CN1379748A - Process for preparing optically active alpha-hydroxy acids and derivatives thereof - Google Patents

Abstract

The invention provides a process for the preparation of optically active alpha-hydroxy acids and derivatives thereof by alcoholysis or hydrolysis of alkylated 1, 3-dioxolanones of the general formula wherein R is₁And R₂May be the same or different and are independently of one another H or C_1－6Alkyl radical R₅Is hydrogen, C_1－16Alkyl or unsubstituted or substituted phenyl R₆Is C_1－8Alkyl radical, C_2－7Alkenyl or unsubstituted or substituted benzyl, wherein the alkylated 1, 3-dioxolanones are obtained using 10-camphorsulfonamide as chiral auxiliary.

Description

Preparation method of optically active α-hydroxy acids and derivatives thereof

field of invention

The invention relates to a preparation method of optically active α-hydroxy acid and its derivatives. Alpha-hydroxy acids are important intermediates for the synthesis of organic compounds used in pharmaceuticals and industrial applications. More specifically, the present invention relates to a method for the enantioselective synthesis of alpha-hydroxy acids via 1,3-dioxolanone using 10-camphorsulfonamide as a chiral auxiliary.

Background of the invention

Optically active α-hydroxyacids are structural subunits of many natural products, such as motuportin, selenine, monocrotaline, and eremantholide A. Alpha-hydroxy acids and their derivatives are important intermediates used in the synthesis of organic compounds used in pharmaceuticals and industrial applications. A number of useful synthetic methods have been developed for the preparation of enantiomerically pure α-branched α-hydroxy acids. Typically, optically active α-hydroxy acids are obtained by microbial methods, and enzymatic and enantioselective synthetic methods employ chiral auxiliaries.

Microbial methods employ microorganisms to convert alpha-hydroxy acid precursors, such as oxo- or hydroxyl-containing compounds, into alpha-hydroxy acids and their derivatives. For example, U.S. Patent No. 5,326,702 discloses a method for the biosynthesis of α-hydroxyamides or α-hydroxyacids, the method comprising, in the presence of sulfite ions, bisulfite ions or dithionite ions, α-hydroxy Nitriles or aldehydes are reacted with microorganisms which produce amides or acids from the corresponding alpha-hydroxynitriles. Related prior art US Patent Nos. 5,371,014, 5,508,181, 5,756,306 and 5,273,895 are also incorporated herein by reference. However, when using microbial methods, it is difficult to isolate the product from the fermentation broth. Purification of the product is complex and costly. Fermentation processes often produce large amounts of waste that are harmful to the environment. This requires additional processing and is therefore uneconomical.

U.S. Patent No. 5,098,841 discloses a method for the preparation of enantiomers of 2-hydroxy-4-phenylbutyric acid, which method comprises the reduction of 2- Oxo-4-phenylbutanoic acid. Related prior art employs enzymatic synthesis methods, such as US Patent Nos. 5,273,895, 5,523,223, 5,686,275 and 5,770,410, which are also incorporated herein by reference. However, enzymes are expensive. Therefore, enzymatic synthesis methods require stoichiometric amounts of expensive cofactors. Furthermore, the optical purity of enantioselective products obtained by enzymatic synthesis is very substrate-dependent.

U.S. Patent No. 5,488,131 discloses a method for the synthesis of compounds with predetermined chirality that can be used in asymmetric synthesis. The method includes acylation of the enantiomers of pseudoephedrine, and then alkylating the α-carbon of the adduct. Alkylation treatment, wherein the alkylation process is carried out in a stereoselective manner and derived from chiral auxiliary pseudoephedrine. Related prior art for enantioselective synthesis using chiral auxiliaries such as US Patents 4,983,766, 5,512,682, 5,512,688, 5,516,930, 5,578,730, 5,760,237 and 5,919,949 are also incorporated herein by reference. There are other disadvantages of using these enantioselective synthesis methods, for example, the enantioselectivity of the product is low, the chiral auxiliary is very expensive and cannot be produced on a large scale; and it is difficult to recover the chiral auxiliary. Therefore, it is still desired to develop more efficient methods to produce optically active compounds.

Taking advantage of the enantioselectivity of 10-camphorsulfonamide, we discovered a method for the enantioselective synthesis of α-hydroxyacids and their derivatives via 1,3-dioxolanone by using 10-camphorsulfonic acid as a chiral auxiliary. The process of the present invention does not suffer from the disadvantages encountered in the prior art and has advantages such as high enantioselectivity and high chemical yield of the product. Furthermore, (S) and (R) type 10-camphorsulfonamide chiral auxiliary agents can be industrially produced on a large scale, and it is easy to recover this chiral auxiliary agent with high yield in the method. Therefore, the method of the present invention has the advantages of high enantioselectivity, high efficiency, economy and easy operation.

Summary of the invention

The present invention relates to a method for preparing α-hydroxy acids and derivatives thereof through 1,3-dioxolanone, and the method uses 10-camphorsulfonamide as a chiral auxiliary agent. 1,3-Dioxolanone is prepared by the catalytic condensation process of dialkoxy acetal, which is treated with α-hydroxy acid by the chiral auxiliary 10-camphorsulfonamide acquired. 1,3-Dioxolanone is enantioselective and thus can be further used in the production of optically active compounds such as α-hydroxy acids and their derivatives. Alkylation of 1,3-dioxolanone followed by alcoholysis or hydrolysis yields mono- and di-substituted alpha-hydroxy acids and their derivatives and 10-camphorsulfonamide. 10-camphorsulfonamide is easy to recover. Detailed description of the invention

The present invention relates to a method for the enantioselective synthesis of α-hydroxyacids and their derivatives via 1,3-dioxolane, using 10-camphorsulfonamide as a chiral auxiliary.

