Compound 5, is a potent inhibitor of FHV protease and is useful in the treatment of infection by FHV and in the treatment of AIDS and ARC without significant side effects or toxicity.

Protease inhibitor compounds can be made by alkylating Compound 4 with a suitable chloromethylfuran. Compound 5, for example, can be prepared by alkylating 4 with 2-chloromethylbenzofuran. Chloromethylfurans can be prepared by reaction of the corresponding hydroxymethylfuran with thionyl chloride. For example, Reichstein et al., Helv. Chim. Acta 1932, 15: 249-253 disclose the reaction of 2-hydroxymethyl-5-methylfuran and thionyl chloride in ether and in the presence of pyridine to obtain 2-chloromethyl-5-methylfuran. As another example, Gaertner et al., J. Am. Chem. Soc. 1951, 73: 4400- 4404, disclose the preparation of 2 chloromethylbenzofuran by heating a mixture of 2-benzofurylcarbinol, thionyl chloride, and toluene under reflux. As still another example, Dann et al., Liebigs Ann.

Chem. 1982, 10: 1836-1869 disclose preparations of 5- and 6-cyano-2 chloromethylbenzofuran by the reactions of 5- and 6-cyano-2-hydroxymethyl benzofuran respectively with thionyl chloride at ambient temperature in ether in the presence of pyridine. As a final example, WO 98/54178 discloses (see Example 4 therein) the preparation of 2-chloromethylbenzofuran by the reaction of 2-hydroxymethylbenzofuran dissolved in methylene chloride with thionyl chloride at 22'C.

Applicants have found that the known processes for chlorinating hydroxymethy1furans using SOC12 are not attractive for the scaled-up production of chloromethylfurans. The known processes produce chloromethylfurans at yields and levels of purity which would require a costly and difficult recovery and purification prior to use of the chloromethylfuran for the production of protease inhibitors (e.g., by alkylation with Compound 4).

Applicants have developed a new, improved process for the preparation of chloromethylfurans which involves reacting hydroxymethy1furan with SOC12 in the presence of diisopropylethylamine (DIEA). Compared to known processes, the improved process of the present invention can provide a chloromethy1furan product at a higher yield and with higher purity in a relatively short reaction time.

20' -9 SUMMARY OF THE INVENTION

The present invention is directed to an improved process for preparing chloromethylfurans. More specifically, the present invention is a process for preparing a compound of Formula (11):

R1 ( Z 1 0 1 C1 R 3 R 2 which comprises reacting a compound of Formula (I):

R 0 1 OH R 3 R (D with thionyl chloride in a solvent and in the presence of diisopropylethylamine to obtain the compound of Formula (H); wherein R1 is hydrogen, halogen, cyano, nitro, Cl-C6 alkyl, halogenated Cl-C6 alkyl, Cl.-C6 alkoxy, halogenated Cl-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, halogenated C2-C8 alkoxyalkyl, (CH2)0-4COORa, (CH2)0-4C(=O)Ra, (CH2)0-4N(RaRb), (CH2)0-4C(=O)N(RaRb), (CH2)0-4SO2Ra, aryl, or substituted aryl; wherein each substituent on substituted aryl is independently halogen, cyano, nitro, C1-C6 alkyl, halogenated Cl-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, Cl.-C6 alkoxy, halogenated CI-C6 alkoxy, (CH2)0-4CO2Ra, (CH2)0-4C(=O)N(RaRb), (CH2)0-4SO2Ra, C2-C8 alkoxyalkyl, or halogenated C2-C8 alkoxyalkyl; Z is a ring which includes the two carbon atoms from the adjacent furan. ring and which is a C5-C7 carbocyclic, ring or a 5to 7-membered heterocyclic ring containing 2V carbon atoms and one or two nitrogen atoms, wherein the ring is aromatic or non aromatic and is unsubstituted or substituted with one or more of halogen, cyano, nitro, C I -C6 alkyl, halogenated C I -C6 alkyl, C 1 -C6 alkoxy, halogenated C 1 -C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, halogenated C2-C8 alkoxyalkyl, (CH2)0-4COORa, C(=O)Ra, N(RaRb), (CH2)0-4C(=O)N(RaRb), (CH2)0-4SO2Ra, or aryl; R2 and R3 are each independently hydrogen or CI-C4 alkyl; and Ra and Rb are each independently C 1 -C4 alkyl or halogenated C I -C4 alkyl.

Embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.

DETAM,ED DESCRIPTION OF TIHE INVENTION

The present invention includes a process for preparing chloromethylfurans by reacting the corresponding hydroxymethylfurans, with thionyl chloride in the presence of DIEA. One embodiment of the present invention is the process is as defined above, except that the compound of Formula (1) has the following definition:

RI is hydrogen, halogen, cyano, nitro, Cl-C4 alkyl, halogenated Cl-C4 alkyl, Cl-C4 alkoxy, halogenated Cl-C4 alkoxy, C3-C7 cycloalkyl, halogenated C3-C7 cycloalkyl, C2-C8 alkoxyalkyl, halogenated C2-C8 alkoxyalkyl, (CH2)0-2COORa, (CH2)0-2C(=O)Ra, (CH2)0-2N(RaRb), (CH2)0-2C(=O)N(RaRb), (CH2)0-2SO2Ra, phenyl, or substituted phenyl; wherein each substituent on substituted phenyl is independently halogen, cyano, nitro, C 1 -C4 alkyl, halogenated C 1 -C4 alkyl, C3-C7 cycloalkyl, halogenated C3-C7 cycloalkyl, C 1 -C4 alkoxy, halogenated C I -C4 alkoxy, (CH2)0-2CO2Ra, (CH2)0-2C(=O)N(RaRb), (CH2)0-2SO2Ra, C2-C8 alkoxyalkyl, or halogenated C2-C8 alkoxyalkyl; Z is an aromatic ring which is unsubstituted or substituted with one or more of halogen, cyano, nitro, Cl-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, 2W_ halogenated Cl -C4 alkoxy, C3-C7 cycloalkyl, halogenated C3-C7 cycloalkyl, C2-C8 alkoxyalkyl, halogenated C2-C8 alkoxyalkyl, (CH2)0-2CO0Ra, C(=0)Ra, N(RaRb), (CH2)0-2C(=0)N(RaRb), (CH2)0-2SO2Ra, or phenyl.

