HK1078005A - Preparation of intermediates useful in the synthesis of antiviral nucleosides - Google Patents

Description

Preparation of intermediates for the synthesis of antiviral nucleosides

This application claims priority from U.S. s.n.60/341,378 filed on 12/14/2001.

Technical Field

This application is in the field of synthetic organic chemistry, and in particular, it relates to an improved process for the synthesis of α -acyloxyacetals and their acetals, which are versatile intermediates, and their use in the synthesis of certain biologically active nucleosides.

Background

Acquired Immune Deficiency Syndrome (AIDS) is a catastrophic disease that has reached a large disease rate. A total of 47,083 cases of AIDS were reported in the united states alone, from month 7 in 1998 to month 6 in 1999. More than two hundred and twenty thousand cases of death occurred in 1998, and HIV/AIDS has now become the fourth leading cause of death, and its effects are increasing. According to the statistics of institutions, more than one thousand and six million people die from AIDS from late seventies of the twentieth century to now.

AIDS was first noticed in 1981 by US Center for Disease Control and preference (CDC), when seemingly healthy homosexually-loved men developed Kaposi Sarcoma (KS) and Pneumocystis Carinii Pneumonia (PCP), a Disease known to affect only immunodeficient patients. Later, the causative agent of AIDS, the lymphadenopathy-associated retrovirus, now known as Human Immunodeficiency Virus (HIV), was isolated at the Pasteur Institute in Paris, and was later independently confirmed by the US National Cancer Institute.

Another virus that causes serious human health problems is Hepatitis B Virus (HBV). HBV is second only to tobacco as a cause of human cancer. The mechanism by which HBV causes cancer is unknown. It has been suggested that HBV may initiate tumor development directly or indirectly via chronic inflammation, cirrhosis and cell regeneration associated with infection.

After a 2-6 month incubation period, during which the host is not usually aware of the infection, HBV infection can lead to acute hepatitis and liver damage, with abdominal pain, jaundice and increased blood levels of some enzymes. HBV can cause fulminant hepatitis, a frequently fatal disease with most of the liver destroyed.

Patients can usually recover from the acute phase of hepatitis b virus infection. However, in some patients, high levels of viral antigens persist in the blood for extended or indefinite periods of time, causing chronic infections. Chronic infection can lead to chronic persistent hepatitis. Patients with chronic persistent HBV are most common in developing countries. By the mid-1991 year, there were about two hundred million and fifteen million chronic HBV carriers in Asia alone, and almost three million carriers worldwide. Chronic persistent hepatitis can cause fatigue, cirrhosis and hepatocellular carcinoma, a major liver cancer.

In western developed countries, high risk HBV infected populations include those who come into contact with HBV carriers or their blood samples. The epidemiology of HBV is similar to HIV/AIDS, which is why HBV is common among patients infected with HIV or suffering from AIDS. However, HBV is more contagious than HIV.

In 1985, the synthetic nucleoside 3 '-azido-3' -deoxythymidine (AZT, zidovudine, ritonavir) was reported to inhibit HIV replication and was the first FDA-approved drug for combating AIDS. Since then, a variety of other synthetic nucleosides have been demonstrated to be effective against HIV, including 2 ', 3 ' -dideoxyinosine (ddI), 2 ', 3 ' -dideoxycytidine (ddC), 2 ', 3 ' -dideoxy-2 ', 3 ' -dideoxythymidine (d4T), (-) -2 ', 3 ' -dideoxy-3 ' -thiacytidine (3TC), and (-) -carbocyclic 2 ', 3 ' -didehydro-2 ', 3 ' -dideoxyguanosine (carbovir) and its prodrug abacavir. After phosphorylation to 5 '-triphosphates by cellular kinases in cells, these synthetic nucleosides are incorporated into the growing strand of viral DNA, causing chain termination due to their lack of a 3' -hydroxyl group. They are also capable of inhibiting the viral enzyme reverse transcriptase.

Oxathiolane nucleoside BCH-189 has potent activity against Human Immunodeficiency Virus (HIV) replication (Bellau B. et al, 5)^thThe discovery of International Conference on AIDS, Montreal, Canada, June 4-9, 1989, # T.C.O.I) encouraged Chu et al to synthesize the chiral products (+) -and (-) -BCH-189(Tetrahedron Lett., 1991, 32, 3791). The latter, lamivudine, also known as 3TC or epivir, is currently used clinically for the treatment of HIV infection and Hepatitis B Virus (HBV) infection. 3TC and interferon are currently the only FDA-approved drugs for the treatment of HBV infection. In approximately 14% of patients, viral resistance developed within 6 months of treatment with 3 TC.

The 5-fluorocytosine analogue (-) -FTC was later demonstrated to be more active against HIV than 3TC (Choi w. et al, j.am. chem.soc., 1991, 113, 9377). It has recently been found that the racemic form of FTC or Racivir exhibits beneficial effects against HIV (SchinaziR. F. et al, Antimicrobial Agents Chemotherapy 1992, 2423, U.S. Pat. Nos. 5,204,665, 5,210,085, 5,914,331, 5,639,814). Triangle Pharmaceuticals, Inc. currently underwent clinical trials for the treatment of HIV and HBV, respectively, on beta- (-) -cis-2-hydroxymethyl-5- (5-fluorocytosin-1-yl) -1, 3-oxathiolane (FTC). See Schinazi et al (1992) for racemate and enantioselective inhibition of cis-5-fluoro-1- [2- (hydroxymethyl) -1, 3-oxathiolan-5-yl ] cytosine against human immunodeficiency virus, Antimicrob. Agents Chemother.2423-2431; US patents 5,210,085, 5,914,331, 5,814,639; WO 91/11186; WO 92/14743.

These nucleosides are prepared by condensing a silylated purine or pyrimidine base with a 1, 3-oxathiolane intermediate. US patent 5,204,466 discloses a process for condensing 1, 3-oxathiolanes with silylated pyrimidines using tin chloride as lewis acid, which process provides absolute beta-stereoselectivity (see also Choi et al, loc. Several US patents disclose processes for preparing 1, 3-oxathiolane nucleosides, including the condensation of 1, 3-oxathiolane-2-carboxylic acid esters with a protected silanated base in the presence of a silicon-based lewis acid, followed by reduction of the ester to the corresponding hydroxymethyl group to obtain the final product (see US patent 5,663,320, 5,693,787, 5,696,254, 5,744,596, 5,756,706, 5,864,164).

US patent 5,272,151 discloses the preparation of nucleosides by condensation with a silylated purine or pyrimidine base in the presence of a titanium catalyst using a 2-O-protected-5-O-acylated-1, 3-oxathiolane.

U.S. Pat. Nos. 5,466,806, 5,538,975 and 5,618,820 disclose methods for preparing 1, 3-oxathiolane nucleosides, which involve coupling a base to an intact sugar moiety.

US patent 6,215,004 discloses a process for the preparation of 1, 3-oxathiolane nucleosides comprising condensing 2-O-protected-methyl-5-chloro-1, 3-oxathiolane with silanized 5-fluorocytosine without the use of lewis catalysts.

In all cases, the 1, 3-oxathiolane ring is prepared by a process comprising: (i) reacting an aldehyde derived from a glyoxylic acid ester or glycolic acid with mercaptoacetic acid in toluene in the presence of p-toluenesulfonic acid to form 5-oxo-1, 3-oxathiolane-2-carboxylic acid (krauss j-l. et al, Synthesis, 1991, 1046); (ii) cyclizing the anhydrous glyoxylic ester with 2-mercaptoacetaldehyde diethyl acetal in toluene under reflux to form 5-ethoxy-1, 3-oxathiolactone (U.S. Pat. No. 5,047,407); (iii) (iii) condensing the glyoxylate with mercaptoacetaldehyde (dimeric form) to form 5-hydroxy-1, 3-oxathiolane-2-carboxylate, or (iv) coupling an acyloxyacetaldehyde with 2, 5-dihydroxy-1, 4-dithiane, dimeric form of 2-mercaptoacetaldehyde, to form 2- (acyloxy) methyl-5-hydroxy-1, 3-oxathiolane. In the synthesis of nucleosides, lactones, 5-oxo compounds, must be reduced to the corresponding lactols. It is also necessary to reduce 2-carboxylic acid or its esters to the corresponding 2-hydroxymethyl derivatives with borane-dimethylsulfide complex.

The key intermediate aldehydes can be prepared using several methods: (i) oxidizing 1, 4-di-O-benzoyl meso-erythritol (Ohle m., be., 1941, 74, 291), 1, 6-di-O-benzoyl D-mannitol (Hudson c.s. et al, j.am.chem.soc., 1939, 61, 2432) or 1, 5-di-O-benzoyl-D-arabitol (Haskins w.t. et al, j.am.chem.soc., 1943, 65, 1663) with lead tetraacetate; (ii) preparation of monoacylated ethylene glycol, followed by oxidation to the aldehyde (Sheikh E.tetrahedron Lett., 1972, 257; Mancuso A.J. & Swern D.Synthesis, 1981, 165; Bauer M., J.Org.Chem., 1975, 40, 1990; Hanessian S. et al, Synthesis, 1981, 394); (iii) acylation of 2-chloroethanol followed by dimethyl sulfoxide oxidation (Kornblum n. et al, j.am.chem.soc., 1959, 81, 4113); (iv) oxidation of 1, 2-isopropylidene glycerol followed by de-acetonation and periodate oxidation (Shao M-J. et al, Synthetic Commun. 1988, 18, 359; Hashiguchi S. et al, Heterocycles, 1986, 24, 2273); (v) lead tetraacetate oxidation (Wolf F.J. & Weijtard j. org. synth., col. vol., 1963, 4, 124); (vi) ozonolysis of allyl or 3-methyl-2-buten-1-ol acylates (Chout. -S. et al, J.Chin.chem.Soc., 1997, 44, 299; Hambock R. & Just G.tetrahedron Lett., 1990, 31, 5445); (vii) and more recently, 2-butene-1, 4-diol was acylated and then ozonolysis was performed (Marshall j.a. et al j.org.chem., 1998, 63, 5962). US patent 6,215,004 also discloses a process for the preparation of acyloxyacetaldehyde diethanols by acylation of 2, 2-diethoxyethanol.

Alpha-acyloxyacetals are not only key intermediates for the synthesis of oxathiolanes and dioxolane nucleosides, but also key intermediates for the synthesis of other biologically active compounds such as mescarane (hopkins m.h. et al, j.am. chem.soc, 1991, 113, 5354), oxocanocin (hambalak R. & Just j., Tetrahedron lett., 1990, 31, 5445), kallillide a (Marshall j.a. et al, j.org.chem., 1998, 63, 5962), (±) -kumurallene and (+) -epi-kumurallene (cheeset.s. et al, j.org.m., 1993, 58, 2468) and 1, 3-dioxolane nucleosides.

Due to the importance of oxathiolanes and dioxolane nucleosides in antiviral therapy, it is an object of the present invention to provide an improved process for preparing the key intermediate α -acyloxyacetaldehyde.

It is another object of the present invention to provide a process for preparing α -acyloxyacetals which is easy to carry out and which is efficient.

It is another object of the present invention to provide a process for preparing α -acyloxyacetals which does not require the use of lead.

It is another object of the present invention to provide a process for preparing alpha-acyloxyacetals which does not require the use of oxidizing or reducing conditions.

It is another object of the present invention to provide a method for preparing α -acyloxyacetals without using ozone.

It is another object of the present invention to provide a process for preparing α -acyloxyacetals which does not require low yield steps such as ethylene glycol monoacylation or selective acylation of sugar alcohols.

Summary of The Invention

The present invention is a highly efficient process for the preparation of α -acyloxyacetaldehyde, a key intermediate in the synthesis of 1, 3-oxathiolanes and 1, 3-dioxolane nucleosides. The α -acyloxyacetaldehyde can be cyclized with a suitable co-cyclizing agent to form an oxathiolane or dioxolane ring, which is then coupled with any desired purine or pyrimidine base to form the desired nucleoside. Examples of nucleoside analogs that can be prepared from available precursors according to this method include BCH-189, 3TC, racemic or enantiomerically enriched FTC, β -D-dioxolanyl-2, 6-diaminopurine (DAPD), and racemic or enantiomerically enriched 5-fluoro-cytosine-1, 3-dioxolane (FDOC). The compounds prepared according to the present invention are also useful as synthetic intermediates for the preparation of a variety of other biologically active compounds including, but not limited to, mescarane, oxyethanocin, kallilidea, (±) -kumasalene and (+) -epi-kumasalene, or pharmaceutically acceptable salts or prodrugs thereof, as well as other derivatives obtainable by functional group change.