Generally, the method of the present invention for preparing optically active α-hydroxy acids comprises the following steps:

(a) make the 10-camphorsulfonamide of following general formula I react with alkoxyl substituted alkane

Wherein, R ₁ and R ₂ can be the same or different, and independently of each other are H or C _1-6 alkyl, forming a dialkoxy acetal of the general formula II

Wherein, R ₁ and R ₂ may be the same or different, independently of each other are H or C _1-6 alkyl, R ₃ and R ₄ may be the same or different, and independently of each other are C _1-4 alkyl;

(b) reacting a dialkoxy acetal of general formula II with an alpha-hydroxy acid of general formula

Wherein, R ₅ is H, C _1-6 alkyl, or unsubstituted or substituted phenyl, forming 1,3-dioxolanone of general formula III

Wherein, R ₁ and R ₂ may be the same or different, independently of each other are H or C _1-6 alkyl, R ₅ is H, C _1-6 alkyl, or unsubstituted or substituted phenyl;

(c) reacting 1,3-dioxolanone of general formula III with an alkylating agent to form alkylated 1,3-dioxolanone of general formula IV

Wherein, R ₁ and R ₂ can be the same or different, each independently is H or C _1-6 alkyl, R ₅ is H, C _1-6 alkyl, or unsubstituted or substituted phenyl, R ₆ is C _1-8 alkyl, C _2-7 alkenyl or unsubstituted or substituted benzyl;

(d) carrying out the alkylated 1,3-dioxolanone of general formula IV

(i) when R ₅ is hydrogen, alcoholysis to form α-hydroxyacid derivatives of 10-camphorsulfonamide and general formula V

Wherein, R ₇ is C _1-6 alkyl, R ₆ is C _1-8 alkyl, C _2-7 alkenyl or unsubstituted or substituted benzyl,

or

(ii) When _R is C _1-6 alkyl or unsubstituted or substituted phenyl, hydrolysis to form 10-camphorsulfonamide and α-hydroxy acid of general formula VI

Wherein, R ₅ is H, C _1-6 alkyl or unsubstituted or substituted phenyl, R ₆ is C _1-8 alkyl, C _2-7 alkenyl or unsubstituted or substituted benzyl.

The 10-camphorsulfonamides of general formula I, the starting materials used in the process of the invention, are known and can be obtained from the prior art. In step (a), 10-camphorsulfonamides of formula I are reacted with alkoxy-substituted alkanes to form dialkoxy acetals of formula II. The reaction is carried out in the presence or absence of catalysts and solvents known to those skilled in the art. The commonly used catalyst is, for example, p-toluenesulfonic acid (p-TSA), and the solvent is, for example, alcohol, such as methanol. In a preferred embodiment of the invention the alkoxy substituted alkane is (CH ₃ O) ₃ CH.

In step (b), the dialkoxy acetal of general formula II produced by step (a) is subjected to a Lewis acid-catalyzed condensation reaction with an alpha-hydroxy acid of general formula R ₅ C(OH)COOH to produce the general 1,3-dioxolanone of formula III, wherein R ₅ is H, C _1-6 alkyl or unsubstituted or substituted phenyl dioxolanone. Reaction conditions for Lewis acid-catalyzed condensation reactions are well known in the art. Reference can be made to the following literature: Farines, M.; Soulier, J.Bull.Soc.Chim.Fr.1970, 332; Petasis, NA; Lu, S.-PJAm.Chem.Soc. WH; Cheng, M.-CJ Org Chem. 1987, 52, 1353; and Hoye, TR; Peterson, BH; Miller, JDJ Org. In an embodiment of the present invention, dialkoxy acetals are reacted with alpha-hydroxy acids, preferably glycolic acid, lactic acid and mandelic acid, the reaction is carried out under an inert atmosphere at a reaction temperature of about -35°C to about -60°C, The reaction is carried out in the presence of ether as solvent. The Lewis acid employed in a preferred embodiment of the present invention is BF ₃ ·OEt ₂ .

Since the 10-camphorsulfonamide of the general formula I has enantioselectivity, the 1,3-dioxolanone of the general formula III also has enantioselectivity, and the 1,3-dioxo The enantioselectivity of pentanecyclones is very suitable for the preparation of optically active compounds such as α-hydroxy acids and their derivatives.

When R ₅ is H, the reaction of step (b) can produce a small amount of by-product 1,3-dioxolanone of general formula IIIa:

Wherein, R ₁ and R ₂ may be the same or different, and are independently H or C _1-6 alkyl. The 1,3-dioxolanones of the general formulas III and IIIa are diastereochiral compounds. Pure 1,3-dioxolanone of general formula III can be obtained by recrystallization or separated from the minor isomers of 1,3-dioxolanone of general formula IIIa by column chromatography. Conditions for recrystallization and column chromatography are well known to those skilled in the art.

When R ₅ is C _1-6 alkyl or unsubstituted or substituted phenyl, the 1,3-dioxolane of general formula III is a single product. The stereochemistry of 1,3-dioxolanone can be confirmed by well-known methods routinely employed in the prior art, such as X-ray crystallographic analysis and Nuclear Warhaus Effect (NOE) experiments.