R2 and R3 are each independently hydrogen or Cl -C4 alky]; and Ra and Rb are each independently Cl -C4 alkyl or halogenated Cl -C4 alkyl.

Another embodiment of the present invention is a process for preparing a compound of Formula (Ra):

MM R' v 1 n i Cl Y 0 (Ha) which comprises reacting a compound of Formula (1a):

MM R OH Y 0 (Ia); with thionyl chloride in a solvent and in the presence of diisopropylethylamine to obtain the compound of Formula (Ha); wherein Y is N or CX; each X is independently hydrogen, halogen, cyano, nitro, Cl -Q alkyl, fluorinated C 1 -Q alkyl, C 1 -C4 alkoxy, fluorinated C 1 -Q alkoxy, C3 -C6 cycloalkyl, fluorinated C3-C6 cycloalkyl, (CH2)14ORc, or (CH2)140Rd, (CH2)0-2CO0Ra, (CHM-2C(=0)Ra, (CH2)0-2N(RaRb), (CH2)0-2C(=0)N(RaRb), or (CHM-2SO2Ra; 20' R1 is hydrogen, fluorine, chlorine, cyano, nitro, CI-C4 alkyl, (CH2)0- 2CF3, C1-C4 alkoxy, OCF3, OCH2CF3, (CH2)1-40CH3, (CH2)1-20CF3, (CH2)0-2COORa, (CH2)0-2C(=O)Ra, (CH2)0-2N(RaRb), (CH2)0-2C(=O)N(RaRb), (CH2)0-2SO2Ra, or phenyl; Ra and Rb are each independently methyl, ethyl, CF3, or CH2CF3; Rc is methyl or ethyl; Rd is CF3 or CH2CF3; and m is an integer from 0 to 3.

Other embodiments of the present invention include the process as originally defined above or as set forth in either of the preceding embodiments, additionally incorporating one or more of the following features:

thionyl chloride is employed in an amount in the range of from about I to about 10 equivalents per equivalent of the compound of Formula (1); diisopropylethylarnine is employed in an amount in the range of from about 0.5 to about 2 equivalents per equivalent of the compound of Formula (1); the compound of Formula (1) is employed in an amount in the range of from about 0. 1 to about 2 moles per liter of solvent; the reaction is conducted at a temperature in the range of from about -5 to about 50 'C; or the solvent is selected from the group consisting Of C6-CIO aromatic hydrocarbons, halogenated C1-C6 alkanes, halogenated C4-C6 cycloalkanes, C2-C6 alkyl ethers, C2-C6 alkyl ketones, C3-C8 dialkyl carboxylic acid amides, and CI-C6 alkyl acetates.

Still another embodiment of the present invention is a process for preparing Compound 2:

2C'- ") CCO I -- CI 2 which comprises reacting Compound 1:

ao OH 1 with thionyl. chloride in a solvent and in the presence of diisopropylethylamine to obtain Compound 2.

Other embodiments of the present invention include the preceding embodiment, additionally incorporating one or more of the following features:

the solvent is selected from the group consisting Of C6-C 10 aromatic hydrocarbons, halogenated CI-C6 alkanes, halogenated C4-C6 cycloalkanes, C2-C6 alkyl ethers, C2-C6 alkyl ketones, C3-C8 dialkyl carboxylic acid amides, and C I -C6 alkyl acetates; the solvent is isopropyl. acetate; thionyl chloride is employed in an amount in the range of from about 1. 1 to about 5.6 equivalents per equivalent of Compound 1; diisopropylethylamine is employed in an amount in the range of from about 0.7 to about 1. 1 equivalents per equivalent of Compound 1; Compound 1 is employed in an amount in the range of from about 0.3 to about 1.3 moles per liter of solvent; the reaction is conducted at a temperature in the range of from about 0 to about 30 'C; or the reaction time is in the range of from about 0.5 to about 5 hours; A further aspect of the present invention is a process for preparing Compound 2:

Y' ' ro 11-- C3 cl 2 which comprises reacting Compound 1:

OH with thionyl chloride in a solvent and in the presence of diisopropylethylan-iine to obtain Compound 2; wherein thionyl chloride is employed in an amount in the range of from about 1. 1 to about 5.6 equivalents per equivalent of Compound 1; diisopropylethylarnine is employed in an amount in the range of from about 0.7 to about 1. 1 equivalents per equivalent of Compound 1; the solvent is isopropyl acetate; Compound 1 is employed in an amount in the range of from about 0.3 to about 1.3 mole per liter of isopropyl acetate; and the reaction is conducted at a temperature in the range of from about 2 to about 22 T.

Still other embodiments of the present invention include the process as originally defined above and any embodiments or aspects thereof as heretofore defined, further comprising recovering the compound of interest (i.e., Compound II, Compound Ha, or Compound 2).

As used herein, the term "Cl -C6 alkyl" means linear or branched chain alkyl groups having from 1 to 6 carbon atoms and includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, see- and t-butyl, nand isopropyl, ethyl and methyl. "Cl-C4 alkyl" means n-, iso-, see- and t-butyl, n- and isopropyl, ethyl and methyl.

20' -'.