The process of the present invention uses an inexpensive 2, 2-dialkoxyethyl halide precursor. In one embodiment, the present invention provides a process for preparing an α -acyloxyacetaldehyde represented by the formula:

wherein R is hydrogen, alkyl (including but not limited to C)_1-9Alkyl), alkenyl (including but not limited to C)_2-9Alkenyl), alkynyl (including but not limited to C)_2-9Alkynyl) or aryl (including but not limited to C_4-10Or C_6-10Aryl) which may be optionally substituted with one or more substituents that do not adversely affect the reaction process, and R may be a chiral group; the method comprises the following steps:

a) 2, 2-dialkoxyethyl halide represented by the following formula

Wherein X is halogen (F, Cl, Br, I), OTs, OMs or any other suitable leaving group; r' is independently alkyl (including but not limited to C)_1-9Alkyl), alkenyl (including but not limited to C)_2-9Alkenyl), alkynyl (including but not limited to C)_2-9Alkynyl), aryl (including but not limited to C)_4-10Aryl or C_6-10Aryl), aralkyl, heteroaryl, or heterocycle;

and formula^-Suitable carboxylate salts are shown by OC (═ O) R, where R is hydrogen, alkyl (including but not limited to C)_1-9Alkyl), alkenyl (including but not limited to C)_2-9Alkenyl), alkynyl (including but not limited to C)_2-9Alkynyl) or aryl (including but not limited to C_4-10Aryl or C_6-10Aryl) which may be optionally substituted with one or more substituents;

to obtain an acetal of the formula

And

b) hydrolyzing the acetal to form an alpha-acyloxyacetaldehyde.

In one embodiment of the invention, the α -acyloxyacetaldehyde may be further cyclized as shown below with the following compounds: thioglycolic acid; mercaptoacetaldehyde (dimeric form); mercaptoacetaldehyde dialkyl acetals such as diethyl acetal; activated and/or protected thioglycolic acid or thioglycolaldehyde; or thioglycolic acid or any other chemical equivalent of thioglycolaldehyde, to form a 1, 3-oxathiolane.

Wherein L is a leaving group including, but not limited to, O-acyl, O-alkyl, O-tosylate, O-mesylate, or halogen (Cl, Br, I, F); and R' are as defined above.

In another embodiment of the invention, the α -acyloxyacetaldehyde may be further cyclized as shown below with the following compounds: glycolic acid; glycolaldehyde (dimeric form); glycolaldehyde dialkyl acetals such as diethyl acetal; activated and/or protected glycolic acid or glycolaldehyde; or glycolic acid or any other chemical equivalent of glycolaldehyde to form 1, 3-dioxolane.

Wherein L is a leaving group including, but not limited to, O-acyl, O-alkyl, O-tosylate, O-mesylate, or halogen (Cl, Br, I, F); and R' are as defined above.

In another embodiment of the invention, the Lewis acid, for example BF, may optionally be present₃.Et₂O、TMSCl、TMSI、TMSTf、SnCl₄Or TiCl₄In the presence of 1, 3-oxathiolane or 1, 3-dioxolane is further coupled with a purine or pyrimidine base, including but not limited to cytosine, thymidine, uridine, guanine, adenine or inosine, which may optionally be substituted as desired with a group including but not limited to halogen (F, Cl, Br, I), such as 5-fluorocytosine, alkyl, alkenyl, alkynyl, cycloalkyl or acyl, to form a protected nucleoside, which is then optionally deprotected stereoselectively or non-stereoselectively.

Y is O or S; b is a purine or pyrimidine or a derivative thereof as described herein.

The R' substituents are generally not particularly important to the reaction because they are hydrolyzed and removed during the formation of the α -acyloxyacetaldehyde. Thus, the R' substituent may be any group that does not interfere with the reaction.

In one embodiment, R is selected as a chiral group that remains in the formed nucleoside as an ester at the 5' -position. Thus leaving the chiral R group in place to facilitate separation of the enantiomers by fractional crystallization, chiral or conventional chromatography, enzymatic resolution, and the like. A variety of chiral groups are known for this purpose, for example menthyl (L or D), methamphetamine (D or L). In general, any chiral group that facilitates separation of enantiomers may be used. Preferred chiral R groups are those whose chiral centers are in close proximity to the nucleoside.

In a specific embodiment of the invention, the nucleoside is a β -D-nucleoside. In another embodiment of the invention, the nucleoside is a β -L-nucleoside.

Detailed Description

The present invention is a highly efficient process for the preparation of α -acyloxyacetaldehyde, a key intermediate in the synthesis of 1, 3-oxathiolane and 1, 3-dioxolane nucleosides, particularly BCH-189, 3TC, racemic or enantiomerically enriched FTC, β -D-DAPD and racemic or enantiomerically enriched FDOC, made from available precursors, which does not include low yield steps such as ethylene glycol monoacylation or selective acylation of sugar alcohols, does not require oxidation or reduction, and is a process that enables large scale production. The α -acyloxyacetaldehyde can be cyclized with a suitable co-cyclizing agent and then coupled as desired to a purine or pyrimidine base by methods known in the art. The compounds prepared according to the present invention are also useful as synthetic intermediates for the preparation of a variety of other biologically active compounds including, but not limited to, mescarane, oxyethanocin, kallilidea, (±) -kumasalene and (+) -epi-kumasalene, or pharmaceutically acceptable salts or prodrugs thereof, as well as other derivatives obtainable by functional group transformations.

The process of the present invention uses an inexpensive 2, 2-dialkoxyethyl halide precursor. In one embodiment, the present invention provides a process for preparing an α -acyloxyacetaldehyde represented by the formula:

wherein R is hydrogen, alkyl (including but not limited to C)_1-9Alkyl), alkenyl (including but not limited to C)_2-9Alkenyl), alkynyl (including but not limited to C)_2-9Alkynyl) or aryl (including but not limited to C_4-10Or C_6-10An aryl group),the group may be optionally substituted with one or more substituents that do not adversely affect the reaction process, and may optionally be a chiral group; the method comprises the following steps:

a) 2, 2-dialkoxyethyl halide represented by the following formula

Wherein X is halogen (F, Cl, Br, I), OTs, OMs or any other suitable leaving group; each R' is independently alkyl (including but not limited to C)_1-9Alkyl), alkenyl (including but not limited to C)_2-9Alkenyl), alkynyl (including but not limited to C)_2-9Alkynyl), aryl (including but not limited to C)_4-10Aryl or C_6-10Aryl), aralkyl, heteroaryl, or heterocycle;

and formula^-Suitable carboxylate salts are shown by OC (═ O) R, where R is hydrogen, alkyl (including but not limited to C)_1-9Alkyl), alkenyl (including but not limited to C)_2-9Alkenyl), alkynyl (including but not limited to C)_2-9Alkynyl) or aryl (including but not limited to C_4-10Aryl or C_6-10Aryl) which may be substituted with one or more substituents that do not adversely affect the reaction process;

to obtain an acetal of the formula

And

b) hydrolyzing the acetal to form an alpha-acyloxyacetaldehyde.

In one embodiment of the invention, the α -acyloxyacetaldehyde may be further cyclized as shown below with the following compounds: thioglycolic acid; mercaptoacetaldehyde (dimeric form); mercaptoacetaldehyde dialkyl acetals such as diethyl acetal; activated and/or protected thioglycolic acid or thioglycolaldehyde; or thioglycolic acid or any other chemical equivalent of thioglycolaldehyde, to form a 1, 3-oxathiolane.

Wherein L is a leaving group including, but not limited to, O-acyl, O-alkyl, O-tosylate, O-mesylate, or halogen (Cl, Br, I, F); and R' are as defined above.

In another embodiment of the invention, the α -acyloxyacetaldehyde may be further cyclized as shown below with the following compounds: glycolic acid; glycolaldehyde (dimeric form); glycolaldehyde dialkyl acetals such as diethyl acetal; activated and/or protected glycolic acid or glycolaldehyde; or glycolic acid or any other chemical equivalent of glycolaldehyde to form 1, 3-dioxolane.

Wherein L is a leaving group including, but not limited to, O-acyl, O-alkyl, O-tosylate, O-mesylate, or halogen (Cl, Br, I, F); and R' are as defined above.

In another embodiment of the invention, the Lewis acid, for example BF, may optionally be present₃.Et₂O、TMSCl、TMSI、TMSTf、SnCl₄Or TiCl₄In the presence of 1, 3-oxathiolane or 1, 3-dioxolane is further coupled with a purine or pyrimidine base, including but not limited to cytosine, thymidine, uridine, guanine, adenine or inosine, which may optionally be substituted as desired with groups including but not limited to halogen (F, Cl, Br, I) (e.g., 5-fluorocytosine), alkyl, alkenyl, alkynyl, cycloalkyl or acyl, to form a protected nucleoside, which is then optionally deprotected stereoselectively or non-stereoselectively.

Y is O or S; b is a purine or pyrimidine or derivative thereof, as described herein.

I. Definition of

The terms "substantially free", "substantially absent" or "isolated" as used herein refer to a nucleoside composition comprising at least 95%, preferably 99% to 100%, by weight of the designated nucleoside enantiomer. In a preferred embodiment, the compounds produced by the process of the present invention are substantially free of enantiomers of opposite configuration.

The term "alkyl" as used herein, unless otherwise specified, refers to a saturated straight, branched or cyclic primary, secondary or tertiary hydrocarbon. The term includes both substituted and unsubstituted alkyl groups. The alkyl group may be optionally substituted with any group that does not adversely affect or improve the reaction process, such groups include, but are not limited to, halogen, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, these groups are unprotected, or protected as desired, as is known to those skilled in the art, see, for example, Greene et al, Protective Groups in organic Synthesis, John Wiley & Sons, Second Edition, 1991, which is incorporated herein by reference.