In the alkylation reaction of step (c), a 1,3-dioxolanone of general formula III is reacted with an alkylating agent to form an alkylated 1,3-dioxolanone of general formula IV , the alkylating agent such as R ₆ X, wherein, R ₆ is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or unsubstituted or substituted benzyl, X is a leaving group dioxolanone. Preferably, the alkylating agent is a halide or sulfonate. The alkylation reaction is carried out at -110°C to room temperature, preferably -100°C to 0°C, more preferably -100°C to -45°C, most preferably -100°C to -78°C, and the alkylation reaction is carried out in the presence of a strong base , such as lithium diisopropylamide (LDA), the reaction is carried out in the presence or absence of a solvent. It has been found that when the deprotonation reaction and the addition reaction of the alkylating agent are carried out at -100°C and then raised to -78°C, both the stereoselectivity and the yield of the product are improved. In the alkylation reaction, no diastereomers were detected by 400 MHz ¹ H NMR measurement. Alkylated 1,3-dioxolanones of formula IV have excellent diastereoselectivities. The stereochemistry of the alkylated 1,3-dioxolanones of formula IV can be checked by conventional means such as X-ray crystallography.

In step (d), the alkylated 1,3-dioxolanone of the general formula IV can be further subjected to alcoholysis or hydrolysis to produce the α-hydroxy acid of the general formula VI and its derivatives of the general formula V. When R ₅ is H, the product of the alkylation undergoes the alcoholysis of step (I). In an embodiment of the present invention, the process of alcoholysis is in anhydrous alcohol (general formula R ₇ OH, wherein R ₇ is C _1-6 alkyl) such as ethanol, by heating the alkylation of formula IV 1,3 - Dioxolanone and anhydrous hydrogen chloride. During alcoholysis, 10-camphorsulfonamides of general formula I are also produced. The α-hydroxy acid derivatives of general formula VI can be isolated and purified according to conventional methods such as column chromatography. Thereby recovering 10-camphorsulfonamide. The reaction scheme of step (d)(i) is shown below:

Wherein, R ₁ and R ₂ can be the same or different, each independently is H or C _1-6 alkyl, R ₅ is H, R ₆ is C _1-8 alkyl, C _2-7 alkenyl or unsubstituted Or substituted benzyl, R ₇ is C _1-6 alkyl.

When R ₅ is C _1-6 alkyl or unsubstituted or substituted phenyl, the alkylated 1,3-dioxolanone of general formula IV undergoes the hydrolysis process of step (ii). The hydrolysis conditions are the same as those conventionally used in the prior art. In a preferred embodiment of the invention, the hydrolysis is carried out by reacting an alkylated 1,3-dioxolanone of general formula IV with a strong base such as sodium hydroxide in the presence of an alcohol such as methanol as solvent . During the hydrolysis process, 10-camphorsulfonamide of general formula I will also be produced, which can be separated and recovered by conventional methods such as extraction process. Purification of alpha-hydroxy acids can be performed by concentration. The reaction scheme of step (d)(ii) is shown above:

Wherein, R ₁ and R ₂ can be the same or different, independently of each other are H or C _1-6 alkyl, R ₅ is C _1-6 alkyl or unsubstituted or substituted phenyl, R ₆ is C _1-8 Alkyl, C _2-7 alkenyl or unsubstituted or substituted benzyl.

Alpha-hydroxy acids and their derivatives are important intermediates for the synthesis of optically active organic compounds used in pharmaceuticals and industrial applications.

The method of the present invention is further described in detail by the following examples, and these examples are only used to illustrate the present invention, and are not intended to limit the protection scope of the present invention.

Abbreviations: Me is methyl, Et is ethyl, Ac is COCH ₃ .

Example

Example 1

Example 1 illustrates the preparation of dialkoxy acetals of general formula II from 10-camphorsulfonamides of general formula I. (1R)-N,N-diisopropyl-(2,2-dimethoxy-7,7-dimethylbicyclo[2.2.1]hept-1-yl)methanesulfonamide

At room temperature, 30 g of (1S)-(+)-N,N-diisopropyl-10-camphorsulfonamide, 1 g of p-toluenesulfonic acid (p-TSA) and 84 mL of CH(OCH ₃ ) ₃ Stir in 150 mL of methanol for 84 hours. The reaction was quenched with 100 mL of saturated sodium bicarbonate (aqueous solution), and methanol was distilled off under reduced pressure. The residue was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine, dried over sodium sulfate (solid), evaporated in vacuo, and the residue was purified by column chromatography ( _SiO2 , hexane-ethyl acetate, 8:1, addition of 1-2% N( C ₂ H ₅ ) ₃ ), yielding 31.46 g (85%) of (1R)-N,N-diisopropyl-(2,2-dimethoxy-7,7-dimethylbicyclo[2.2 .1] Hept-1-yl)methanesulfonamide as a white solid.

mp=73.8-74.6°C;

[α] _D ²⁵ +16.54 (c1.00, CHCl ₃ );

IR (KBr) 2973, 2871, 2836, 1748, 1460, 1402, 1377, 1330, 1199, 1136 cm ^-1 .