The term "Cl-C6 alkoxy" means an -0-alkyl group whereinalkyl is Cl to C6 alkyl. "Cl-C4 alkoxy" has an analogous meaning; i.e., it is an alkoxy group selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert butoxy, and sec-butoxy.

The term "C2-C8 alkoxyalkyl" means a linear or branched Cl - C6 alkyl group as defined above having as a substituent a Cl -C6 alkoxy group as defined above, wherein the alkoxyalkyl group has a total of from 2 to 8 carbon atoms.

Representative examples of suitable alkoxyalkyl groups include, but are not limited to, the Cl-C6 alkoxy-substituted methyl groups (methoxymethyl, ethoxymethyl, n propoxymethyl, isopropoxymethyl, and the butyloxymethyl, pentyloxymethyl, and hexyloxymethyl isomers), and the C l-C6 alkoxy-substituted ethyl groups. Other suitable alkoxyalkyl groups include the series (CH2)1-60CH3, (CH2)14OCH3, (CH2)1-60CH2CH3, and (CH2)140CH2CH3.

The term "C3-C8 cycloalkyF' means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl). The term "C3-C6 cycloalkyF' refers to a cyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "Q-C6 cycloalkyl" has an analogous meaning.

The term "halogen" (which may alternatively be referred to as "halo") refers to fluorine, chlorine, bromine and iodine (alternatively, fluoro, chloro, bromo, and iodo).

The term "halogenated Cl-C6 alkyl" (which may alternatively be referred to as "C I-C6 haloalkyl") means a Cl to C6 linear or branched alkyl group as defined above with one or more halogen (e.g., fluorine) substituents. The term 'Ialogenated Cl-C4 alkyl" has an analogous meaning. The terms "fluorinated Cl-C6 alkyl" and "fluorinated Cl-C4 alkyl" have the same meaning as the preceding "halogenated" terms, except that the halogen substituent(s) are limited to fluorine.

Representative examples of suitable fluoroalkyls include the series (CH2)04CF3 (i.e., trifluoromethyl, 2,2,2-tiifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.), 1- fluoroethyl, 2 fluoroethyl, 2,2-difluoroethyl, 3,3,3-trifluoroisopropyl, 1,1,1,3,3,3 hexafluoroisopropyl, and perfluorohexyl.

The tenn "halogenated C3-CS cycloalkyl" (which may alternatively be referred to as "C3-C8 halocycloalkyl") means a cycloalkyl group as defined above with one or more halogen substituents. The terms "halogenated C3-C7 cycloalkyF' 2T and "halogenated C3-C6 cycloalkyl" have analogous meanings. The terms Muorinated C3-C8 cycloalkyl", Muorinated C3-C7 cycloalkyP' and "fluorinated C3-C6 cycloalkyl" have the same meaning as the preceding "halogenated" terms, except that the halogen substituent(s) are limited to fluorine. Representative examples of suitable fluorocycloalkyls include all isomers of fluorocyclohexyl (i.e., 1-, 2-, 3-, and 4-fluorocyclohexyl), difluorocyclohexyl (e.g., 2,4- difluorocyclohexyl, 3,4-difluorocyclohexyl, etc.), fluorocyclopentyl, and so forth.

The term 'Ialogenated C I -C6 alkoxy" (which may alternatively be referred to as "C 1 -C6 haloalkoxy") means a C 1 -C6 alkoxy group as defined above wherein the alkyl moiety has one or more halogen substituents. The term "halogenated Cl-C4 alkoxy" has an analogous meaning. The terms "fluorinated Cl C6 alkoxy" and "fluorinated C I -Q alkoxy" have the same meaning as the preceding "halogenated" terms, except that the halogen substituent(s) are limited to fluorine.

Representative examples of suitable fluoroalkoxy groups include the series O(CH2)04CF3 (i.e., trifluorornethoxy, 2,2,2-trifluoroethoxy, 3,3,3trifluoro n-propoxy, etc.), 1,1,1,3,3,3-hexafluoroisopropoxy, and so forth.

The term "halogenated C2-C8 alkoxyalkyP' means C2-C8 alkoxyalkyl as defined above, wherein either or both the alkoxy moiety and the alkyl moiety has one or more halogen substituents. The term "fluorinated C2-C8 alkoxyalkyP' has the same meaning as the preceding "halogenated" term, except that the halogen substituent(s) are limited to fluorine. Representative examples of suitable fluorinated alkoxyalkyl groups include, but are not limited to, the Cl-C6 fluoroalkoxy-substituted methyl groups (e.g., fluoromethoxymethyl, 2-fluoroethoxymethyl, and 3- fluoro-n propoxymethyl), Cl-C6 difluoroalkoxymethyl groups (e.g., difluoromethoxymethyl and 2,2-difluoroethoxymethyl), Cl -C6 trifluoroalkoxy-substituted methyl groups (e.g., trifluoromethoxymethyl and 2,2,2-trifluoroethoxymethyl), Cl-C6 alkoxy substituted fluoromethyl groups (e.g., methoxy- or ethoxy-fluoromethyl), and Cl-C6 alkoxy-substituted difluoromethyl groups (e.g., methoxy- or ethoxydifluoromethyl).

Other suitable fluorinated alkoxyalkyl groups include the series (CH2)160CF3, (CH2)1-40CF3, (CH2)1-60CH2CF3, and (CH2)14OCH2CF3.

The term "aryl" refers herein to aromatic mono- and poly-carbocyclic ring systems, wherein the carbocyclic rings in the polyring systems may be fused or attached via a single ring carbon. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, and biphenylenyl.

20' "Substituted aryl" refers to aryl groups as defined above having one or more substituents independently selected from halogen, cyano, nitro, C I - C6 alkyl, halogenated C I -C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C I -C6 alkoxy, halogenated CI-C6 alkoxy, (CH2)0-4CO2Ra, (CH2)0-4C(=O)N(RaRb), (CH2)0-4SO2Ra, C2-C8 alkoxyalkyl, and halogenated C2-C8 alkoxyalkyl; wherein Ra and Rb are as heretofore defined.