In this context, when the term C (alkyl range) is used, the term independently includes each member of the range as if specifically and individually indicated. As a non-limiting example, the term "C_1-9"independently represents each member within the range. Alkyl groups include, but are not limited to, the following groups of alkanes: methane, ethanePropane, cyclopropane, 2-methylpropane (isobutane), n-butane, 2-dimethylpropane (neopentane), cyclobutane, 1-dimethylcyclopropane, 2-methylbutane, trans-1, 2-dimethylcyclopropane, ethylcyclopropane, n-pentane, methylcyclobutane, cis-1, 2-dimethylcyclopropane, spirocyclopentane, 2-dimethylbutane, 1, 2-trimethylcyclopropane, 2, 3-dimethylbutane, 2-methylpentane, 3-methylpentane, 1, 2, 3-trimethylcyclopropane, n-hexane, ethylcyclobutane, methylcyclopentane, 2-dimethylpentane, 2, 4-dimethylpentane, cyclohexane, 2, 3-trimethylbutane, 3, 3-dimethylpentane, 1-dimethylcyclopentane, 2, 3-dimethylpentane, 2-methylhexane, trans-1, 3-dimethylcyclopentane, cis-1, 3-dimethylcyclopentane, 3-methylhexane, trans-1, 2-dimethylcyclopentane, 3-ethylpentane, tetracyclo-ne (tetracyclo [2, 2,1, 0 ]^2.6，0^3.5]Heptane), n-heptane, 2, 4-trimethylpentane, cis-1, 2-dimethylcyclopentane, methylcyclohexane, ethylcyclopentane, 1, 3-trimethylcyclopentane, 2-dimethylhexane, 2, 5-dimethylhexane, 1, trans-2, cis-4-trimethylcyclopentane, 2, 4-dimethylhexane, 2, 3-trimethylpentane, 1, trans-2, cis-3-trimethylcyclopentane, 3, 3-dimethylhexane, 2, 3, 4-trimethylpentane, 1, 2-trimethylcyclopentane, 2, 3, 3-trimethylpentane, 2, 3-dimethylhexane, 3-ethyl-2-methylpentane, 1, cis-2, trans-4-trimethylcyclopentane, 1, cis-2, trans-3-trimethylcyclopentane, 2-methylheptane, 4-methylheptane, 3, 4-dimethylhexane, 1, cis-2, cis-4-trimethylcyclopentane, 3-ethyl-3-methylpentane, 3-ethylhexane, 3-methylheptane, cycloheptane (cork alkane), trans-1, 4-dimethylcyclohexane, 1-dimethylcyclohexane, cis-1, 3-dimethylcyclohexane, trans-1-ethyl-3-methylcyclopentane, trans-1-ethyl-2-methylcyclopentane, cis-1-ethyl-3-methylcyclopentane, methyl-3-ethylcyclopentane, methyl-2-ethylcyclopentane, methyl-4-ethylcyclopentane, methyl-2-ethylcyclopentane, methyl-ethyl-3-ethylcyclopentane, methyl-2-ethylcyclopentane, methyl-, 1-ethyl-1-methylcyclopentane, 2, 4, 4-tetramethylpentane, 1, cis-2, cis-3-trimethylcyclopentane, trans-1, 2-dimethylcyclohexane, 2, 5-trimethylhexane, trans-1, 3-dimethylhexaneMethylcyclohexane, n-octane, isopropylcyclopentane, 2, 4-trimethylhexane, cis-1-ethyl-2-methylcyclopentane, cis-1, 2-dimethylcyclohexane, 2, 4, 4-trimethylhexane, n-propylcyclopentane, 2, 3, 5-trimethylhexane, ethylcyclohexane, 2-dimethylheptane, 2, 3, 4-tetramethylpentane, 2, 4-dimethylheptane, methylcycloheptane, 2, 3-trimethylhexane, 4-ethyl-2-methylhexane, 3-ethyl-2, 2-dimethylpentane, 4, 4-dimethylheptane, 2, 6-dimethylheptane, 2, 5-dimethylheptane, 3, 5-dimethylheptane, dimethylheptane, Bicyclo [4.2.0]Octane, cis-bicyclo [3.3.0]Octane, 2, 4-dimethyl-3-ethylpentane, 1, 3-trimethylcyclohexane, 3, 3-dimethylheptane, 2, 5, 5-tetramethylhexane, 2, 3, 3-trimethylhexane, 3-ethyl-2-methylhexane, trans-1, 3, 5-trimethylcyclohexane, 2, 3, 4-trimethylhexane, cis-1, 3, 5-trimethylcyclohexane, trans-1, 2, 4-trimethylcyclohexane, 2, 3, 3-tetramethylpentane, 4-ethyl-3-methylhexane, 3,3, 4-trimethylhexane, 2, 3-dimethylheptane, 3, 4-dimethylheptane, 3-ethyl-3-methylhexane, dimethylheptane, 4-ethylheptane, 2, 3,3, 4-tetramethylpentane, 2, 3-dimethyl-3-ethylpentane, trans-1, 2, 3-trimethylcyclohexane, 1-isopropyl-e-methylcyclopentane (pulegane), 4-methyloctane, 1-isopropyl-2-methylcyclopentane, 3-ethylheptane, 2-methyloctane, cis-1, 2, 3-trimethylcyclohexane, 3-methyloctane, 2, 4, 6-trimethylheptane, cis-1, 2, 4-trimethylcyclohexane, 3, 3-diethylpentane, 2-dimethyl-4-ethylhexane, 2, 4-trimethylheptane, 2, 4, 5-tetramethylhexane, 2, 2, 5-trimethylheptane, 2, 6-trimethylheptane, 2, 3, 5-tetramethylhexane, nopoline (7, 7-dimethylbicyclo [ 3.1.1)]Heptane), trans-1-ethyl-r-methylcyclohexane, cyclooctane, 1-ethyl-2-methylcyclohexane, n-nonane, 1,3, 3-trimethylbicyclo [2.2.1 ]]Heptane (fenchyne), trans-1-ethyl-4-methylcyclohexane, cis-1, 1,3, 5-tetramethylcyclohexane, cis-1-ethyl-4-methylcyclohexane, 2, 5, 5-trimethylheptane, 2, 4, 4-trimethylheptane, 2, 3,3, 5-tetramethylhexane, 2, 4, 4-tetramethylhexane, isopropylhexaneCyclohexane, 1, 2, 2-tetramethylcyclohexane, 2, 2, 3, 4-tetramethylhexane, 2, 2-dimethyloctane, 3-ethyl-2, 2, 4-trimethylpentane, 3, 5-trimethylheptane, 2, 4-dimethyloctane, d, 1-cis-1-ethyl-3-methylcyclohexane, d, 1-2, 5-dimethyloctane, 1,3, 5-tetramethylcyclohexane, n-butylcyclopentane, n-propylcyclohexane, 2, 3, 5-trimethylheptane, 2, 5-dimethyl-3-ethylhexane, 2, 4, 5-trimethylheptane, 2, 4-dimethyl-3-isopropylpentane, 2, 2, 3-trimethylheptane, 2, 4-dimethyl-4-ethylhexane, 2-dimethyl-3-ethylhexane, 2, 3, 4, 4-pentamethylpentane, 1,3, 4-tetramethylcyclohexane, 5-ethyl-2-methylheptane, 2, 7-dimethyloctane, 3, 6-dimethyloctane, 3, 5-dimethyloctane, 4-isopropylheptane, 2, 3, 3-trimethylheptane, 4-ethyl-2-methylheptane, 2, 6-dimethyloctane, 2, 3, 3-tetramethylhexane, trans-1-isopropyl-4-methylcyclohexane (p-menthane), 4, 4-dimethyloctane, 2, 3, 4, 5-tetramethylhexane, 5-ethyl-e-methylheptane, 3-dimethyloctane, 4, 5-dimethyloctane, 3, 4-diethylhexane, 4-propylheptane, 1, 4-trimethylcycloheptane (eugenol), trans-1, 2, 3, 5-tetramethylcyclohexane, 2, 3, 4, 4-tetramethylhexane, 2, 3, 4-trimethylheptane, 3-isopropyl-2-methylhexane, 2, 7-trimethylbicyclo [2.2.1 ] trimethyl bicyclo]Heptane (. alpha. -freechane), 3-methylheptane, 2, 4-dimethyl-3-ethylhexane, 3, 4, 4-trimethylheptane, 3,3, 4-trimethylheptane, 3, 4, 5-trimethylheptane, 2, 3-dimethyl-4-ethylhexane, 1-methyl-e-propylcyclohexane, 2, 3-dimethyloctane, d, 1-pinane, 2, 3,3, 4-tetramethylhexane, 3, 3-dimethyl-4-ethylhexane, 5-methylnonane, 4-methylnonane, 3-ethyl-2-methylheptane, d, 1-isopropyl-3-methylcyclohexane (d, 1-m-menthane), 2, 3,3, 4-pentamethylpentane, trans-1, 2, 4, 5-tetramethylcyclohexane, 3-diethylhexane, 2-methylnonane, d-1-isopropyl-3-methylcyclohexane (d-m-menthane), 3-ethyl-4-methylheptane, 4-ethyl-3-methylheptane, 4-ethyl-4-methylheptane, 1-beta-pinane, 3-methylnonane, 3-ethylcyclohexaneCyclooctane, 4-ethyloctane, 3-ethyl-2, 2, 3-trimethylpentane, 1-1-isopropyl-3-methylcyclohexane (1-m-menthane), cis-1-isopropyl-4-methylcyclohexane (cis-p-menthane), cis-1, 2, 3, 5-tetramethylcyclohexane, 2, 3-dimethyl-3-ethylhexane, 1-isopropyl-4-methylcyclohexane (p-menthane), 3, 4-dimethyl-3-ethylhexane, 3, 4, 4-tetramethylhexane, cyclononane, 1-isopropyl-2-methylcyclohexane (o-menthane), cis-1, 2, 4, 5-tetramethylcyclohexane, methyl-1-ethyl-3-methylcyclohexane, methyl-1, 2, 4, 5-tetramethylcyclohexane, methyl-1, 3, 5-tetramethylcyclohexane, 1-methyl-1-propylcyclohexane, 1-methyl-4-propylcyclohexane, 1-methyl-2-propylcyclohexane, n-pentylcyclopentane, n-butylcyclohexane, and isopentylcyclohexane. It will be understood by those skilled in the art that the relevant alkyl groups are named by adding a "base" suffix to an alkane.

The term "alkenyl" as used herein refers to an unsaturated straight or branched chain hydrocarbon group containing one or more double bonds. The alkenyl groups disclosed herein may be optionally substituted with any group that does not adversely affect the reaction, such groups include, but are not limited to, alkyl, halo, haloalkyl, hydroxy, carboxy, acyl, acyloxy, amino, amido, carboxy derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate, these groups are unprotected, or protected as desired, as is known to those skilled in the art, see, for example, Greene et al, Protective Groups in Organic Synthesis, John Wiley & Sons, Second Edition, 1991, which is incorporated herein by reference. Non-limiting examples of alkenyl groups include methyl alkenyl, vinyl, methyl vinyl, isopropenyl, 1, 2-ethane-diyl, 1-ethane-diyl, 1, 3-propane-diyl, 1, 2-propane-diyl, 1, 3-butane-diyl, and 1, 4-butane-diyl.

The term "alkynyl" as used herein refers to an unsaturated straight or branched chain acyclic hydrocarbon radical containing one or more triple bonds. Alkynyl Groups may optionally be substituted with any group that does not adversely affect the reaction process, such Groups including, but not limited to, hydroxy, halo (independently including F, Cl, Br and I), perfluoroalkyl including trifluoromethyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, acyl, acylamino, carboxamido, carboxylate, thiol, alkylthio, azido, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, which Groups are unprotected, or protected as desired, as known to those skilled in the art, for example, see Greene et al, Protective Groups in Organic Synthesis, John Wiley & Sons, Second Edition, 1991, which is incorporated herein by reference. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butin-1-yl, butin-2-yl, pentin-1-yl, pentin-2-yl, 4-methoxypentyn-2-yl, 3-methylbutin-1-yl, hexin-2-yl and hexin-3-yl, 3-dimethylbutyn-1-yl.

The terms "alkoxy" and "alkoxyalkyl" include straight or branched chain oxy groups having an alkyl moiety, such as methoxy. The term "alkoxyalkyl" also includes alkyl groups having one or more alkoxy groups attached to the alkyl group to form monoalkoxyalkyl and dialkoxyalkyl groups. An "alkoxy" group may be substituted with one or more halogen atoms, such as fluorine, chlorine or bromine, to provide a "haloalkoxy". Examples of such groups include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy and fluoropropoxy.

The term "alkylamino" refers to "monoalkylamino" and "dialkylamino" containing one or two alkyl groups attached to the amino group, respectively. The term arylamino refers to "monoarylamino" and "diarylamino" groups that contain one or two aryl groups, respectively, attached to an amino group. The term "aralkylamino" includes aralkyl radicals attached to an amino group. Aralkylamino refers to "monoaralkylamino" and "diaralkylamino" groups containing one or two aralkyl groups attached to the amino group, respectively. The term aralkylamino also refers to "monoaralkylmonoalkylamino" containing one aralkyl group and one alkyl group attached to the amino group.