¹ H NMR (CDCl ₃ , 400 MHz) δ3.70 (septet, J=6.8Hz, 2H), 3.46(d, J=15.6Hz, 1H), 3.30(s, 3H), 3.13(s, 3H) , 2.72(d, J=15.6Hz), 2.29(td, J=12.6, J=5.2Hz, 1H), 2.16(dt, J=13.2, J=3.6Hz, 1H), 1.91(ddd, J=7.7 , J=7.7, J=3.6Hz), 1.84-1.76(m, 1H), 1.63(t, J=4.8Hz, 1H), 1.30(d, J=6.8Hz, 6H), 1.29(d, J= 6.8Hz, 6H), 1.28-1.22(m, 1H), 1.18(d, J=13.2Hz, 1H), 0.99(s, 3H), 0.88(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ108.5, 53.3, 52.1, 51.1, 49.4, 48.2, 47.4, 43.0, 41.2, 27.0, 24.7, 22.4, 22.2, 21.5, 20.4;

Anal. _Calcd . for _Ci8H35NO4S : C, 59.80; H, 9.76; N, 3.87; S, 8.87 _. Found: C, 60.07; H, 9.60; N, 4.22; S, 8.51.

Example 2a-d

Examples 2a-d illustrate the preparation of 1,3-dioxolanes of formulas III and IIIa from dialkoxyacetals of formula II by Lewis acid-catalyzed condensation reactions. The general procedure for Lewis acid-catalyzed condensation reactions of dialkoxy acetals with α-hydroxy acids is as follows:

A solution of dialkoxy acetal (1 mmol) in dichloromethane (1 mL) was added to the α-hydroxyacid and BF ₃ -O(C ₂ H ₅ ) under argon atmosphere at -50°C over 10 min. ₂ (1.6 eq.) in a mixture in ether. After stirring for about 30 to 60 minutes, the reaction was quenched with (C ₂ H ₅ ) ₃ N (0.6 mL). The solution was poured into 5 mL of ice water and extracted with ether (3 x 20 mL). The combined organic phases were washed with brine, dried over sodium sulfate, evaporated in vacuo and the residue was purified by column chromatography ( _SiO2 , hexane-ethyl acetate, 6:1) to give 1,3-dioxolane Condensation products of ketones.

Example 2a (1R, 2S)-N, N-diisopropyl-[2-spiro-2'-(1'-3'-dioxolane-4'-one)-7,7-dimethyl Base-bicyclo[2.2.1]-hept-1-yl]methanesulfonamide

From (1R)-N, N-diisopropyl-(2,2-dimethoxy-7,7-dimethylbicyclo[2.2.1]hept-1-yl)methanesulfonamide and glycolic acid (2.2 equivalents) were subjected to a condensation reaction to prepare the title compound.

74% yield

mp=140.3-140.7°C;

[α] _D ²⁵ -7.99 (c1.00, CHCl ₃ );

IR(KBr)cm ^-1 2974, 2879, 1806, 1468, 1394, 1281, 1258, 1338, 1258, 1243, 1198, 1154;

¹ H NMR (CDCl ₃ , 400MHz) δ4.44 (d, J=14.2Hz, 1H), 4.28 (d, J=14.2Hz, 1H), 3.68 (septet, J=6.8Hz, 2H), 3.30( d, J=13.2Hz, 1H), 2.56(d, J=13.2Hz, 1H), 2.38-2.26(m, 2H), 1.80-1.90(m, 3H), 1.76(d, J=13.6Hz, 1H ), 1.39-1.38(m, 1H), 1.28(d, J=6.8, Hz, 3H), 1.27(d, J=6.8, 3H), 0.99(s, 3H), 0.87(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ171.0, 119.2, 64.7, 54.6, 52.4, 48.3, 45.5, 44.0, 26.1, 26.6, 22.36, 22.2, 20.5, 20.1,

Anal. _Calcd . for _C18H31NO5S : C, 57.88; H _, 8.37; N, 3.75; S, 8.59. Found: C, 57.36; H, 8.34; N, 3.65;

Example 2b (1R, 2R)-N, N-diisopropyl-[2-spiro-2'-(1'-3'-dioxolane-4'-one)-7,7-dimethyl Bicyclo[2.2.1]hept-1-yl]methanesulfonamide

The title compound is the preparation of (1R,2S)-N,N-diisopropyl-[2-spiro-2'-(1'-3'-dioxolane-4'-one)-7,7-di Methyl-bicyclo[2.2.1]hept-1-yl]methanesulfonamide Process by-product.

mp=139.9-140.2°C;

[α] _D ²⁵ -13.35 (c1.00, CHCl ₃ );

IR (KBr) 2997, 2968, 2934, 1800, 1458, 1333, 1270, 1240, 1199, 1174, 1136cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ4.42 (d, J=14.6Hz, 1H), 4.11 (d, J=14.6Hz, 1H), 3.69 (septet, J=6.8Hz, 2H), 3.17( d, J=14Hz, 1H), 2.59(d, J=14Hz, 1H), 2.50-2.40(m, 1H), 2.26(dt, J=13.2, 2.8Hz, 1H), 1.84-1.72(m, 3H ), 1.69(d, J=14Hz, 1H), 1.38-1.30(m, 1H), 1.27(d, J=7.2Hz, 12H); 1.00(s, 3H); 0.88(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ172.2, 118.3, 62.9, 54.8, 52.3, 50.8, 48.3, 44.8, 44.2, 26.5, 25.2, 22.3, 22.2, 20.4, 20.1;

Anal. _Calcd . for _C18H31NO5S : C, 57.88; H, _8.37 ; N, 3.75; S, 8.59. Found: C, 57.76; H, 8.24; N, 3.92; Example 2c (1R, 2S, 5'S)-N, N-diisopropyl-[2-spiro-2'-(5'-methyl-1', 3'-dioxolane-4' -keto)-7,7-dimethylbicyclo[2.2.1]hept-1-yl]methanesulfonamide

The title compound is composed of (1R)-N,N-diisopropyl-(2,2-dimethoxy-7,7-dimethylbicyclo[2.2.1]hept-1-yl)methanesulfonamide and Racemic lactic acid (4.5 equivalents) was prepared by condensation.