The term "substituted" includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution is chemically allowed.

It is understood that the definition of a substituent (e.g., C02Ra) or variable (e.g., Ra) at a particular location in a molecule (e.g., Compound I) is independent of its definitions at other locations in that molecule. Thus, for example, when R1 is C02Ra = C02Me, and Z is a substituted carbocycle (e.g., benzene) wherein at least one of the substituents is C02Ra, it is understood that C02Ra in Z can be any one of C02Me, C02Et, C02Pr, etc.

It is further understood that substituents and substitution pattems on compounds of Formula (I) are limited to those which provide compounds of Formula (1) that are chemically stable under the reaction conditions employed in the process of the invention and which result in the formation of stable, recoverable compounds of Formula (II). These substituents and substituent patterns can be easily recognized by the person of ordinary skill in the art in view of the description of the process of the invention set forth herein.

Exemplary fused ring furanyl reactants of Formula (1) are the following:

OH H 0 5, 7X ("N' 0 H N OH N 0 209 --.,XOH OH NX> 0 NC'J-0 0 NC \ 0 H C I --- I \N OH -0 N H N OH N -O N 0 OH OH 00 j:L) H3CO 0 H3C H3C The hydroxymethyl substituted fused ring furans of Formula (1) can be prepared by methods known and described in the art. For example, as disclosed in Comprehensive Heterocyclic Chemistry, 4, edited by Katritzky and Rees, Pergamon Press, New York, 1984, p. 697, the alkaline degradation of 3-halo, 4-halo, or 3,4 dihalo cournarins will provide the corresponding cournarilic acids, which can be reduced with lithium aluminum hydride to obtain the corresponding 2- hydroxymethyl benzofurans (see, e.g., Gaertner et al., J. Am. Chem. Soc. 1951, 73: 4400- 4404).

Another example is provided by Saroja et al., Indian J. Chem. 1971, 9: 1316-1318, who disclose refluxing 4-arylcoumarins with mercuric oxide and alkali to obtain the corresponding 3-arylcoumarilic acids, esterification of the acids to the corresponding methyl cournarilates, followed by reduction with LAH to provide the corresponding 2-hydroxymethylbenzofurans. As still another example, Hirota et al., J. Heterocycl.

Chem. 1986, 23: 1715-1716, disclose the preparation of 2-fonnylbenzofurans from the corresponding phenoxyacetaldehyde diethyl acetals by the Vilsmeier reaction (DMF-phosphoryl chloride). The 2-formylbenzofurans so obtained can then be reduced to the corresponding 2-hydroxymethyl derivatives via hydrogenation or via sodium borohydride, as described in Example 2 of WO 98/54178. As still another 20F example, 2-hydroxymethylbenzofuran can be prepared by reaction of 2- iodophenol with propargyl alcohol in the presence of Pd(OAc)2, triphenylphosphine, n-butylamine, and Cul, as described in Example 3 of WO 98/54178.

2-Hydroxymethyl-benzofuran is also available commercially (e.g., from Zeneca).

In the process of the invention, a compound of Formula (H) is prepared by reacting a compound of Formula (I) with thionyl chloride in a solvent and in the presence of DIEA. The reaction is typically conducted by first dissolving DIEA and the compound of Formula (1) in the solvent, and then adding thionyl chloride to the resulting solution. The order of addition of the reactants is not critical, however, and thus the reaction can be conducted by adding Compound I and DIEA, together or separately, to a mixture of thionyl chloride and solvent. The reaction mixture is typically agitated (e.g., stirred) during the mixing of the reactants and during the subsequent chlorination reaction. The reaction is conducted under an inert atmosphere such as nitrogen or argon. Because the mixing Of SOC12 and Compound I is exothermic, the mixing temperature is kept relatively low. For example, when SOC12 is added to a solution of Compound 1, the solution of Compound I is typically cooled to a relatively low temperature (e.g., from about -5 to about YC) prior to the start of addition, and the solution is typically maintained at or close to that temperature during the addition. Once the addition is complete, the reaction mixture can be maintained at the temperature employed during SOC12 addition for the entire course of the reaction, or the reaction mixture can be maintained for a period of time at the temperature employed during SOC12 addition and then raised to a higher temperature (e.g., from about 10 to about 15'C) until the reaction is complete, or, more typically, the reaction can be conducted by warming the reaction mixture to a higher temperature immediately after SOC12 addition and maintaining the mixture at the higher temperature throughout the reaction.

The solvent employed in the process of the invention can be any organic compound which under the reaction conditions employed is in the liquid phase, is chemically inert, and will dissolve Compound 1 and DIEA. Suitable solvents include, but are not limited to, C6-Clo aromatic hydrocarbons (e.g., benzene and toluene), halogenated Cl-C6 alkanes (e.g., chloroform, methylene chloride, and trifluoroethane), halogenated C4-C6 cycloalkanes, C2-C6 alkyl ethers (e.g. , ethyl ether), C2-C6 alkyl ketones (e.g., acetone, ethyl ketone, and methyl ethyl ketone), C3-C8 dialkyl carboxylic acid amides (e.g., dimethylfonnamide and dimethylacetamide), and Cl-C6 alkyl acetates (e.g., ethyl acetate, acetate, isopropyl 20"! acetate, i sobutyl acetate, and hexyl acetate). In one aspect of the invention, the solvent is isopropyl acetate. In another aspect, the solvent is toluene.