The term "aryl", alone or in combination, refers to a carbocyclic aromatic system containing 1, 2 or 3 rings, wherein such rings may be linked together in a pendant manner or may be fused together. Non-limiting examples of aryl groups include phenyl or aryl groups formed by removing hydrogen from the following aromatic rings: benzene, toluene, ethylbenzene, 1, 4-xylene, 1, 3-xylene, 1, 2-xylene, isopropylbenzene (cumene), n-propylbenzene, 1-ethyl-3-methylbenzene (m-ethyltoluene), 1-ethyl-4-methylbenzene (p-ethyltoluene), 1,3, 5-trimethylbenzene (mesitylene), 1-ethyl-2-methylbenzene (o-ethyltoluene), tert-butylbenzene, 1, 2, 4-trimethylbenzene (pseudo-cumene), isobutylbenzene, sec-butylbenzene, 3-isopropyl-methylbenzene (3-isopropyltoluene; m-cymene), 1, 2, 3-trimethylbenzene (hemimellitene), trans-propenylbenzene, indane, 4-isopropyl-1-methylbenzene (4-isopropyltoluene; 4-cymene), 2-isopropyl-methylbenzene (2-isopropyltoluene; 2-cymene), 1, 3-diethylbenzene, 1-methyl-3-propylbenzene (m-propyltoluene), indene, n-butylbenzene, 1-methyl-4-propylbenzene (p-propyltoluene), 1, 2-diethylbenzene, 1, 4-diethylbenzene, 1, 3-dimethyl-5-ethylbenzene, 1-methyl-2-propylbenzene (o-propyltoluene), 2-dimethyl-1-phenylpropane (neopentylbenzene), 1, 4-dimethyl-2-ethylbenzene, 2-methylindane, 3-methyl-2-phenylbutane, 1-methylindane, 1, 3-dimethyl-4-ethylbenzene, 3-tert-butyl-methylbenzene (3-tert-butyltoluene), 1, 2-dimethyl-4-ethylbenzene, 1, 3-dimethyl-2-ethylbenzene, 3-phenylpentane, 1-ethyl-3-isopropylbenzene, 2-methyl-2-phenylbutane, 4-tert-butyl-1-methylbenzene (4-tert-butyltoluene), 1-ethyl-2-isopropylbenzene, 2-phenylpentane, 1, 2-dimethyl-3-ethylbenzene, 3-sec-butyl-1-methylbenzene (3-sec-butyltoluene), 3-isobutyl-1-methylbenzene (3-isobutyltoluene), d-2-methyl-1-phenylbutane, toluene, 1, 3-dimethyl-5-isopropylbenzene, 2-phenyl-cis-2-butene, 4-isobutylmethylbenzene (p-isobutyltoluene), 2-sec-butyl-1-methylbenzene (2-sec-butyltoluene), 2-isobutyl-1-methylbenzene (o-isobutyltoluene), 1, 4-dimethyl-2-isopropylbenzene, 1-ethyl-4-isopropylbenzene, d, 1-2-methyl-1-phenylbutane, 1, 2, 3, 5-tetramethylbenzene (isodurene), 3-methyl-1-phenylbutane (isopentylbenzene), 1, 3-dimethyl-2-isopropylbenzene, 1, 3-dimethyl-4-isopropylbenzene, 2-sec-butyltoluene, 2-isobutyltoluene, 3-methyl-1-phenylbutane (isopent, 3-methylindene, 4-sec-butyl-1-methylbenzene (p-sec-butyltoluene), 2-tert-butyl-1-methylbenzene (2-tert-butyltoluene), 3, 5-diethyl-1-methylbenzene (3, 5-diethyltoluene), 2-butyl-1-methylbenzene (2-butyltoluene), 1-ethyl-3-propylbenzene, 1, 2-dimethyl-4-isopropylbenzene, 1, 2-dimethyl-3-isopropylbenzene, 1-ethyl-2-propylbenzene, 1, 3-diisopropylbenzene, 1, 2-diethyl-4-methylbenzene, 1, 2-diisopropylbenzene, 1, 4-dimethyl-2-propylbenzene, 2-di-n-butyl-1-methylbenzene, 2-tert-butyl-1-methylbenzene, 1-ethyl-3-propylbenzene, 1, 2-dimethyl-4-, 1, 2, 3, 4-tetramethylbenzene (durene), 1-ethyl-4-propylbenzene, 3-butyl-1-methylbenzene (m-butyltoluene), 2, 4-diethyl-1-methylbenzene (2, 4-diethyltoluene), n-pentylbenzene, 3-methyl-3-phenylpentane, 1, 3-dimethyl-5-tert-butylbenzene, 1, 3-dimethyl-4-propylbenzene, 1, 2-diethyl-3-methylbenzene, 4-butyl-1-methylbenzene, 1, 2, 3, 4-tetrahydronaphthalene, 1, 3-diethyl-2-propylbenzene, 2, 6-diethyl-1-methylbenzene, 2-ethyl-1-methylbenzene, 3-methyl-butyl-3-phenyl-1, 3-methyl-1, 3-ethyl-2-propyl-benzene, 2,1, 2-dimethyl-4-propylbenzene, 1, 3-dimethyl-5-propylbenzene, 2-methyl-3-phenylpentane, 4-tert-butyl-1, 3-dimethylbenzene, 1, 4-diisopropylbenzene, 1, 2-dimethyl-3-propylbenzene, 1-tert-butyl-4-ethylbenzene, d, 1-3-phenylhexane, 2-ethyl-1, 3, 5-trimethylbenzene, 3-ethyl-4-isopropyl-1-methylbenzene, 5-ethyl-1, 2, 4-trimethylbenzene, 6-ethyl-1-2, 4-trimethylbenzene, 2-phenylhexane, 2-methyl-1-phenylpentane, 1-tert-butyl-4-ethylbenzene, 2-methyl-3-phenylpentane, 4-tert-butyl-1, 3-trimethylbenzene, 3-ethyl-1, 4-isopropyl-1-propylbenzene, 1, 3-dipropylbenzene, 5-ethyl-1, 2, 3-trimethylbenzene, 1, 2, 4-triethylbenzene, 1,3, 5-triethylbenzene, 2-methyl-1, 2, 3, 4-tetrahydronaphthalene, 1-methyl-1, 2, 3, 4-tetrahydronaphthalene, 4-ethyl-1, 2, 3-trimethylbenzene, 1, 4-dipropylbenzene, 3-methyl-1-phenylpentane, 2-propyl-1, 3, 5-trimethylbenzene, 1-dimethyl-1, 2, 3, 4-tetrahydronaphthalene, 3-tert-butyl-1-isopropylbenzene, 1-methyl-3-pentylbenzene, 2-methyl-1, 3, 4-trimethylbenzene, 1, 4-methyl-1, 3, 4-trimethylbenzene, 4-tert-butyl-1-isopropylbenzene, 2-methyl-2-phenylhexane, 2, 4-diisopropyl-1-methylbenzene, 3-methyl-3-phenylhexane, n-hexylbenzene, 3-phenylheptane, 2, 6-diisopropyl-1-methylbenzene, 5-propyl-1, 2, 4-trimethylbenzene, 6-methyl-1, 2, 3, 4-tetrahydronaphthalene, 2-dimethyl-1, 2, 3, 4-tetrahydronaphthalene, 2-phenylheptane, 5-methyl-1, 2, 3, 4-tetrahydronaphthalene, 2-ethyl-1, 2, 3, 4-tetrahydronaphthalene, cyclohexylbenzene, 1-ethyl-1, 2, 3, 4-tetrahydronaphthalene, 2, 5-dimethyl-1, 2, 3, 4-tetrahydronaphthalene, 2, 8-dimethyl-1, 2, 3, 4-tetrahydronaphthalene, 2, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalene, 2, 6-dimethyl-1, 2, 3, 4-tetrahydronaphthalene, 1, 4-di-sec-butylbenzene, 1, 5-dimethyl-1, 2, 3, 4-tetrahydronaphthalene, 3-ethyl-3-phenylhexane, 6-ethyl-1, 2, 3, 4-tetrahydronaphthalene, 2-methyl-1-phenyl-1-butene, 5-ethyl-1, 2, 3, 4-tetrahydronaphthalene, n-heptylbenzene, 1-methylnaphthalene, 5, 6-dimethyl-1, 2, 3, 4-tetrahydronaphthalene, 6, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalene, 5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalene, 2-ethylnaphthalene, 1, 7-dimethylnaphthalene, 1, 6-dimethylnaphthalene, 1, 3-dimethylnaphthalene, n-octylbenzene, 1-allylnaphthalene, 1-isopropylnaphthalene, 1, 4-dimethylnaphthalene, 1-diphenylethane, 2-isopropylnaphthalene, 2-propylnaphthalene, 1,3, 7-trimethylnaphthalene, 1-isopropyl-7-methylnaphthalene, n-nonylbenzene, 2-butylnaphthalene, 2-tert-butylnaphthalene, 1-butylnaphthalene, 4, 5-benzindane, N-decylbenzene, 1-pentylnaphthalene, 2-pentylnaphthalene, n-undecylbenzene, 1-hexylnaphthalene, 2-hexylnaphthalene, n-dodecylbenzene, 1-heptylnaphthalene, 2-heptylnaphthalene, tridecylbenzene, 1-octylnaphthalene, 2-octylnaphthalene, 1-nonylnaphthalene, 2-nonylnaphthalene, 1-decylnaphthalene, 1, 2, 6-trimethylnaphthalene, diphenylmethane, 1, 2, 3-trimethylnaphthalene, 1, 6, 7-trimethylnaphthalene, 2-isopropylazulene, 1, 4-dimethyl-7-isopropylazulene, 2, 6-dimethylphenanthrene, 1, 2, 5-trimethylnaphthalene, 1-propylphenanthrene, 5-isopropylazulene, 2-propylphenanthrene, 2-methylnaphthalene, 1-ethyl-5-methylnaphthalene, 9-isopropylnaphthalene, 6-isopropylazulene, 2-ethyl-6-methylnaphthalene, 2-isopropylphenanthrene, 6-isopropyl-1-methylphenanthrene, 2-ethylazulene, 2, 5-dimethylphenanthrene, 1,3, 5-trimethylnaphthalene, 3-ethyl-6-methylphenanthrene, 2-methylazulene, 1,3, 8-trimethylnaphthalene, 4-methylphenanthrene, 1, 4-dimethylphenanthrene, bibenzyl, methylenefluorene, 3, 5-dimethylphenanthrene, 1, 3-dimethylazulene, 7-methyl-3, 4-triphenylene, pentamethylbenzene, 1, 2, 4-trimethylnaphthalene, 3-dimethylstilbene, 1, 4,5, 7-tetramethylnaphthalene, 1, 2, 4, 8-tetramethylnaphthalene, 2, 9-dimethylphenanthrene, 1, 5-dimethylphenanthrene, 2-benzylnaphthalene, 1, 2-dimethylazulene, 9-propylphenanthrene, 1, 7-dimethyl-4-isopropylnaphthalene, 3-methylphenylene, 3, 4-dimethylphenylene, 1-ethylphenanthrene, p-tolyne, 9-ethylphenanthrene, 1, 4, 5-trimethylnaphthalene, 4-methylfluorene, 1, 4,6, 7-tetramethylnaphthalene, 1, 2, 3-trimethylphenanthrene, 1, 8-dimethylnaphthalene, 8-methyl-3, 4-triphenylene, 2-ethylphenanthrene, 3, 4-triphenylene, 1, 4-dimethylphenanthrene, 1,3, 7-trimethylphenanthrene, 4-isopropyl-1-methylphenanthrene, 4, 8-dimethylazulene, biphenyl, 2-methyl-3, 4-triphenylene, 3-methylpyrene, 1, 4, 7-trimethylphenylene, 1, 4-dimethylanthracene, 4, 9-dimethyl-1, 2-benzanthracene, benzofluorene, 1, 3-dimethylphenylene, 1-methyl-3, 4-triphenylene, 3-isopropyl-1-methylphenanthrene, 1, 2-binaphthyl, 2, 3-dimethylphenylene, 1-ethyl-2-methylphenanthrene, 1, 5-dimethylnaphthalene, 6-methyl-3, 4-triphenylene, naphthalene, 1,3, 6, 8-tetramethylnaphthalene, 1-ethyl-7-methylphenanthrene, 9-methylanthracene, 1-isopropyl-7-methylphenanthrene, 6-methylanthracene, 1, 3-dimethylanthracene, 2-dimethylstilbene, 1-methylanthracene, 1, 7-dimethylphenenanthrene, 1, 6-diphenylnaphthalene, 1, 6-dimethylphenenanthrene, 1, 9-dimethylphenenanthrene, 9-methylphenanthrene, 1, 2, 10-trimethylanthracene, 7-ethyl-1-methylphenanthrene, triphenylmethane, 5-isopropylnaphthoanthracene, 3, 9-dimethyl-1, 2-benzanthracene, 5, 6-benzindane, 12-isopropylnaphthoanthracene, dihydroacenaphthylene, 2, 7-dimethylnaphthalene, 7-isopropyl-1-methylfluorene, azulene, limonene, phenanthrene, 2, 7-dimethylphenanthrene, 2, 3, 6-trimethylnaphthalene, 2-phenylnaphthalene, 1, 2, 3, 4-tetrahydroanthracene, 2, 3-dimethylnaphthalene, ethylidenefluorene, 1, 7-dimethylfluorene, 1-dinaphthylmethane, fluoranthene, 2, 6-dimethylnaphthalene, 2, 4-dimethylphenanthrene, fluorene, 4, 10-dimethyl-1, 2-benzanthracene, 4 h-cyclopenta (def) phenanthrene, 1,3, 8-trimethylphenanthrene, 11-methylnaphthoanthracene, 5-methylchrysene, 1, 2, 5, 6-tetramethylnaphthalene, cycloheptane (fg) acenaphthylene, 1, 2, 7-trimethylphenanthrene, 1, 10-dimethyl-1, 2-dibenzanthracene, 9, 10-dimethyl-1, 2-benzanthracene, benzo (bc) anthrylene, 1-methylphenanthrene, 1, 6, 7-trimethylphenanthrene, 1-di (acenaphthylene), trans-stilbene, 3, 4-benzofluorene, 9-isopropylnaphthoanthracene, 6-methylnaphthoanthracene, 5, 8-dimethyl-1, 2-benzanthracene, 8-isopropylnaphthoanthracene, 1, 4,5, 8-tetramethylnaphthalene, 12-methylnaphthoanthracene, 2-methyl-1, 2-benzopyrene, 1, 5-dimethylanthracene, 7-methylnaphthoanthracene, 3, 6-dimethylphenanthrene, 5-methyl-3, 4-triphenylene, 1, 4-dimethylchrysene, 1, 2-dimethylphenylene, 8, 10-dimethyl-1, 2-benzanthracene, 1, 2, 8-trimethylphenanthrene, 3-methyl-1, 2-benzopyrene, 9-phenylfluorene, 2-methylnaphthoanthracene, pyrene, 9-methylnaphthoanthracene, 4-methylcephalene, trans-1, 4-diphenyl-1, 3-butadiene, cinnamylidene fluorene, 5-methylnaphthoanthracene, 1, 2-benzanthracene, 8-methylnaphthoanthracene, 1-binaphthyl, di-1-naphthostilbene, 6-methylchrysene, 3-methylnaphthoanthracene, 2, 6-dimethyl-1, 2-benzanthracene, cyclopentaphenanthrene, 10, 11-benzanthracene, hexamethylbenzene, 3-methylcanthrene, cholanthracene, 6-methyl-1, 2-benzopyrene, 6, 7-dimethyl-1, 2-benzanthracene, 1, 2-benzopyrene, 5, 10-dimethyl-1, 2-benzanthracene, 4, 5-benzopyrene, 9, 10-dimethylanthracene, 10-methylnaphthoanthracene, 5, 6-dimethyl-1, 2-benzanthracene, 2-binaphthyl, 1, 2-benzofluorene, 1, 8-dimethylphenanthrene, 8-methyl-1, 2-benzopyrene, bifluorene (bifluorenylidene), 1, 2, 7, 8-dibenzoanthracene, 4-methylnaphthoanthracene, 1, 2, 3, 4-dibenzoanthracene, di-2-fluorenylmethane, 2, 3-benzofluorene, 5-methyl-1, 2-benzopyrene, anthracene, 11, 12-benzofluoranthene, 4-methyl-1, 2-benzopyrene, 2, 8-dimethylachrysene, 2-methylachrysene, 6, 12-dimethylachrysene, 1, 2-triphenylene, di-2-naphthostilbene, 1-methylachrysene, 2, 3, 6, 7-dibenzophenanthrene, 2, 3, 5, 6-dibenzophenanthrene, 1, 2, 5, 6-dibenzoanthracene, perylene, picene, 1, 2, 3, 4,5, 6,7, 8-tetrabenzoanthracene, coronene. The term aryl includes both substituted and unsubstituted aryl groups. The aryl group may be optionally substituted with any group that does not adversely affect the reaction, such Groups including, but not limited to, halogen, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, or any other variable functional group that does not inhibit the pharmacological activity of the compound, either unprotected, or protected as desired, as is known to those skilled in the art, for example, see Greene et al, Protective Groups in Organic Synthesis, John Wiley & Sons, Second Edition, 1991, which is incorporated herein by reference. Non-limiting examples of aryl groups include heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, heteroarylalkoxy, arylamino, aralkylamino, arylthio, monoarylamidosulfonyl, arylsulfonylamino, diarylamidosulfonyl, monoarylamidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, aroyl, heteroaroyl, aralkoyl, heteroaralkanoyl, hydroxyaralkyl, hydroxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl, An aralkyloxycarbonyl group.