77% yield;

mp=94.4-94.6°C;

[α] _D ²⁵ +6.36 (c1.00, CHCl ₃ );

IR (net value) 2973, 2949, 2879, 1794, 1370, 1334, 1133, 976, 658cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ4.43 (q, J=6.4Hz, 1H), 3.70 (septet, J=6.4Hz, 2H), 3.30 (d, J=13.2Hz, 1H), 2.56( d, J=13.2Hz, 1H), 2.39(ddd, J=13.2, 9.6, 3.6Hz, 1H), 2.29(dt, 1H, J=9.6, 3.6Hz, 1H), 1.92(td, J=13.2, 3.6Hz, 1H), 1.85-1.80(m, 2H), 1.71(d, J=13.2Hz, 1H), 1.53(d, J=6.4Hz, 1H), 1.38-1.22(m, 1H), 1.29( d, J=6.4Hz, 6H), 1.1.27(d, J=6.4Hz, 6H), 1.02(s, 3H), 0.90(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ173.0, 116.2, 70.6, 53.7, 52.1, 50.7, 48.2, 44.2, 43.9, 26.6, 26.1, 22.4, 22.2, 20.5, 20.2, 15.4; MS(EI)m/ z (relative intensity) 387(M ⁺ , 0.1), 372(3), 223(21), 215(7), 151(100), 123(47), 109(56), 81(35);

HRMS calcd for C ₁₉ H ₃₃ O ₅ NS(M ⁺ -Me) m/z 372.1842, found 372.1847;

Anal. _Calcd . for _C19H33O5NS : C, 58.89; H, 8.58; N, 3.61 _; S, 8.27; Found: C, 58.79; H, 8.34; N, 3.64;

Example 2d (1R.2S, 5'S)-N, N-diisopropyl-[2-spiro-2'-(5'-phenyl-1', 3'-dioxolane-4' -keto)-7,7-dimethylbicyclo[2.2.1]hept-1-yl]methanesulfonamide

The title compound is composed of (1R)-N,N-diisopropyl-(2,2-dimethoxy-7,7-dimethylbicyclo[2.2.1]hept-1-yl)methanesulfonamide and Prepared by condensation reaction of racemic mandelic acid (2.2 equivalents).

56% yield;

Silica gel column chromatography (hexane-ethyl acetate, 6:1);

mp=112.3-112.6°C;

[α] D ²⁵ +2.29 (c1.00, CHCl ₃ );

IR (KBr) 3070, 2970, 2879, 1799, 1458, 1335, 1121, 977, 774cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ7.61-7.59 (m, 2H), 7.36-7.32 (m, 3H), 5.36 (s, 1H), 3.43 (septet, J=6.9Hz, 1H), 3.28 (d, J=13.7Hz, 1H), 2.53(d, J=13.7Hz, 1H), 2.46(dt, J=13.4, 4.0Hz, 1H), 2.34-2.29(m, 1H), 2.09(dt, J=5.1, 13.4Hz, 1H), 1.90-1.80(m, 4H), 1.41-1.35(m, 1H), 1.16(d, J=6.9Hz, 6H), 1.22(d, J=6.9Hz, 6H ), 1.07(s, 3H), 0.94(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ170.2, 133.4, 128.6, 128.3, 127.3, 116.6, 75.0, 53.9, 51.7, 50.6, 48.0, 44.2, 44.0, 26.6, 25.7, 22.7, 21.6, 20.6, 20.2;

MS(EI) m/z (relative intensity) 449(M ⁺ , 0.04), 434(4), 284(7), 257(10), 151(100), 123(42), 109(60), 93 (21), 81(38), 67(21);

HRMS calculated value for C ₂₄ H ₃₅ O ₅ NS(M ⁺ -Me) m/z 434.1999, found value 434.2003;

Anal. _Calcd . for _C24H35O5NS : _C , 64.11; H, 7.85; N, 3.12; S, 7.13; Found: C, 64.00; H, 7.64;

Example 3a-i

Examples 3a-i illustrate the alkylation of 1,3-dioxolanones of formula III wherein _R5 is hydrogen.

Example 3a (1R, 2S, 5'R)-N, N-diisopropyl-[2-spiro-2'-(5'-methyl-1', 3'-dioxolane-4' -keto)-7,7-dimethylbicyclo[2.2.1]hept-1-yl]methanesulfonamide

Lithium diisopropylamide (LDA) was prepared from diisopropylamine (0.14 mL, 1.0 mmol) and n-butyllithium solution (2.2 M in hexane, 0.44 mL) at 0 °C under an argon atmosphere. Tetrahydrofuran (THF) (1.0 mL) solution. After stirring for 30 hours, hexamethylphosphoramide (HMPA) (1.2 equiv) was added and cooled to -78°C. Within 20 minutes, (1R,2S)-N,N-diisopropyl-[2-spiro-2′-(1′-3′-dioxolan-4′-one)-7,7 - Dimethyl-bicyclo[2.2.1]heptan-1-yl]methanesulfonamide (0.8 mmol) in THF (1.0 mL), the mixture was stirred for 30 minutes, then methyl halide (1.5 equiv) was added. The mixture was stirred for another 1 hour. 1% H ₂ C ₂ O ₄ (aq) (1 mL) was added to the mixture and warmed to 0° C., neutralized with 1% H ₂ C ₂ O ₄ (aq) to pH=6˜7. The solution was extracted with ethyl acetate, the combined organic phases were washed with brine, dried over sodium sulfate and evaporated in vacuo, the residue was purified by silica gel column chromatography to give the title compound. The diastereoselectivity of the product was 93.5%.