The reaction temperature is suitably in the range of from about -5 to about 50'C, and is typically in the range of from about 0 to about 30'C (e.g., from about 0 to about 25'C). In one aspect, the reaction temperature is in the range of from about 2 to about 22'C (e.g., from about 5 to about 15'C). In another aspect, the reaction temperature is in the range of from about 0 to about 18'C (e.g., from about 5 to about 18'C).

The reaction time can vary widely depending upon the choice of reaction temperature, the choice and concentration of reactant Compound 1, the relative amounts of the reactants, and the degree of conversion desired. Nonetheless, the reaction time is generally in the range of from about 30 minutes to about 5 hours, and typically in the range of from about 1.5 to about 4 hours (e.g., from about 1.5 to about 2 hours or from about 2 to about 3 hours).

The amount of Compound I employed in the process of the invention is suitably in the range of from about 0.1 to about 2 moles, and is typically from about 0.3 to about 1.3 moles, per liter of solvent at 25'C.

DIEA is suitably employed in an amount in the range of from about 0.5 to about 2 equivalents, and is typically in the range of from about 0.7 to about 1. 1 equivalents (e.g., from about I to about 1. 1 equivalents), per equivalent of Compound I. While not wishing to be bound by any particular theory, it is believed that the DIEA functions as a proton scavenger in the process of the invention.

Thionyl chloride is suitably employed in an amount in the range of from about I to about 10 equivalents (e.g., from about 1.1 to about 5.6 equivalents), and typically in an amount in the range of from about 1.1 to 6 equivalents (e.g., from about 1.2 to about 2.2 equivalents), per equivalent of Compound 1.

Because thionyl chloride reacts quickly and exothermically with water, it is desirable to prevent or at least minimize the presence of water in the reaction mixture in order to conduct the reaction safely and without an unnecessary waste of reagent. This may be accomplished by such measures as employing dry solvents and reagents (which may be obtained by pretreatment with dry molecular sieves, followed by filtering to remove sieve dust), sparging the reaction mixture with nitrogen prior to addition of thionyl chloride, and/or conducting the reaction under a dry atmosphere.

In one aspect of the process of the invention, the solution of Compound L solvent and DIIEA prior to addition of thionyl chloride has a KF value in micrograms/mL of less 20"1 than about 500 (e.g., less than about 250). The KF value is a measure of the amount of water present in the solution as determined by a standard Karl Fischer titration.

The disappearance of Compound I and/or the formation of Compound H can be monitored by BPLC, NMR and IR spectrophotometry, and the reaction is suitably carried out until at least a major portion of the starting hydroxyalkylfuran (Compound I) has been converted. The reaction is typically carTied out to a degree of conversion of at least about 90% (e.g., at least about 95%).

After the chlorination reaction is completed, the reaction is quenched, typically by the addition of cold water. If the reaction is conducted at a temperature of about 10'C or higher, the reaction mixture is typically cooled to about O'C before quenching in cold water, in order to prevent or at least minimize back reaction due to hydrolysis. The desired compound of Formula (III) can be recovered via conventional separation techniques such as extraction, chromatography, and distillation.

As noted above, an embodiment of the invention is a process for preparing Compound 2:

0 70 ' CI 2 3 which comprises reacting Compound 1:

OH with thionyl chloride in a solvent and in the presence of diisopropylethylarnine to obtain Compound 2. The yield and purity of the resulting Compound 2 are generally quite high, and are substantially higher than observed for analogous chlorinations conducted with other proton scavengers such as pyridine, DEPA, and Et3N. Yields are typically at least about 90% (e.g., at least about 93%) and commonly at least about 95% (e.g., at least about 98%).

205'.9 While not wishing to be bound by any particular theory, the conversion of Compound 1 to Compound 2 is believed to involve the formation of sulfite intermediate 3:

0 S = 0 0 2 3 wherein the formation of 3 from 1 is relatively fast, and the conversion of 3 to 2 relatively slow. The process of the invention is generally characterized by the fast conversion of 3 to 2, compared to the conversion A to A in the presence of proton scavengers other than D1EA (e.g., pyridine) under analogous reaction conditions.

In an aspect of this embodiment, the solvent is isopropyl acetate and the operating conditions are as set forth in Table 1 below.

TABLE l a

Conditions Operating Range Typical Value Conch of 1 in EPAc (moles/L of 0.3 to 1.30 1.2 IPAc) Reaction temperature (C) 2 to 22 5 to 18 D1EA charge (eq/eq of 1) 0.7 to 1.1 1.0 SOC12 charge (eqleq of 1) 1. 1 to 5.6 1.2Reaction time (hr) 1.5 to 4 2 to 3 a. A suitable KF value (ggImL) of 1 in IPAc and D1EA is <500, and a typical value is <250.

The present invention also includes a process for preparing a compound of Formula (IH):

209 R' R 2 R 3 N 0 OH H PH N,,. - 0';NHC(CH3)3 0 which comprises (A) reacting a compound of Formula (I):

R' 00 OH R 3 R 2 with thionyl chloride in a solvent and in the presence of diisopropylethylamine to obtain a compound of Formula (][I):

R' o 1 Z 1 0 1 cl R 3 R2 (11); and (B) contacting the compound of Fonnula (II) with Compound 4:

HN OH N PH PH :zI - N,,,.

O^NHC(CH3)3 0 8 4 2'-59 to obtain the compound of Formula (HI); wherein R 1, R2 and R3 are as heretofore defined. An aspect of this process is the process wherein the compound of Formula (1) is a compound of Formula (1a) as heretofore defined, and the compound of Formula (H) is a compound of Formula (Ila) as heretofore defined. A further aspect of this process is the process wherein the compound of Formula (1) is Compound I as heretofore defined and the compound of Formula (II) is Compound 2 as heretofore defined.