The term "alkaryl" or "alkylaryl" refers to an alkyl group with an aryl substituent. The term "aralkyl" or "arylalkyl" refers to an aryl group having an alkyl substituent.

The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.

The term "heteroatom" as used herein refers to oxygen, sulfur, nitrogen and phosphorus.

The term "acyl" refers to a carboxylic acid ester in which the non-carbonyl portion of the ester group is any group that does not adversely affect or provide a beneficial effect to the reaction process. Non-limiting examples are selected from linear, branched or cyclic alkyl or lower alkyl, alkoxyalkyl including methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as phenoxymethyl, aryl including phenyl which may optionally be substituted by halogen, alkyl or alkoxy, sulfonate esters such as alkyl or aralkylsulfonyl including methanesulfonyl, mono-, di-or triphosphate, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g. dimethyl-tert-butylsilyl) or diphenylmethylsilyl.

The term "protected" as used herein, unless otherwise indicated, refers to a group that is added to an oxygen, nitrogen or phosphorus atom to prevent further reaction thereof or for other purposes. Various oxygen and nitrogen protecting groups are well known to those skilled in the art of organic synthesis.

The term "purine base" or "pyrimidine base" includes, but is not limited to, adenine, N⁶-alkylpurine, N⁶Acylpurines (in which the acyl group is C (O) (alkyl, aryl, alkylaryl or arylalkyl), N⁶-benzylpurine, N⁶-halopurine, N⁶-vinyl purine, N⁶-ethynylpurine, N⁶-acylpurine, N⁶-hydroxyalkylpurine, N⁶Alkylthio purines, N²-alkylpurine, N²-alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine including 6-azacytosine, 2-and/or 4-mercaptopyrimidine, uracil, 5-halouracil including 5-fluorouracil, C⁵Alkyl pyrimidines, C⁵-benzylpyrimidine, C⁵-halogenopyrimidine, C⁵-vinyl pyrimidine, C⁵-ethynylpyrimidine, C⁵Acyl pyrimidine, C⁵-hydroxyalkylpurine, C⁵Acylaminopyrimidine, C⁵-cyanopyrimidine, C⁵-nitropyrimidine, C⁵Amino-pyrimidines, N²-alkylpurine, N²-alkyl-6-thiopurine, 5-azacytidine, 5-azauracil, triazolopyridine, imidazopyridine, pyrrolopyrimidine, pyrazolopyrimidine, guanine, adenine, hypoxanthine, 2, 6-diaminopurine, optionally substituted in the 6-position with an amino or carbonyl groupAnd 6- (Br, Cl or I) -purines optionally substituted at the 2-position with substituents including amino or carbonyl. The oxygen or nitrogen functionality on the base may be protected as desired or required. Suitable protecting groups are well known to those skilled in the art and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, trityl, alkyl and acyl groups such as acetyl and propionyl, methanesulfonyl and p-toluenesulfonyl.

The term "heteroaryl" or "heteroaromatic" as used herein refers to an aryl group containing at least one oxygen, sulfur, nitrogen or phosphorus in the aromatic ring.

The term "heterocycle" refers to a non-aromatic cyclic group in which at least one heteroatom such as sulfur, oxygen, nitrogen, or phosphorus is included in the ring.

Non-limiting examples of heteroaryl and heterocyclyl groups include furyl, pyridyl, pyrimidinyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuryl, benzothienyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1, 2, 4-thiadiazolyl, isoxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthine, hypoxanthine, thiophene, furan, pyrrole, isoxazole, pyrazole, imidazole, 1, 2, 3-triazole, 1, 2, 4-triazole, oxazole, isoxazole, thiazole, isothiazole, pyrimidine or pyridazine, and pteridinyl, aziridine, thiazole, isothiazole, 1, 2, 3-oxadiazole, Thiazine, pyridine, pyrazine, piperazine, pyrrolidine, oxaziridine, phenazine, phenothiazinyl, morpholinyl, pyrazolyl, pyridazinyl, pyrazinyl, quinoxalinyl, xanthine, hypoxanthine, pteridinyl, 5-azacytidine, 5-azauracil, triazolopyridine, imidazopyridine, pyrrolopyrimidine, pyrazolopyrimidine, adenine, N⁶-alkylpurine, N⁶-benzylpurine, N⁶-halopurine, N⁶-vinyl purine, N⁶-ethynylpurine, N⁶-acylpurine, N⁶-hydroxyalkylpurine, N⁶Alkylthio purines, thymines, cytosines, 6-azapyrimidines, 2-mercaptopyrimidines, uracils, N⁵Alkyl pyrimidines, N⁵-benzylpyrimidine, N⁵Halogenated pyrimidines, N⁵-vinyl pyrimidine, N⁵-ethynylpyrimidine, N⁵Acyl pyrimidine N⁵-hydroxyalkylpurine and N⁶Alkylthiopurines and isoxazolyls. The heteroaryl group may be optionally substituted as described above for aryl. The heterocyclyl or heteroaryl group may be optionally substituted with one or more substituents selected from: halogen, haloalkyl, alkyl, alkoxy, hydroxy, carboxy derivative, amido, amino, alkylamino, dialkylamino. The heteroaryl group may be partially or fully hydrogenated as desired. As a non-limiting example, dihydropyridine may be used instead of pyridine. Oxygen or nitrogen functional groups on the heterocyclic or heteroaryl groups may be protected as needed or desired. Suitable protecting groups are well known to those skilled in the art and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl, acyl groups such as acetyl and propionyl, methanesulfonyl and p-toluenesulfonyl. The heterocyclic or heteroaryl group may be substituted with any group that does not adversely affect the reaction, such groups including, but not limited to, those described above with respect to aryl groups.

The term "chiral" refers to any carbon center in which a carbon atom is attached to 4 different substituents. The chiral group may be in the D or L configuration. Examples of chiral groups include, but are not limited to, menthyl, demethylephedrine, 2-octyl, ethyl 3-hydroxybutyrate, ethyl 4-chloro-3-hydroxybutyrate, ethyl 2-hydroxy-4-phenylbutyrate, 2- (1-hydroxyethyl) -pyridine, methyl 3-hydroxybutyrate, ethyl 3-hydroxybutyrate, 2-hydroxy-4-phenyl-butyrate, 1- (3, 4-methylenedioxyphenyl) -2-propanol, 6-methyl-5-hepten-2-ol, 1- (2-naphthyl) -ethanol, trans-4-phenyl-3-buten-2-ol, trans-4-buten-2-ol, and mixtures thereof, 1-phenylethanol, 1-phenyl-2-propanol, 4-phenyl-2-butanol, ethyl lactate, 4-cyanophenylmethanol chiral dichlorophthalate, 4-bromophenylcarbinol chiral dichlorophthalate, 4-methoxyphenylmethanol chiral dichlorophthalate, 4-chlorophenylmethanol chiral dichlorophthalate, 4-nitrophenylmethanol chiral dichlorophthalate, 1-phenyl-2-propanol, 4-phenyl-2-butanol, ethyl lactate, 4-cyanophenylmethanol chiral dichlorophthalate, 4-phenylphenylmethanol chiral dichlorop, 4-nitrophenyl methyl alcohol chiral dichlorophthalate, (4-bromophenyl) - (4-methylphenyl) methyl alcohol chiral dichlorophthalate, (4-bromophenyl) -phenyl-d 5 methyl alcohol chiral dichlorophthalate, (4-bromophenyl) -phenyl-d 5 methyl alcohol chiral dichlorophthalate, and chiral dichlorophthalyl alcohol (dichlorophthalic alcohol).

Stereochemistry II

The nucleosides formed by these coupling reactions can have asymmetric centers and can exist as racemates, racemic mixtures, individual diastereomers or enantiomers, with all isomeric forms being included within the scope of the present invention. Nucleosides having a chiral center can exist and be isolated in optically active and racemic forms. Such compounds may exhibit polymorphism. Nucleosides formed by the coupling reaction can include forms of racemic, optically active, polymorphic, or stereoisomers, or mixtures thereof, having useful properties as described herein. Optically active forms can be prepared, for example, by the following methods: resolution from racemic forms using recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, chromatographic separation using a chiral stationary phase, or enzymatic resolution.

In one embodiment, R is selected as a chiral group that remains in the formed nucleoside as an ester at the 5' -position. Thus leaving the chiral R group in place to facilitate separation of the enantiomers by fractional crystallization, chiral or conventional chromatography, enzymatic resolution, and the like. The optically active forms of the compounds can be prepared by any method known in the art, including resolution from racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.

Examples of the method for obtaining an optically active substance include at least the following methods:

i) physically separated crystalsA technique for separating the macroscopic crystals of the individual enantiomers by hand. This technique can be used if crystals of the individual enantiomers are present, i.e. if the substance is an agglomerate and the crystals are clearly visible;

ii) simultaneous crystallizationA technique for the crystallization of individual enantiomers separately from a solution of the racemate, which can be used only when the enantiomer crystallized later is a solid agglomerate;

iii) enzymatic resolutionA technique for partial or complete separation of racemates using the difference in the reaction rate of the enantiomers with the enzyme;

iv) enzyme asymmetric synthesis-one such synthesis technique, wherein an enzymatic reaction is used in at least one synthesis step to obtain a synthetic precursor of the desired enantiomer, enantiomerically pure or enriched in the enantiomer;

v) chemical asymmetric synthesisOne such synthesis technique, wherein the desired enantiomer is synthesized under conditions that produce asymmetry (i.e., chirality) in the product, such conditions may be achieved using chiral catalysts or chiral auxiliaries;

vi) diastereomer separationOne such technique, in which a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) to convert the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization using their more pronounced structural differences, followed by removal of the chiral auxiliary to obtain the desired enantiomers；

vii) First or second order asymmetric transformationA technique in which the conversion from the racemate to the diastereomer reaches an equilibrium in which the conversion from the desired enantiomer to the diastereomer in solution predominates, or in which the diastereomer preferentially crystallizes from the desired enantiomer breaks the equilibrium, so that ultimately substantially all of the material is converted from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is thus liberated from the diastereomer;

viii) power splittingThis technique refers to the partial or complete resolution of the racemate (or the further resolution of partially resolved compounds) using the different reaction rates of enantiomers with chiral non-racemic reagents or catalysts under kinetic conditions;

ix) enantiospecific synthesis from non-racemic precursors-a synthesis technique in which the desired enantiomer is obtained from achiral starting materials and which involves no or only very little stereochemical integrity during the synthesis;

x) chiral liquid chromatographyOne such technique, in which enantiomers of a racemate are separated in a liquid mobile phase (including via chiral HPLC) using different phase interactions of the enantiomers with a stationary phase. The stationary phase may be made of chiral material, or the mobile phase may contain additional chiral material to provoke different interactions;

xi) chiral gas chromatographyOne such technique, in which racemates are volatilized and separated by the different phase interactions of the enantiomers in a gas mobile phase with a column containing a non-racemic chiral adsorbent stationary phase;

xii) extraction with chiral solvent-a technique wherein enantiomers are separated by preferential dissolution of one enantiomer into a particular chiral solvent;

xiii) transport via chiral membranesOne such technique, in which the racemate is brought into contact with a thin film barrier layer. The barrier typically separates two miscible fluids, one of which contains the racemate, and the driving force, e.g., concentration or pressure differential, causes preferential transport through the membrane barrier. Separation is achieved because the non-racemic nature of the membrane allows only one enantiomer of the racemate to pass through.

In one embodiment, chiral chromatography, including simulated moving bed chromatography, is used. A variety of different chiral stationary phases are commercially available.

Detailed description of the method steps

The key intermediate of this process is the appropriate 2, 2-dialkoxyethyl halide of the formula

Wherein X is halogen (F, Cl, Br, I) and each R' is independently alkyl (including but not limited to C)_1-9Alkyl), alkenyl (including but not limited to C)_2-9Alkenyl), alkynyl (including but not limited to C)_2-9Alkynyl), aryl (including but not limited to C)_4-10Aryl or C_6-10Aryl), aralkyl, heteroaryl, or heterocycle.