77% yield;

Silica gel column chromatography (hexane-ethyl acetate, 6:1);

mp=106.0-107.0°C;

[α]D ²⁵ -17.67 (c1.00, CHCl ₃ );

IR (KBr) 3002, 2973, 2886, 1801, 1457, 1413, 1375, 1328, 1283, 1257, 1240, 1200, 1154, 1117, 1034cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ4.60 (quat, J=6.8Hz, 1H), 3.68 (septet, J=6.8Hz, 2H), 3.28 (d, J=13.6Hz, 1H), 2.55( d, J=13.6Hz, 1H), 2.37-2.24(m, 2H), 1.90-1.76(m, 4H), 1.43(d, J=7.2Hz 3H), 1.40-1.30(m, 1H), 1.271( d, J=6.8, Hz, 6H), 1.268(d, J=6.8, 6H), 1.00(s, 3H), 0.87(s, 3H); ¹³ C NMR (CDCl ₃ , 100.6MHz) δ173.7, 117.5, 72.3, 54.8, 52.5, 51.2, 48.3, 47.2, 44.1, 26.6, 25.9, 22.5, 22.2, 20.6, 20.2, 19.0;

Anal. _Calcd . for _C19H33O5NS : C, 58.89; H, 8.58; N, 3.61 _; S, 8.27; Found: C, 58.87; H, 8.50; N, 3.91;

Example 3b

Example 3a was repeated, except that HMPA was omitted and the reaction temperature was increased from -100°C to -78°C. The yield of the title compound was 84%, with a diastereoselectivity greater than 98%.

Example 3c

Example 3a was repeated except that the reaction temperature was increased from -100°C to -78°C. The yield of the title compound was 86%, and the diastereoselectivity was greater than 98%.

Example 3d (1R, 2S, 5'S)-N, N-diisopropyl-{2-spiro-2'-[5'-(prop-2"-enyl)-1', 3'- Dioxolane-4'-one]-7,7-dimethylbicyclo[2.2.11hept-1-yl}methanesulfonamide

Lithium diisopropylamide (LDA) was prepared from diisopropylamine (0.14 mL, 1.0 mmol) and n-butyllithium solution (2.2 M in hexane, 0.44 mL) at 0 °C under an argon atmosphere. Tetrahydrofuran (THF) (1.0 mL) solution. After stirring for 30 hours, the reaction mixture was cooled to -100°C. Within 20 minutes, (1R,2S)-N,N-diisopropyl-[2-spiro-2′-(1′-3′-dioxolan-4′-one)-7,7 -Dimethyl-bicyclo[2.2.1)hept-1-yl]methanesulfonamide (0.8mmol) in THF (1.0mL), the mixture was stirred for 30 minutes, then allyl halide (1.5eq) was added . The mixture was warmed again to -78°C and stirred for an additional 1 hour. 1% H ₂ C ₂ O ₄ (aq) (1 mL) was added to the mixture and warmed to 0° C., neutralized with 1% H ₂ C ₂ O ₄ (aq) to pH=6˜7. The solution was extracted with ethyl acetate, the combined organic phases were washed with brine, dried over sodium sulfate and evaporated in vacuo, the residue was purified by silica gel column chromatography to give the title compound. The diastereoselectivity of the product is greater than 98%.

76% yield;

Silica gel column chromatography (hexane-ethyl acetate, 6:1);

mp=149.5-151.4°C;

[α]D ²⁵ -3.77 (c1.00, CHCl ₃ );

IR (KBr) 3007, 2973, 2881, 1798, 1332, 1283, 1240, 1201, 1153, 1136 ^{cm -1} .

¹ H NMR (CDCl ₃ , 400MHz) δ5.74-5.85 (m, 1H), 5.20-5.13 (m, 2H), 4.62 (dd, J=6.8, J=4.8Hz, 1H), 3.68 (septet, J=6.8Hz, 2H), 3.29(d, J=13.6Hz, 1H), 2.64-2.50(m, 1H), 2.56(d, J=13.6, 1H), 2.62-2.54(m, 1H), 2.48 -2.23(m, 2H), 1.90-1.73(m, 4H), 1.38-1.30(m, 1H, 1.28(d, J=6.8Hz, 6H), 1.27(d, J=6.8Hz, 6H), 0.99 (s, 3H), 0.86(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ172.3, 132.1, 118.9, 117.6, 75.8, 54.7, 52.3, 51.0, 48.2, 47.2, 43.8, 36.7, 26.4, 25.7, 22.4, 22.0, 20.4, 20.0;

Anal. _Calcd . for _C21H35O5NS : C, 60.99; H, 8.53; N, 3.39 _; S, 7.75; Found: C, 60.65; H, 8.85; N, 3.27;

Example 3e

Example 3d was repeated, except that HMPA was added. The yield of the title compound was 76%, with a diastereoselectivity greater than 98%.