Compound 4 can be prepared as described in US 6618937 (see, e.g., Examples 1-27 therein) or as described in US 5717097 (see, e.g., Example 15, steps 1-9). The conditions for alkylating compound 4 with Compound H in step (B) are the same as or similar to the procedures described in US 5413999 (see, e.g., step 10 of Example 15 and Example 16) and US 5646148 (see, e.g., step 6 of Example 2 and Example 3).

Abbreviations used in the instant specification are as follows:

Ac = acetate AIDS acquired immune deficiency syndrome ARC AIDS related complex DIEA diisopropylethylarnine DEPA diisopropylamine DMIF dimethy1formamide eq = equivalent(s) Et = ethyl Et3N triethylamine EtOH ethanol BPLC high performance liquid chromatography IPAc = isopropyl acetate IR = infrared KF = Karl Fisher LAH = lithium aluminum hydride Me = methyl NMR = nuclear magnetic resonance Pr = propyl 2('--9 The following examples serve only to illustrate the invention and its practice. The examples are not to be construed as limitations on the scope or spirit of the invention.

In the chlorination reactions set forth in Examples 1-7 below:

(i) The progress of the reactions was monitored by BPLC analysis:

cm Zorbax C8-RX column, 60:40 acetonitrile/10 mM (KH2PO4/K2BP04), 1.0 mUmin, injection volume 10 gL, detection 220 nm, sample preparation = 100 X dilution. The approximate retention times were:

Retention time Eluate (min) 3.6 2-hydroxymethylbenzofuran 6.5 2-chloromethylbenzofuran 11.5 sulfite intermediate 2!13 impurities (ii) The results of the reactions are reported as the per cent yield of product and the percent purity of product, as determined by BPLC. % Yield is defined by the following formula:

% Yield = [ACproduct /(ACReactant + ACIntermediate + ACproduct)] x 100 wherein ACproduct = BPLC area count of Compound 2; ACReactant = BPLC area count of Compound 1; ACIntermediate = HPLC area count of Compound 3. % Purity is defined as:

% Purity = [ACProduct /J(AC)] x 100 wherein ACproduct is as defined above, and I(AC) = the sum of the BPLC area counts for the reactant, product, intermediate and impurities.

(iii) The amounts of scavenger and thionyl chloride employed are given in equivalents per equivalent of Compound 1.

205"Q EXAMPLE I

Chlorination of 2-Hydroxymethylbenzofuran (1) SOC]2 ao I 00 ' JI-1- OH DIEA, EPAc - I C1 I 1 2 A solution of 2-hydroxymethylbenzofuran 1 (0.5 g, 3.4 mmol) and DIEA (1.0 eq) in isopropyl acetate (1.22 moles of I per liter of IPAc) (KF titration of water <100 gg/mL) in a 50 mL 3-neck round bottom flask equipped with a thermocouple probe, mechanical stirrer, and a nitrogen inlet adapter and bubbler, was cooled to O'C. Thionyl chloride (1.2 eq) was then added over a period of about 10 minutes, while the temperature was maintained in the range of from 0 to 5 T with an ice-water cooling bath. After addition, the mixture was stirred at 2 to 5 T and monitored for the disappearance of 1 by BPLC. After 3 hours, when 1 was less than 1.0 A%, the reaction was quenched into ice-cold water (3.0 mL) and partitioned with EPAc (3.0 mL). The mixture was agitated and the layers were separated. The isopropyl acetate layer was washed with water (3.0 mL), then twice with saturated aqueous NaHC03 (2 x 3.0 mL), and brine (3.0 mL). The isopropyl acetate extract containing 2 was assayed by HPLC analysis, and the yield and purity is shown in Table 2.

EXAMPLES 2- 7

Chlorination of 2-Hydroxymethylbenzofuran A series of chlorinations were conducted in the manner described in Example 1, using the proton scavengers and the reaction conditions shown in Table 2.

The yields and purities obtained in these chlorinations are also shown in Table 2.

205'-9 TABLE 2

Example Scavengera Moles of 1 Eq. of Temp. Rx Time % Yield of 2 No. /L of EPAc SOC12 (OC) (hr) (% Purity) 1 D1EA 1.22 1.2 2-5 3.0 99.7(98.5) 2 pyridine 1.22b 1.2 2-5 4.5 89(76.6) 3 Et3N 1.22b 1.2 2-5 5.5 69(61.0) 4 DIPA 1.22b 1.2 2-5 5.0 71(63.7) pyridine 0.31 1.2 2-5 4.5 50(45.2) 6 Et3N 0.31 1.2 2-5 5.0 13(9.28) 7 DIPA 1.25 1.2 22c 3.5 91(87.0) a. The scavenger is present in an amount of 1 eq.

b. The reaction mixture is a heterogeneous mixture; i.e., a very thick slurry. In contrast, the reaction mixture of Example 1 is homogeneous; i.e., a solution.

c. Thionyl chloride was added to the reaction mixture as described in Example 1. After addition, the mixture was warmed to and then maintained at 22 'C with stirring.

209 EXAMPLE8

Preparation of N-(2(R)-hydroxy-I(S)-indanyl)-2(R)-phenylmethy]-4(S)hydroxy-5-(1(4-(2-benzo[blfuranylmethyl)-2(S)-N'-(t-butylearboxamido)piperazinyl))pentaneamide (5) CH2C1 HN OH o N 1 OH 2 [166.51 NH z 0 Nal, aq. KHC03, t-BuNH-'!-0 BU4NBr, IPAc 4 [523] N OH 1OH H z 0 t-BuNH-'o [652.8] Isolated penultimate solid 4 (13.1 g, 25 mmol) was combined with IPAc (60 niL), water (20 mL), KHC03 (4.25 g, 42.5 mmol), sodium iodide (1. 88 g, 12.5 mmol) and tetrabutylammonium bromide (600 mg, 1.86 mmol) and the mixture heated to 45 'C under nitrogen atmosphere. 2-(Chloromethyl)benzofuran (4. 6 g, 27.5 mmol) was added and the resulting mixture was heated to 59-61'C for 5 hrs. The mixture was allowed to cool to room temperature and diluted with EPAe (100 mL) and the aqueous layer was separated. The organic layer was washed with 3 x 50 mI, water, then 50 mI, brine solution and dried (M9S04) and the filtrate concentrated in vacuo and flushed with 100 mI, IPAc and concentrated atmospherically to 80 mL, cooled to 25'C, seeded and aged with agitation for 2 hrs. The solids were filtered and washed with cold EPAc (2 x 15 mL) to afford free base 5.