In another embodiment, X is OTs, OMs, or any other suitable leaving group. The 2, 2-dialkoxyethyl halides are commercially available or can be prepared by any known method, including standard substitution and/or addition techniques. Because 2, 2-dialkoxyethyl halides are inexpensive, in one embodiment, 2, 2-dialkoxyethyl halides are purchased.

A2, 2-dialkoxyethyl halide may be reacted with a compound of formula^-Suitable carboxylate salts are shown by OC (═ O) R, where R is hydrogen, alkyl (including but not limited to C)_1-9Alkyl group), C_2-9Alkenyl, alkynyl (including but not limited to C)_2-9Alkynyl) or aryl(including but not limited to C_4-10Aryl or C_6-10Aryl) which may be substituted with one or more substituents. The carboxylic acid salts are commercially available or can be prepared by any known method, including reacting the corresponding carboxylic acid with a suitable base to obtain an alkali or alkaline earth metal salt of the carboxylic acid. The reaction may be carried out in a compatible solvent at a suitable temperature to form the corresponding acetal.

The acetal formation can be carried out in any reaction solvent that is capable of reaching the desired temperature and of dissolving the reaction components. Non-limiting examples are any aprotic solvent including, but not limited to, alkyl solvents such as hexane and cyclohexane, toluene, acetone, ethyl acetate, dithianes, THF, dioxane, acetonitrile, dichloromethane, dichloroethane, diethyl ether, pyridine, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide, hexamethylphosphoric triamide, or any combination thereof. In one embodiment, the solvent is a polar aprotic solvent, such as acetonitrile, DMF, DMSO, or hexamethylphosphoric triamide, preferably DMF.

The acetal formation may be carried out at any temperature suitable to achieve the desired result, i.e., to allow the reaction to proceed at an acceptable rate without promoting decomposition or producing excessive by-products. Preferred temperatures are reflux conditions, such as 153 ℃ of refluxing DMF.

The hydrolysis of the acetal to produce the α -acyloxyacetaldehyde can be carried out using any suitable organic or inorganic acid. For example, aqueous formic acid may be used to facilitate hydrolysis.

The reaction can be carried out at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or producing excessive by-products. The preferred temperature is room temperature.

Suitable solvents include any protic or aprotic solvent, including but not limited to alkyl solvents such as hexane and cyclohexane, toluene, acetone, ethyl acetate, dithianes, THF, dioxane, acetonitrile, dichloromethane, dichloroethane, diethyl ether, pyridine, Dimethylformamide (DMF), Dimethylsulfoxide (DMSO), dimethylacetamide, or any combination thereof, preferably THF.

The α -acyloxyacetaldehyde can then be cyclized by known methods to form a 1, 3-oxathiolane ring or a 1, 3-dioxolane ring. For example, a 1, 3-oxathiolane ring can be prepared by one of the following methods: (i) reacting an aldehyde derived from a glyoxylic acid ester or glycolic acid with mercaptoacetic acid in toluene in the presence of p-toluenesulfonic acid to form 5-oxo-1, 3-oxathiolane-2-carboxylic acid (Kraus J-l. et al, Synthesis, 1991, 1046); (ii) cyclizing the anhydrous glyoxylic ester with 2-mercaptoacetaldehyde diethyl acetal in toluene under reflux to form 5-ethoxy-1, 3-oxathiolactone (U.S. Pat. No. 5,047,407); (iii) (iii) condensing the glyoxylate with mercaptoacetaldehyde (dimeric form) to form 5-hydroxy-1, 3-oxathiolane-2-carboxylate, or (iv) coupling an acyloxyacetaldehyde with 2, 5-dihydroxy-1, 4-dithiane, dimeric form of 2-mercaptoacetaldehyde, to form 2- (acyloxy) methyl-5-hydroxy-1, 3-oxathiolane. In the synthesis of nucleosides, lactones, 5-oxo compounds, must be reduced to the corresponding lactols. It is also necessary to reduce 2-carboxylic acid or its esters to the corresponding 2-hydroxymethyl derivatives with borane-dimethylsulfide complex. Glycolic acid can be used as the 1, 3-dioxolane ring; glycolaldehyde (dimeric form); glycolaldehyde dialkyl acetals such as diethyl acetal; activated and/or protected glycolic acid or glycolaldehyde, or any chemical equivalent of glycolic acid or glycolaldehyde, is prepared in a similar manner. In a particular embodiment, the 1, 3-dioxolane ring is formed with trimethylsilyl (trimethylsilyl) acetate.

beta-D or beta-L-nucleosides can be prepared by condensing a silylated purine or pyrimidine base with a 1, 3-oxathiolane or 1, 3-dioxolane intermediate. U.S. Pat. No. 5,204,466 discloses a process for condensing 1, 3-oxathiolanes with silylated pyrimidines using tin chloride as a Lewis acid, which process provides full beta-stereoselectivity (see also Choi et al, loc. cit.). Many US patents disclose processes for preparing 1, 3-oxathiolane nucleosides, including the condensation of 1, 3-oxathiolane-2-carboxylic acid esters with a protected silanated base in the presence of a silicon-based lewis acid, followed by reduction of the ester to the corresponding hydroxymethyl group to obtain the final product (see US patent 5,663,320, 5,693,787, 5,696,254, 5,744,596, 5,756,706, 5,864,164).

US patent 5,272,151 discloses the use of 2-O-protected-5-O-acylated-1, 3-oxathiolanes for the preparation of nucleosides by condensation with a silylated purine or pyrimidine base in the presence of a titanium catalyst.

US patent 6,215,004 discloses a process for the preparation of 1, 3-oxathiolane nucleosides comprising condensing 2-O-protected-methyl-5-chloro-1, 3-oxathiolane with silanized 5-fluorocytosine without the use of lewis catalysts.

Other biologically active compounds such as mescarine (Hopkins m.h. et al, j.am. chem.soc., 1991, 113, 5354), oxetanocin (hambalak R. & Just, Tetrahedron lett., 1990, 31, 5445), kallillide a (Marshall j.a. et al, j.org.chem., 1998, 63, 5962), (-) -kumausanone and (+) -epi-kumaullone (gret.s. et al, j.org.chem., 1993, 58, 2468) can be synthesized by similar methods using α -acyloxyacetaldehyde as a precursor.

The following examples are provided to further understand the preparation process of the present invention. These examples are given for the purpose of illustration and are not intended to limit the scope of the invention. Equivalent, similar or suitable solvents, reagents or reaction conditions may be substituted for the specific solvents, reagents or reaction conditions described in the examples without departing from the general scope of the process of the invention.

Examples

Melting points were determined using a Met-temp II laboratory setup and were uncorrected. NMR spectra were recorded at Bruker250 and AMX 400400Recorded on a MHz spectrometer using tetramethylsilane as an internal standard; chemical shifts (δ) are given in parts per million (ppm) and signals are described as s (singlet), d (doublet), t (triplet), q (quartet), bs (broad singlet), dd (doublet), and m (multiplet). The UV spectra were obtained on a Beckman DU650 spectrophotometer. Optical rotations were measured on a Jasco DIP-370 digital polarimeter. Mass spectra were measured with a Micromass inc. The infrared spectra were recorded on a Nicolet 510 FT-IR spectrometer. Elemental analysis was performed by Atlantic Microlab, inc. All reactions were monitored using thin layer chromatography on Analtech, 200mm silica gel GF plates. Anhydrous 1, 2-dichloroethane, dichloromethane and acetonitrile are prepared by reacting CaH with acetonitrile before use₂Obtained by distillation. Anhydrous THF was obtained by distillation from Na and benzophenone solutions as they turned purple.

Example 1

Preparation of benzoyloxy acetaldehyde diethyl acetal (3)

Mixing NaOBz (2, R)¹Ph, M ═ Na) (0.055mol, 7.9g) to bromoacetaldehyde diethyl acetal (1, R)²Et) (0.1mol, 19.7g, 15.0mL) in DMF (150mL) and the mixture was refluxed for 2 hours. NaOBz (0.055mol, 7.9g) was added portionwise under reflux. Reflux was continued for a total of 5 hours and the mixture was then allowed to cool to room temperature. Water (150mL) was added and the mixture was extracted with EtOAc (4X 50 mL). The combined extracts were washed with water (4X 25mL) and dried (Na)₂SO₄) And concentrated in vacuo. The residue was azeotroped with toluene (2X 20mL) to give benzoyloxyacetaldehyde diethyl acetal 3 (R)¹＝Ph，R²Et) as a dark oily product (21.45g, 90%). The product was used directly in the next step without purification.

The following exemplary α -acyloxyacetaldehyde diethanols were prepared in a similar manner using the corresponding sodium carboxylates:

the preparation method of the acetoxy-acetaldehyde diethyl acetal,

n-propionyloxy acetaldehyde diethyl acetal,

isopropionyloxyacetaldehyde diethyl acetal,

n-butyl acyloxy acetaldehyde diethyl acetal,

the sec-butyl-acyloxy-acetaldehyde diethyl acetal,

a tertiary butyryloxy acetaldehyde diethyl acetal,

the valeryl-oxy-acetaldehyde diethyl acetal,

the caproyloxy acetaldehyde diethyl acetal has the structure of ethyl hexanoyl acetal,

the ethanol acetal of the caprylyl-oxy-acetaldehyde,

the benzoyloxy acetaldehyde diethyl acetal is used as a raw material,

p-toluoyloxy acetaldehyde diethyl acetal,

m-toluene formyloxy acetaldehyde diethyl acetal,

o-toluoyloxy acetaldehyde diethyl acetal,

p-chlorobenzoyloxy acetaldehyde diethyl acetal,

m-chlorobenzoyloxy acetaldehyde diethyl acetal,

o-chlorobenzoyloxy acetaldehyde diethyl acetal,

p-bromobenzoyloxy acetaldehyde diethyl acetal,

m-bromobenzoyloxyacetaldehyde diethyl acetal,

o-bromobenzoyloxy acetaldehyde diethyl acetal,

p-methoxybenzoyloxy acetaldehyde diethyl acetal,

m-methoxybenzoyloxy acetaldehyde diethyl acetal,

o-methoxybenzoyloxy acetaldehyde diethyl acetal,

p-nitrobenzoyloxy acetaldehyde diethyl acetal,

m-nitrobenzoyloxy acetaldehyde diethyl acetal,

o-nitrobenzoyloxy acetaldehyde diethyl acetal,

o-acetylsalicyloyloxyacetaldehyde diethyl acetal.

The following exemplary α -acyloxyacetalcohols were prepared in a similar manner using the corresponding acetaldehyde dimethyl acetal:

the preparation method of the acetoxy acetaldehyde dimethyl acetal,

n-propionyloxy acetaldehyde dimethyl acetal,

isopropionyloxyacetaldehyde dimethyl acetal,

n-butyl acyloxy acetaldehyde dimethyl acetal is used,

the sec-butyl-acyloxy-acetaldehyde dimethyl acetal,

a tertiary butyryloxy acetaldehyde dimethyl acetal,

a pentanoyloxy acetaldehyde dimethyl acetal,

hexanoyloxy acetaldehyde dimethyl acetal is used as a raw material,

the synthesis of the octanoyloxy acetaldehyde dimethyl acetal,

the benzoyloxy acetaldehyde dimethyl acetal is used as a raw material,

p-toluoyloxy acetaldehyde dimethyl acetal,

m-toluene formyloxy acetaldehyde dimethyl acetal,

o-toluoyloxy acetaldehyde dimethyl acetal,

p-chlorobenzoyloxy acetaldehyde dimethyl acetal,

m-chlorobenzoyloxy acetaldehyde dimethyl acetal,

o-chlorobenzoyloxy acetaldehyde dimethyl acetal,

p-bromobenzoyloxy acetaldehyde dimethyl acetal,

m-bromobenzoyloxy acetaldehyde dimethyl acetal,

o-bromobenzoyloxy acetaldehyde dimethyl acetal,

p-methoxybenzoyloxy acetaldehyde dimethyl acetal,

m-methoxybenzoyloxy acetaldehyde dimethyl acetal,

o-methoxybenzoyloxy acetaldehyde dimethyl acetal,

p-nitrobenzoyloxy acetaldehyde dimethyl acetal,

m-nitrobenzoyloxy acetaldehyde dimethyl acetal,

o-nitrobenzoyloxy acetaldehyde dimethyl acetal,

o-acetylsalicyloyloxyacetaldehyde dimethyl acetal.