Example 3f (1R, 2S, 5'R)-N, N-diisopropyl-[2-spiro-2'-(5'-ethyl-1',-3'-dioxolane-4 '-keto)-7,7-dimethylbicyclo[2.2.1]hept-1-yl]methanesulfonamide

Lithium diisopropylamide (LDA) was prepared from diisopropylamine (0.14 mL, 1.0 mmol) and n-butyllithium solution (2.2 M in hexane, 0.44 mL) at 0 °C under an argon atmosphere. Tetrahydrofuran (THF) (1.0 mL) solution. After stirring for 30 hours, hexamethylphosphoramide (HMPA) (1.2 equiv) was added and cooled to -78°C. Within 20 minutes, (1R,2S)-N,N-diisopropyl-[2-spiro-2′-(1′-3′-dioxolan-4′-one)-7,7 - Dimethyl-bicyclo[2.2.1]heptan-1-yl]methanesulfonamide (0.8 mmol) in THF (1.0 mL), the mixture was stirred for 30 minutes, then ethyl halide (1.5 equiv) was added. The mixture was stirred for another 1 hour. 1% H ₂ C ₂ O ₄ (aq) (1 mL) was added to the mixture and warmed up to 0° C., neutralized with 1% H ₂ C ₂ O ₄ (aq) to pH=6˜7. The solution was extracted with ethyl acetate, the combined organic phases were washed with brine, dried over sodium sulfate and evaporated in vacuo, the residue was purified by silica gel column chromatography to give the title compound. The diastereoselectivity of the product was >98%. The recovery yield of (1S)-(+)-N,N-diisopropyl-10-camphorsulfonamide was 57%.

36% yield.

Silica gel column chromatography (hexane-ethyl acetate, 6:1); mp=143.1-143.8°C;

[α]D ²⁵ -7.17 (c1.00, CHCl ₃ );

IR (KBr) 3002, 2968, 2949, 2891, 1800, 1328, 1238, 1155, 1136cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ4.49 (dd, J=6.6, J=4.8Hz, 1H), 3.69 (septet, J=6.8Hz, 2H), 3.30 (d, J=13.6, 1H) , 2.57(d, J=13.6Hz, 1H), 2.36-2.24(m, 2H), 1.93-1.68(m, 6H), 1.39-1.31(m, 1H), 1.284(d, J=6.8Hz, 6H ), 1.278(d, J=13.6Hz, 6H), 1.006(s, 3H), 1.004(t, J=7.2Hz, 3H), 0.87(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ173.0, 117.5, 77.2, 54.8, 52.4, 51.1, 48.3, 47.0, 43.9, 26.5, 25.72, 25.68, 22.5, 22.1, 20.5, 20.1, 9.3;

Anal. Calcd. for _C20H35O5NS : _C , 59.82; H, 8.79; N, 3.49 _, S, 7.99; Found: C, 59.82; H, 8.77; N, 3.77;

Example 3g

Example 3f was repeated except that the reaction temperature was increased from -100°C to -78°C. The yield of the title compound was 65%, with >98% diastereoselectivity.

Example 3h (1R, 2S, 5'R)-N, N-diisopropyl-[2-spiro-2'-(5'-phenylmethyl-1',-3'-dioxolane -4'-keto)-7,7-dimethylbicyclo[2.2.1]hept-1-yl]methanesulfonamide

Lithium diisopropylamide (LDA) was prepared from diisopropylamine (0.14 mL, 1.0 mmol) and n-butyllithium solution (2.2 M in hexane, 0.44 mL) at 0 °C under an argon atmosphere. Tetrahydrofuran (THF) (1.0 mL) solution. After stirring for 30 hours, hexamethylphosphoramide (HMPA) (1.2 equiv) was added and cooled to -78°C. Within 20 minutes, (1R,2S)-N,N-diisopropyl-[2-spiro-2′-(1′-3′-dioxolan-4′-one)-7,7 - Dimethyl-bicyclo[2.2.1]heptan-1-yl]methanesulfonamide (0.8 mmol) in THF (1.0 mL), the mixture was stirred for 30 minutes, then benzyl halide (1.5 eq) was added. The mixture was warmed to -45°C, and the mixture was stirred for another 1 hour. 1% H ₂ C ₂ O ₄ (aq) (1 mL) was added to the mixture and warmed to 0° C., neutralized with 1% H ₂ C ₂ O ₄ (aq) to pH=6˜7. The solution was extracted with ethyl acetate, the combined organic phases were washed with brine, dried over sodium sulfate and evaporated in vacuo, the residue was purified by silica gel column chromatography to give the title compound. The diastereoselectivity of the product was >98%.

60% yield;

Silica gel column chromatography (hexane-ethyl acetate, 6:1);

mp=106.3-161.0°C;

[α] D ²⁵ +1.78 (c1.00, CHCl ₃ );

IR (KBr) 2992, 2944, 2886, 1787, 1336, 1240, 1199, 1149, 1134cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ7.30-7.20(m, 5H), 4.83(t, J=5.2Hz, 1H), 3.67(septet, J=6.8Hz, 2H), 3.25(d, J =13.2Hz, 1H), 3.25(d, J=13.2Hz, 1H), 3.08(d, J=5.2Hz, 2H), 2.51(d, J=13.2Hz, 1H), 2.42(m, 1H, 1.82 (td, J=12.6, 1H), 1.76-1.60(m, 3H), 1.26(d, J=6.8Hz, 12H), 1.30-1.18(m, 1H), 1.16(d, J=13.6Hz, 1H ), 0.91(s, 3H), 0.8(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ172.5, 136.2, 129.8, 128.3, 126.9, 118.0, 77.4, 54.8, 52.4, 51.0, 48.3, 45.9, 43.7, 38.1, 26.4, 25.7, 22.5, 22.0, 20.4, 20.1;

Anal. _Calcd . for _C25H37O5NS : C, 64.76; H, _8.04 ; N, 3.02; S, 6.92; Found: C, 64.76;

Example 3i

Example 3h was repeated except that the reaction temperature was increased from -100°C to -78°C. The yield of the title compound was 70%, >98% diastereomers.