2017'9 EXAMPLE9

Preparation of the Sulfate Salt of 5 N OH P h 0 H N N, 0 H H2SO4 EtOH (H3C)3CHN "\O 0 Sulfate salt of 5 Freebase 5 (25 g, 38.3 mmol) was dissolved in absolute ethanol (150 mL) at 22'C. The batch was filtered through a 5 Am filter and the filter flushed with absolute ethanol (50 mL). A solution of sulfuric acid/ethanol was prepared at < PC by charging concentrated sulfuric acid (3.91 g, 38.3 mmol) into a cooled solution (< 5 'C) of absolute ethanol (50 mL) at such a rate that the temperature remained < 5'C. A portion of the acid solution (10 mL, 20 vol %) was charged into the Compound A batch solution at 22'C. The Compound 5 batch, which may or may not be seeded at this point with Compound 5esulfate (500 mg) at 22'C, was seeded, in order to relieve supersaturation during crystallization. The slurTy was aged at 20 25'C for 30 minutes. The remainder of the acid solution was charged into the batch via cannula over 60 minutes. The batch temperature remained 20-25'C during the addition (note: the acid solution was held at <'5 C.) The final batch slurry was aged at 20-25'C for 60 minutes and filtered. The cake was washed with absolute ethanol (2 X 25 mL) and dried in vacuo (25 in. Hg, 20 C) for 18 hours with a nitrogen bleed to afford the Compound 5 sulfate.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, the practice of the invention encompasses all of the usual variations, adaptations and/or modifications that come within the scope of the following claims.

205-9

Claims (23)

1. WHAT IS CLAIMED IS:

   I. A process for preparing a compound of Formula (111):

   R1 (Z 1 0 1 C1 R 3 R 2 which comprises reacting a compound of Formula (I):

   R1 (Z 0 1 OH R3 R 2 with thionyl. chloride in a solvent and in the presence of diisopropylethylamine to obtain the compound of Formula (11); wherein RI is hydrogen, halogen, cyano, nitro, Cl-C6 alkyl, halogenated Cl.-C6 alkyl, Cl-C6 alkoxy, halogenated Cl-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, halogenated C2-C8 alkoxyalkyl, (CH2)0-4COORa, (CH2)0-4C(=O)Ra, (CH2)O-4N(RaRb), (CH2)0-4C(=O)N(RaRb), (CH2)0-4SO2Ra, aryl, or substituted aryl; wherein each substituent on substituted aryl is independently halogen, cyano, nitro, Cl.-C6 alkyl, halogenated CI-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, Cl-C6 alkoxy, halogenated CI-C6 alkoxy, (CH2)0-4CO2Ra, (CH2)0-4C(=O)N(RaRb), (CH2)0-4SO2Ra, C2-C8 alkoxyalkyl, or halogenated C2-C8 alkoxyalkyl; Z is a ring which includes the two carbon atoms from the adjacent furan ring and which is a C5-C7 carbocyclic ring or a 5- to 7-membered heterocyclic ring containing carbon atoms and one or two nitrogen atoms, wherein the ring is aromatic or non 20550 aromatic and is unsubstituted or substituted with one or more of halogen, cyano, nitro, C 1 -C6 alkyl, halogenated C 1 -C6 alkyl, C 1 -C6 alkoxy, halogenated C 1 -C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, halogenated C2-C8 alkoxyalkyl, (CH2)04CO0Ra, C(=0)Ra, N(RaRb), (CH2)0-4C(=0)N(RaRb), (CH2)04SO2Ra' or aryl; R2 and R3 are each independently hydrogen or Cl-C4 alkyl; and Ra and Rb are each independently Cl-C4 alkyl or halogenated Cl-C4 alkyl.
2. 2. The process according to claim 1, wherein R1 is hydrogen, halogen, cyano, nitro, Cl-C4 alkyl, halogenated Cl-C4 alkyl, Cl-C4 alkoxy, halogenated Cl-C4 alkoxy, C3-C7 cycloalkyl, halogenated C3-C7 cYcloalkyl, C2-C8 alkoxyalkyl, halogenated C2-C8 alkoxyalkyl, (CH2)0-2CO0Ra, (CH2)0-2C(=0)Ra, (CH2)0-2N(RaRb), (CH2)0-2C(=0)N(RaRb), (CH2)0-2SO2Ra, phenyl, or substituted phenyl; wherein each substituent on substituted phenyl is independently halogen, cyano, nitro, Cl-C4 alkyl, halogenated Cl-C4 alkyl, C3-C7 cycloalkyl, halogenated C3-C7 cycloalkyl, Cl-C4 alkoxy, halogenated Cl-Q alkoxY, (CH2)0-2CO2Ra, (CH2)0-2C(=0)N(RaRb), (CH2)0-2SO2Ra, C2-C8 alkoxyalkyl, or halogenated C2-C8 alkoxyalkyl; and Z is an aromatic ring which is unsubstituted or substituted with one or more of halogen, cyano, nitro, C 1 -C4 alkyl, halogenated C 1 -Q alkyl, C 1 -C4 alkoxy, halogenated Cl-Q alkoxy, C3-C7 cycloalky], halogenated C3-C7 cycloalkyl, C2-C8 alkoxyalkyl, halogenated C2-C8 alkoxyalkyl, (CH2)0-2CO0Ra, C(=0)Ra, N(RaRb), (CH2)0-2C(=0)N(RaRb), (CH2)0-2SO2Ra, or phenyl.
3. 3. The process according to claim 1, wherein thionyl chloride is employed in an amount in the range of from about 1 to about 10 equivalents per equivalent of the compound of Formula (1).