The following exemplary α -acyloxyacetaldehyde acetals were prepared in a similar manner using the corresponding acetaldehyde dibenzyl alcohols:

the acetoxyacetaldehyde dimethyl acetal is used as the raw material,

n-propionyloxy acetaldehyde dimethyl acetal,

isopropionyloxyacetaldehyde dimethyl acetal,

n-butyl acyloxy acetaldehyde dimethyl acetal is used,

sec-butyl-acyloxy-acetaldehyde dimethyl acetal,

tert-butyryloxy acetaldehyde dimethyl acetal,

valeryloxy acetaldehyde dimethyl acetal is used as the raw material,

hexanoyloxy acetaldehyde dimethyl acetal and diethyl acetal in the presence of hydrogen chloride,

the octanoyloxy acetaldehyde dimethyl acetal is used as the raw material,

benzoyloxy acetaldehyde dimethyl acetal and benzyl alcohol diethyl acetal,

p-toluoyloxy acetaldehyde dibenzyl acetal,

m-toluoyloxy-acetaldehyde diphenyl carbinol,

o-toluoyloxy acetaldehyde dibenzyl alcohol,

p-chlorobenzoyloxy acetaldehyde dimethyl acetal,

m-chlorobenzoyloxy acetaldehyde dimethyl acetal,

o-chlorobenzoyloxy acetaldehyde dimethyl acetal,

p-bromobenzoyloxy acetaldehyde dimethyl acetal,

m-bromobenzoyloxy aldehyde condensed benzhydryl alcohol,

o-bromobenzoyloxy acetaldehyde dimethyl acetal,

p-methoxybenzoyloxy acetaldehyde dibenzyl acetal,

m-methoxybenzoyloxy acetaldehyde dibenzyl acetal,

o-methoxybenzoyloxy acetaldehyde dibenzyl acetal,

p-nitrobenzoyloxy acetaldehyde dimethyl acetal,

m-nitrobenzoyloxy acetaldehyde dimethyl acetal,

o-nitrobenzoyloxy acetaldehyde dimethyl acetal,

o-acetylsalicyloyloxyacetaldehyde dibenzyl alcohol.

The following exemplary α -acyloxyacetaldehyde acetals were prepared in a similar manner using the corresponding acetaldehyde dineopentanol:

the acetoxy acetaldehyde diethyl acetal is used as the raw material,

n-propionyloxy acetaldehyde diethyl acetal,

isopropionyloxyacetaldehyde diethyl acetal,

n-butyl acyloxy acetaldehyde diethyl acetal,

sec-butyl acyloxy acetaldehyde diethyl acetal,

tert-butyryloxy acetaldehyde diethyl acetal,

valeryloxy acetaldehyde diethyl acetal,

hexanoyloxy acetaldehyde diethyl acetal,

the octanoyloxy acetaldehyde diethyl acetal is used as the raw material,

benzoyloxy acetaldehyde diethyl acetal,

p-toluoyloxy acetaldehyde diethyl acetal,

m-toluene formyloxy acetaldehyde diethyl acetal,

o-toluoyloxy acetaldehyde diethyl acetal,

p-chlorobenzoyloxy acetaldehyde diethyl acetal,

m-chlorobenzoyloxy acetaldehyde diethyl acetal,

o-chlorobenzoyloxy acetaldehyde diethyl acetal,

p-bromobenzoyloxy acetaldehyde diethyl acetal,

m-bromobenzoyloxy acetaldehyde diethyl acetal,

o-bromobenzoyloxy acetaldehyde diethyl acetal,

p-methoxybenzoyloxy acetaldehyde diethyl acetal,

m-methoxybenzoyloxy acetaldehyde diethyl acetal,

o-methoxybenzoyloxy acetaldehyde diethyl acetal,

p-nitrobenzoyloxy acetaldehyde diethyl acetal,

m-nitrobenzoyloxy acetaldehyde diethyl acetal,

o-nitrobenzoyloxy acetaldehyde diethyl acetal,

salicyloyloxy acetaldehyde diethyl acetal.

The following exemplary α -acyloxyacetaldehyde acetals were prepared in a similar manner using the corresponding acetaldehyde dimercaptan:

the compound of the acetoxy acetaldehyde dimercaptan,

n-propionyloxy acetaldehyde dimercaptan,

isopropionyloxyacetaldehyde dimercaptan,

n-butyl acyloxy acetaldehyde dimercaptan,

sec-butyl-oxy-acetaldehyde dimercaptan,

tertiary butyryloxy acetaldehyde dimercaptan,

a valeryloxy acetaldehyde dimercaptan,

the amount of hexanoyloxy acetaldehyde dimercaptan,

the preparation method of the compound comprises the steps of (1) octanoyloxy acetaldehyde dimementhanol,

benzoyloxy acetaldehyde dimercaptan is used as a raw material,

p-toluoyloxy acetaldehyde dimercaptan,

m-toluoyloxy acetaldehyde dimercaptan,

o-toluoyloxy acetaldehyde dimercaptan,

p-chlorobenzoyloxy acetaldehyde dimercaptan,

m-chlorobenzoyloxy acetaldehyde dimercaptan,

o-chlorobenzoyloxy acetaldehyde dimercaptan,

p-bromobenzoyloxy acetaldehyde dimercaptan,

m-bromobenzoyloxy acetaldehyde dimercaptan,

o-bromobenzoyloxy acetaldehyde dimercaptan,

p-methoxybenzoyloxy acetaldehyde dimercaptan,

m-methoxybenzoyloxy acetaldehyde dimercaptan,

o-methoxybenzoyloxy acetaldehyde dimercaptan,

p-nitrobenzoyloxy acetaldehyde dimercaptan,

m-nitrobenzoyloxy acetaldehyde dimercaptan,

o-nitrobenzoyloxy acetaldehyde dimercaptan,

o-acetylsalicyloyloxyacetaldehyde dimercaptan.

Example 2

Hydrolysis of the acetal (3) to the aldehyde (4)

Reacting acetal 3 (R)¹＝Ph，R²Et)2.38g, 10mol) in aqueous formic acid (HCO)₂H/H₂O8/2 v/v, 24mL) was stirred at room temperature for 3 hours and concentrated to dryness under reduced pressure (aspirator). The residue was evaporated with toluene (2X 10mL) to give aldehyde 4 (R)¹＝Ph)。

Or, converting acetal 3 (R)¹＝Ph，R²Et, 2.38g) was treated with a mixture of trifluoroacetic acid (11mL), THF (10mL) and water (3mL) at rt for 3 h, then the solvent was evaporated to give the same aldehyde 4 (R)¹Ph). The aldehyde is not pureThe reaction was used directly in the next reaction.

The following α -acyloxyacetaldehyde diethanols were prepared in a similar manner using the corresponding sodium carboxylates:

an acetoxy-acetaldehyde (Acetoxyacetaldehyde),

n-propionyloxy-acetaldehyde, and its salt,

(ii) an isopropanoxyacetaldehyde, to which is added,

n-butyroyloxyacetaldehyde (Naphthylacetic acid),

the sec-butyl-acyloxy-acetaldehyde is used,

a tertiary butanoyloxy-acetaldehyde,

a valeryl-oxy-acetaldehyde (E),

the amount of the caproyloxy acetaldehyde to be used,

the reaction product of octanoyloxy acetaldehyde and octanoyloxy acetaldehyde,

a benzoyloxy-acetaldehyde (I) is used,

a p-toluoyloxy acetaldehyde (P-toluoyloxy acetaldehyde),

the m-toluoyloxy acetaldehyde is used as a raw material,

an o-toluoyloxy acetaldehyde to be used as a raw material,

a p-chlorobenzoyloxy acetaldehyde (APA),

the m-chlorobenzoyloxy acetaldehyde is used as a raw material,

an o-chlorobenzoyloxy acetaldehyde to be used as a raw material,

a p-bromobenzoyloxy-acetaldehyde, which is,

m-bromobenzoyloxy acetaldehyde is obtained by reacting m-bromobenzoyloxy acetaldehyde,

o-bromobenzoyloxy-acetaldehyde is obtained by reacting o-bromobenzoyloxy-acetaldehyde,

a p-methoxybenzoyloxy acetaldehyde (APA),

a meta-methoxybenzoyloxy acetaldehyde (M-methoxybenzoyloxy acetaldehyde),

an o-methoxybenzoyloxy acetaldehyde (I) is obtained,

a p-nitrobenzoyloxy acetaldehyde (p-nitrobenzoyloxy acetaldehyde),

the m-nitrobenzoyloxy acetaldehyde is used as a raw material,

an o-nitrobenzoyloxy acetaldehyde (I) is obtained,

o-acetylsalicyloyloxyacetaldehyde.

Example 3

Cyclization and acetylation

To a solution of the above aldehyde 4 in anhydrous THF (24mL) was added dithiane-2, 5-diol (0.912g, 6mmol) and BF₃.Et₂O (4.8mmol, 0.64mL, decreasing the amount of catalyst), the mixture was stirred at room temperature for 2 hours. The solids were removed by filtration. To the filtrate were added the following: pyridine (28.8mmol, 2.3g, 2.3mL), acetic anhydride (15mmol, 1.42mL), and 4-dimethylaminopyridine (1mmol, 122 mg). The mixture was then stirred at room temperature for 16 hours. The solvent was removed and the residue was dissolved in EtOAc (100 mL). The mixture was washed with water (3X 10mL) and dried (Na)₂SO₄). The solvent was removed and the residue was purified by silica gel column chromatography (eluted with 20% EtOAc in hexane) to give racemic 5-acetoxy-2- (benzoyloxy) methyl-1, 3-oxathiolane 5 (R)¹Ph) as an oil. This procedure gave 2.2g of product, with a total yield of 78% over the three steps.

The following 2- (acyloxy) -5-acetoxy-1, 3-oxathiolane was prepared in a similar manner using the corresponding acyloxyacetaldehyde:

5-acetoxy-2- (acetoxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (n-propionyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (isopropionyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (n-butyryloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (sec-butyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (tert-butanoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2-pentanoyloxymethyl-1, 3-oxathiolane,

5-acetoxy-2-hexanoyloxymethyl-1, 3-oxathiolane,

5-acetoxy-2- (octanoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2-benzoyloxymethyl-1, 3-oxathiolane,

5-acetoxy-2- (p-toluoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (m-toluoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (o-toluoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (p-chlorobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (m-chlorobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (o-chlorobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (p-bromobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (m-bromobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (o-bromobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (p-methoxybenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (m-methoxybenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (o-methoxybenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (p-nitrobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (m-nitrobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (o-nitrobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (O-acetylsalicyloyloxy) methyl-1, 3-oxathiolane.

Claims (22)

1. A process for preparing an α -acyloxyacetaldehyde represented by the formula:

wherein R is hydrogen, alkyl, alkenyl, alkynyl or aryl, which groups may optionally be substituted with one or more substituents that do not adversely affect the reaction process, and R may be a chiral group; the method comprises the following steps:

a) 2, 2-dialkoxyethyl halide represented by the following formula

Wherein X is halogen or a suitable leaving group;

and each R' is independently alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, or heterocycle;

with a suitable carboxylate salt of the formula OC (═ O) R, where R is hydrogen, alkyl, alkenyl, alkynyl or aryl, which groups may be optionally substituted with one or more substituents;

to obtain an acetal of the formula

And

b) hydrolyzing the acetal to form an alpha-acyloxyacetaldehyde.

2. The method of claim 2, wherein the acetal is an α -acyloxyacetaldehyde dialkyl acetal.

3. The method of claim 2, wherein the α -acyloxyacetaldehyde dialkyl acetal is α -acyloxyacetaldehyde diethyl acetal.

4. The process of claim 3 wherein the α -acyloxyacetaldehyde diethyl acetal is selected from n-propionyloxyacetaldehyde diethyl acetal,

isopropionyloxyacetaldehyde diethyl acetal,

n-butyl acyloxy acetaldehyde diethyl acetal,

the sec-butyl-acyloxy-acetaldehyde diethyl acetal,

a tertiary butyryloxy acetaldehyde diethyl acetal,

the valeryl-oxy-acetaldehyde diethyl acetal,

the caproyloxy acetaldehyde diethyl acetal has the structure of ethyl hexanoyl acetal,

the ethanol acetal of the caprylyl-oxy-acetaldehyde,

p-toluoyloxy acetaldehyde diethyl acetal,

m-toluene formyloxy acetaldehyde diethyl acetal,

o-toluoyloxy acetaldehyde diethyl acetal,

p-chlorobenzoyloxy acetaldehyde diethyl acetal,

m-chlorobenzoyloxy acetaldehyde diethyl acetal,

o-chlorobenzoyloxy acetaldehyde diethyl acetal,

p-bromobenzoyloxy acetaldehyde diethyl acetal,

m-bromobenzoyloxyacetaldehyde diethyl acetal,

o-bromobenzoyloxy acetaldehyde diethyl acetal,

p-methoxybenzoyloxy acetaldehyde diethyl acetal,

m-methoxybenzoyloxy acetaldehyde diethyl acetal,

o-methoxybenzoyloxy acetaldehyde diethyl acetal,

p-nitrobenzoyloxy acetaldehyde diethyl acetal,

m-nitrobenzoyloxy acetaldehyde diethyl acetal,

o-nitrobenzoyloxy acetaldehyde diethyl acetal, and

o-acetylsalicyloyloxyacetaldehyde diethyl acetal.

5. The method of claim 2, wherein the α -acyloxyacetaldehyde dialkyl acetal is α -acyloxyacetaldehyde dimethyl acetal.

6. The process of claim 5, wherein the α -acyloxyacetaldehyde dimethyl acetal is selected from the group consisting of acetoxyacetaldehyde dimethyl acetal,

n-propionyloxy acetaldehyde dimethyl acetal,

isopropionyloxyacetaldehyde dimethyl acetal,

n-butyl acyloxy acetaldehyde dimethyl acetal is used,

the sec-butyl-acyloxy-acetaldehyde dimethyl acetal,

a tertiary butyryloxy acetaldehyde dimethyl acetal,

a pentanoyloxy acetaldehyde dimethyl acetal,

hexanoyloxy acetaldehyde dimethyl acetal is used as a raw material,

the synthesis of the octanoyloxy acetaldehyde dimethyl acetal,

the benzoyloxy acetaldehyde dimethyl acetal is used as a raw material,

p-toluoyloxy acetaldehyde dimethyl acetal,

m-toluene formyloxy acetaldehyde dimethyl acetal,

o-toluoyloxy acetaldehyde dimethyl acetal,

p-chlorobenzoyloxy acetaldehyde dimethyl acetal,

m-chlorobenzoyloxy acetaldehyde dimethyl acetal,

o-chlorobenzoyloxy acetaldehyde dimethyl acetal,

p-bromobenzoyloxy acetaldehyde dimethyl acetal,

m-bromobenzoyloxy acetaldehyde dimethyl acetal,

o-bromobenzoyloxy acetaldehyde dimethyl acetal,

p-methoxybenzoyloxy acetaldehyde dimethyl acetal,

m-methoxybenzoyloxy acetaldehyde dimethyl acetal,

o-methoxybenzoyloxy acetaldehyde dimethyl acetal,

p-nitrobenzoyloxy acetaldehyde dimethyl acetal,

m-nitrobenzoyloxy acetaldehyde dimethyl acetal,

o-nitrobenzoyloxy acetaldehyde dimethyl acetal, and

o-acetylsalicyloyloxyacetaldehyde dimethyl acetal.

7. The process of claim 2, wherein the α -acyloxyacetaldehyde dialkyl acetal is selected from the group consisting of acetoxyacetaldehyde diethyl acetal,

n-propionyloxy acetaldehyde diethyl acetal,

isopropionyloxyacetaldehyde diethyl acetal,

n-butyl acyloxy acetaldehyde diethyl acetal,

sec-butyl acyloxy acetaldehyde diethyl acetal,

tert-butyryloxy acetaldehyde diethyl acetal,

valeryloxy acetaldehyde diethyl acetal,

hexanoyloxy acetaldehyde diethyl acetal,

the octanoyloxy acetaldehyde diethyl acetal is used as the raw material,

benzoyloxy acetaldehyde diethyl acetal,

p-toluoyloxy acetaldehyde diethyl acetal,

m-toluene formyloxy acetaldehyde diethyl acetal,

o-toluoyloxy acetaldehyde diethyl acetal,

p-chlorobenzoyloxy acetaldehyde diethyl acetal,

m-chlorobenzoyloxy acetaldehyde diethyl acetal,

o-chlorobenzoyloxy acetaldehyde diethyl acetal,

p-bromobenzoyloxy acetaldehyde diethyl acetal,

m-bromobenzoyloxy acetaldehyde diethyl acetal,

o-bromobenzoyloxy acetaldehyde diethyl acetal,

p-methoxybenzoyloxy acetaldehyde diethyl acetal,

m-methoxybenzoyloxy acetaldehyde diethyl acetal,

o-methoxybenzoyloxy acetaldehyde diethyl acetal,

p-nitrobenzoyloxy acetaldehyde diethyl acetal,

m-nitrobenzoyloxy acetaldehyde diethyl acetal,

o-nitrobenzoyloxy acetaldehyde diethyl acetal, and

salicyloyloxy acetaldehyde diethyl acetal.

8. The process of claim 1 wherein the acetal is an α -acyloxyacetaldehyde diaryl alcohol.

9. The process of claim 8, wherein the α -acyloxyacetaldehyde diaryl alcohol is selected from the group consisting of acetoxyacetaldehyde benzyl acetal,

n-propionyloxy acetaldehyde dimethyl acetal,

isopropionyloxyacetaldehyde dimethyl acetal,

n-butyl acyloxy acetaldehyde dimethyl acetal is used,

sec-butyl-acyloxy-acetaldehyde dimethyl acetal,

tert-butyryloxy acetaldehyde dimethyl acetal,

valeryloxy acetaldehyde dimethyl acetal is used as the raw material,

hexanoyloxy acetaldehyde dimethyl acetal and diethyl acetal in the presence of hydrogen chloride,

the octanoyloxy acetaldehyde dimethyl acetal is used as the raw material,

benzoyloxy acetaldehyde dimethyl acetal and benzyl alcohol diethyl acetal,

p-toluoyloxy acetaldehyde dibenzyl acetal,

m-toluoyloxy-acetaldehyde diphenyl carbinol,

o-toluoyloxy acetaldehyde dibenzyl alcohol,

p-chlorobenzoyloxy acetaldehyde dimethyl acetal,

m-chlorobenzoyloxy acetaldehyde dimethyl acetal,

o-chlorobenzoyloxy acetaldehyde dimethyl acetal,

p-bromobenzoyloxy acetaldehyde dimethyl acetal,

m-bromobenzoyloxy aldehyde condensed benzhydryl alcohol,

o-bromobenzoyloxy acetaldehyde dimethyl acetal,

p-methoxybenzoyloxy acetaldehyde dibenzyl acetal,

m-methoxybenzoyloxy acetaldehyde dibenzyl acetal,

o-methoxybenzoyloxy acetaldehyde dibenzyl acetal,

p-nitrobenzoyloxy acetaldehyde dimethyl acetal,

m-nitrobenzoyloxy acetaldehyde dimethyl acetal,

o-nitrobenzoyloxy acetaldehyde dibenzyl alcohol, and

o-acetylsalicyloyloxyacetaldehyde dibenzyl alcohol.

10. The method of claim 1, wherein the acetal is an α -acyloxyacetaldehyde diterpene acetal.

11. The method of claim 10, wherein the α -acyloxyacetaldehyde diterpene acetal is selected from the group consisting of acetoxyacetaldehyde dimercaptan,

n-propionyloxy acetaldehyde dimercaptan,

isopropionyloxyacetaldehyde dimercaptan,

n-butyl acyloxy acetaldehyde dimercaptan,

sec-butyl-oxy-acetaldehyde dimercaptan,

tertiary butyryloxy acetaldehyde dimercaptan,

a valeryloxy acetaldehyde dimercaptan,

the amount of hexanoyloxy acetaldehyde dimercaptan,

the preparation method of the compound comprises the steps of (1) octanoyloxy acetaldehyde dimementhanol,

benzoyloxy acetaldehyde dimercaptan is used as a raw material,

p-toluoyloxy acetaldehyde dimercaptan,

m-toluoyloxy acetaldehyde dimercaptan,

o-toluoyloxy acetaldehyde dimercaptan,

p-chlorobenzoyloxy acetaldehyde dimercaptan,

m-chlorobenzoyloxy acetaldehyde dimercaptan,

o-chlorobenzoyloxy acetaldehyde dimercaptan,

p-bromobenzoyloxy acetaldehyde dimercaptan,

m-bromobenzoyloxy acetaldehyde dimercaptan,

o-bromobenzoyloxy acetaldehyde dimercaptan,

p-methoxybenzoyloxy acetaldehyde dimercaptan,

m-methoxybenzoyloxy acetaldehyde dimercaptan,

o-methoxybenzoyloxy acetaldehyde dimercaptan,

p-nitrobenzoyloxy acetaldehyde dimercaptan,

m-nitrobenzoyloxy acetaldehyde dimercaptan,

o-nitrobenzoyloxy acetaldehyde dimercaptan, and

o-acetylsalicyloyloxyacetaldehyde dimercaptan.

12. The process of claim 1, wherein the α -acyloxyacetaldehyde is selected from the group consisting of acetoxyacetaldehyde,

n-propionyloxy-acetaldehyde, and its salt,

(ii) an isopropanoxyacetaldehyde, to which is added,

n-butyroyloxyacetaldehyde (Naphthylacetic acid),

the sec-butyl-acyloxy-acetaldehyde is used,

a tertiary butanoyloxy-acetaldehyde,

a valeryl-oxy-acetaldehyde (E),

the amount of the caproyloxy acetaldehyde to be used,

the reaction product of octanoyloxy acetaldehyde and octanoyloxy acetaldehyde,

a benzoyloxy-acetaldehyde (I) is used,

a p-toluoyloxy acetaldehyde (P-toluoyloxy acetaldehyde),

the m-toluoyloxy acetaldehyde is used as a raw material,

an o-toluoyloxy acetaldehyde to be used as a raw material,

a p-chlorobenzoyloxy acetaldehyde (APA),

the m-chlorobenzoyloxy acetaldehyde is used as a raw material,

an o-chlorobenzoyloxy acetaldehyde to be used as a raw material,

a p-bromobenzoyloxy-acetaldehyde, which is,

m-bromobenzoyloxy acetaldehyde is obtained by reacting m-bromobenzoyloxy acetaldehyde,

o-bromobenzoyloxy-acetaldehyde is obtained by reacting o-bromobenzoyloxy-acetaldehyde,

a p-methoxybenzoyloxy acetaldehyde (APA),

a meta-methoxybenzoyloxy acetaldehyde (M-methoxybenzoyloxy acetaldehyde),

an o-methoxybenzoyloxy acetaldehyde (I) is obtained,

a p-nitrobenzoyloxy acetaldehyde (p-nitrobenzoyloxy acetaldehyde),

the m-nitrobenzoyloxy acetaldehyde is used as a raw material,

o-nitrobenzoyloxyacetaldehyde, and

o-acetylsalicyloyloxyacetaldehyde.

13. A process for preparing 1, 3-oxathiolanes of the formula:

wherein R is hydrogen, alkyl, alkenyl, alkynyl or aryl, which groups may optionally be substituted with one or more substituents that do not adversely affect the reaction process, and R may be a chiral group; b is a purine or pyrimidine base; the method comprises the following steps:

a) preparing an α -acyloxyacetal according to the process of claim 1 and then reacting with thioglycolic acid, a mercaptoaldehyde or a mercaptoacetaldehyde dialkyl acetal to form an intermediate 1, 3-oxathiolane of the formula:

wherein R is hydrogen, alkyl, alkenyl, alkynyl or aryl, which groups may optionally be substituted with one or more substituents that do not adversely affect the reaction process, and R may be a chiral group; l is a leaving group; and

b) reacting the intermediate 1, 3-oxathiolane with a purine or pyrimidine base in the presence of a lewis acid to obtain the 1, 3-oxathiolane.

14. The method of claim 13, wherein the leaving group is selected from the group consisting of O-acyl, O-alkyl, O-tosylate, O-mesylate and halogen (F, Cl, Br, I).

15. The process of claim 13, wherein the lewis acid is selected from TMSC1, TMSI, TMSTf, SnCl₄And TiCl₄。

16. A process for preparing 1, 3-dioxolanes represented by the formula:

wherein R is hydrogen, alkyl, alkenyl, alkynyl or aryl, which groups may optionally be substituted with one or more substituents that do not adversely affect the reaction process, and R may be a chiral group; b is a purine or pyrimidine base; the method comprises the following steps:

a) preparing an α -acyloxyacetal according to the process of claim 1 and then reacting with glycolic acid, glycolaldehyde or glycolaldehyde dialkyl acetal to form an intermediate 1, 3-dioxolane of the formula:

wherein R is hydrogen, alkyl, alkenyl, alkynyl or aryl, which groups may optionally be substituted with one or more substituents that do not adversely affect the reaction process, and R may be a chiral group; l is a leaving group; and

b) reacting the intermediate 1, 3-dioxolane with a purine or pyrimidine base in the presence of a Lewis acid to obtain the 1, 3-dioxolane nucleoside.

17. The method of claim 16, wherein the leaving group is selected from the group consisting of O-acyl, O-alkyl, O-tosylate, O-mesylate, and halogen.

18. The process of claim 17, wherein the lewis acid is selected from TMSC1, TMSI, TMSTf, SnCl₄And TiCl₄。

19. The process of claim 1, wherein the acetal hydrolysis is carried out with an organic acid.

20. The method of claim 19, wherein the organic acid is aqueous formic acid.

21. The process of claim 13 wherein said intermediate 1, 3-oxathiolane is selected from the group consisting of

5-acetoxy-2- (acetoxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (n-propionyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (isopropionyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (n-butyryloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (sec-butyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (tert-butanoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2-pentanoyloxymethyl-1, 3-oxathiolane,

5-acetoxy-2-hexanoyloxymethyl-1, 3-oxathiolane,

5-acetoxy-2- (octanoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2-benzoyloxymethyl-1, 3-oxathiolane,

5-acetoxy-2- (p-toluoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (m-toluoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (o-toluoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (p-chlorobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (m-chlorobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (o-chlorobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (p-bromobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (m-bromobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (o-bromobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (p-methoxybenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (m-methoxybenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (o-methoxybenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (o-nitrobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (m-nitrobenzoyloxy) methyl-1, 3-oxathiolane,

5-acetoxy-2- (o-nitrobenzoyloxy) methyl-1, 3-oxathiolane, and

5-acetoxy-2- (O-acetylsalicyloyloxy) methyl-1, 3-oxathiolane.

22. The method of claim 13 or 16, wherein the pyrimidine base is selected from cytosine and 5-fluorocytosine.