   205,"",
4. 4. The process according to claim 1, wherein dilsopropylethylamine is employed in an amount in the range of from about 0.5 to about 2 equivalents per equivalent of the compound of Formula (I).
5. 5. The process according to claim 1, wherein the compound of Formula (I) is employed in an amount in the range of from about 0.1 to about 2 moles per liter of solvent.
6. 6. The process according to claim 1, wherein the reaction is conducted at a temperature in the range of from about -5 to about 50 'C.
7. 7. The process according to claim 1, wherein the solvent is selected from the group consisting Of C6-Clo aromatic hydrocarbons, halogenated Cl-C6 alkanes, halogenated C4-C6 cycloalkanes, C2-C6 alkyl ethers, C2-C6 alkyl ketones, C3-C8 dialkyl carboxylic acid amides, and Cl -C6 alkyl acetates.
8. 8. The process according to claim 1, which further comprises recovering the compound of Formula (H).
9. 9. The process according to claim 1, wherein the compound of Formula (II) is MM R' W v 1 n 1 Cl Y 0 and the compound of Formula (I) is:

   MM R' OH Y 0 (Ia); wherein Y is N or CX; 209 each X is independently hydrogen, halogen, cyano, nitro, C I-C4 alkyl, fluorinated Cl-C4 alkyl, Cl-C4 alkoxy, fluorinated Cl-C4 alkoxy, C3-C6 cycloalkyl, fluorinated C3-C6 cycloalkyl, (CH2)1-40Rc, or (CH2)1-40Rd, (CH2)0-2CO0Ra, (CHM-2C(=0)Ra, (CH2)0-2N(RaRb), (CH2)0-2C(=0)N(RaRb), or (CH2)0-2SO2Ra; R 1 i s hydrogen, fluorine, chlorine, cyano, nitro, C 1 -C4 alkyl, (CH2)02CF3, C 1 -C4 alkoxy, OCF3, OCH2CF3, (CH2)1-40CH3, (C142)1-20CF3, (CH2)0-2CO0Ra, (CH2)0-2C(=0)Ra, (CH2)0-2N(RaRb), (CH2)0-2C(=0)N(RaRb), (CH2)0-2SO2Ra, or phenyl; Ra and Rb are each independently methyl, ethyl, CF3, or CH2CF3; Rc is methyl or ethyl; Rd is CF3 or CH2CF3; and m is an integer from 0 to 3.
10. 10. The process according to claim 9, which further comprises recovering Compound Ha.
11. 11. The process according to claim 9, wherein Compound fia is Compound 2:

    croj-- Cl 2 and Compound la is Compound 1:

    20' -) C co: OH 1
12. 12. The process according to claim 11, wherein the solvent is selected from the group consisting Of C6-Clo aromatic hydrocarbons, halogenated C I -C6 alkanes, halogenated C4-C6 cycloalkanes, C2-C6 alkyl ethers, C2- C6 alkyl ketones, C3-C8 dialkyl carboxylic acid amides, and Cl-C6 alkyl acetates.
13. 13. The process according to claim 12, wherein the solvent is isopropyl acetate.
14. 14. The process according to claim 11, wherein thionyl chloride is employed in an amount in the range of from about 1. 1 to about 5.6 equivalents per equivalent of Compound 1.
15. 15. The process according to claim 11, wherein diisopropylethylamine is employed in an amount in the range of from about 0.7 to about 1. 1 equivalents per equivalent of Compound 1.
16. 16. The process according to claim 11, wherein Compound 1 is employed in an amount in the range of from about 0.3 to about 1.3 moles per liter of solvent.
17. 17. The process according to claim 11, wherein the reaction is conducted at a temperature in the range of from about 0 to about 30 'C.
18. 18. The process according to claim 11, wherein the reaction time is in the range of from about 0.5 to about 5 hours.
19. 19. The process according to claim 11, which further comprises recovering Compound 2.
20. 20) 20. The process according to clairn 11, wherein thionyl chloride is employed in an amount in the range of from about 1. 1 to about 5.6 equivalents per equivalent of Compound 1; diisopropylethylamine is employed in an amount in the range of from about 0.7 to about 1. 1 equivalents per equivalent of Compound 1; the solvent is isopropyl acetate; Compound 1 is employed in an amount in the range of from about 0.3 to about 1.3 mole per liter of isopropyl acetate; and the reaction is conducted at a temperature in the range of from about 2 to about 22 'C.
21. 21. The process according to claim 1, which further comprises contacting the compound of Formula (H) with Compound 4:

    HN OH N H OH N 0^ NHC(CH3)3 0 4 to obtain a compound of Formula (IH):

    R' R 2 R 3 N OH 0 0 H PH z N/,..

    ^ 0 WC(CH3),3 0 20550
22. 22. The process according to claim 9, which further comprises contacting the compound of Formula (11a) with Compound 4:

    HN OH N H PH N,,,.

    0 NHC(CH3)3 0 4 to obtain a compound of Formula (IIIa):

    R 3 (X)M \ 0 OH H PH -Y N 0 NHC(CH3)3 0
23. 23. The process according to claim 22, wherein Compound Ila is Compound 2:

    a03, Cl 2 and Compound Ella is Compound 5:

    20559 -N \ 0 OH CP Z.

    H 9H - N,,.:1 0j NHC(CH3)3 0 8.

    1