Example 4a-g

Examples 4a-g illustrate the alkylation of 1,3-dioxolanones of formula III wherein _R5 is methyl or phenyl. The general procedure of the alkylation process is as follows:

Lithium diisopropylamide (LDA) was prepared from diisopropylamine (0.14 mL, 1.0 mmol) and n-butyllithium solution (2.2 M in hexane, 0.44 mL) at 0 °C under an argon atmosphere. Tetrahydrofuran (THF) (1.0 mL) solution. After stirring for 30 hours, the reaction was cooled to -100°C. A solution of 1,3-dioxolanone (0.8 mmol) of formula III in THF (1.0 mL) was added over 20 minutes and the mixture was stirred for 30 minutes before addition of the alkylating agent (1.5 equiv). The mixture was warmed to -78°C, and the mixture was stirred for another 1 hour. 1% H ₂ C ₂ O ₄ (aq) (1 mL) was added to the mixture and warmed to 0° C., neutralized with 1% H ₂ C ₂ O ₄ (aq) to pH=6˜7. The solution was extracted with ethyl acetate, the combined organic phases were washed with brine, dried over sodium sulfate and evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane-ether 4:1) to give the title compound.

Example 4a (1R, 2S, 5'R)-N, N-diisopropyl-[2-spiro-2'-(5'-ethyl-5'-methyl-1', 3'-two Oxolane-4'-one)-7,7-dimethylbicyclo[2.2.1]hept-1-yl]methanesulfonamide

According to the conventional procedure, from (1R, 2S, 5′S)-N, N-diisopropyl-[2-spiro-2′-(5′-methyl-1′, 3′-dioxolane- The title compound was prepared by reaction of 4'-keto)-7,7-dimethyl-bicyclo[2.2.1]hept-1-yl]methanesulfonamide with ethyl halide. The diastereoselectivity of the product was >98%.

79% yield;

mp=185.4-185.5°C;

[α] _D ²⁵ +9.52 (c1.00, CHCl ₃ );

IR (KBr) 3007, 2977, 1796, 1635, 1458, 1330, 1189, 1148, 1135, 1115, 983, 774cm ^-1 ;

¹ H NMR (CDCl ₃ , 400 MHz) δ3.69 (septet, J=6.4Hz, 2H), 3.28 (d, J=13.2Hz, 1H), 2.58 (d, J=13.2Hz, 1H), 2.35 -2.24(m, 2H), 2.06-1.98(m, 1H), 1.84-1.68(m, 5H), 1.48(s, 3H), 1.38-1.21(m, 1H), 1.33(d, J=6.4Hz , 6H), 1.28(d, J=6.4Hz, 6H), 1.02(s, 3H), 1.0(t, J=8.0Hz, 3H), 0.91(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ174.74, 115.1, 80.7, 54.1, 51.8, 50.4, 48.0, 46.5, 44.10, 30.36, 26.36, 25.6, 22.5, 21.7, 20.4, 20.0, 19.7, 7.2;

MS(EI) m/z (relative intensity) 415(M ⁺ , 67), 267(22), 251(20), 171(29), 151(100), 109(63), 86(61), 55 (77);

HRMS calculated for C ₂₁ H ₃₇ O ₅ NS(M ⁺ -Me) m/z 400.2163, found 400.2154;

Anal. Calcd. for _C21H37O5NS : C, 60.69; H, 8.90; _N , 3.37 _; S, 7.72; Found: C, 60.59; H, 8.71; N, 3.43;

Example 4b (1R, 2S, 5'R)-N, N-diisopropyl-[2-spiro-2'-(5'-methyl-5'-propyl-1', 3'-two Oxolane-4'-one) 7,7-dimethylbicyclo[2.2.1]hept-1-yl)methanesulfonamide

According to the conventional procedure, from (1R, 2S, 5′S)-N, N-diisopropyl-[2-spiro-2′-(5′-methyl-1′, 3′-dioxolane- The title compound was prepared by reaction of 4'-keto)-7,7-dimethyl-bicyclo[2.2.1]hept-1-yl]methanesulfonamide with propyl halide. The diastereoselectivity of the product was >98%.

67% yield;

mp=191.6-191.8°C;

[α] _D ²⁵ +2.17 (c1.00, CHCl ₃ );

IR (KBr) 2965, 2877, 1798, 1635, 1334, 1187, 1114, 1039, 982, 775, ^660cm-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ3.69 (septet, J=6.4Hz, 2H), 3.27(d, J=13.6Hz, 1H), 2.58(d, J=13.6Hz, 1H), 2.34- 2.23(m, 2H), 2.06-1.99(m, 1H), 1.84-1.76(m, 3H), 1.71-1.21(m, 5H), 1.49(s, 3H), 1.29(d, J=6.4Hz, 6H), 1.27(d, J=6.4Hz, 6H), 1.01(s, 3H), 0.93(t, J=7.2Hz, 3H), 0.91(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ174.9, 115.3, 80.6, 54.3, 51.9, 50.4, 48.1, 46.5, 44.3, 39.8, 26.4, 25.7, 22.6, 21.8, 20.5, 20.5, 20.1, 16.4, 14.1;

MS (EI) m/z (relative intensity) 429 (M ⁺ , 0.2), 151 (32), 123 (15), 109 (25), 86 (75), 84 (100), 69 (9);

HRMS calculated for C ₂₂ H ₃₉ O ₅ NS(M ⁺ -Me) m/z 414.2349, found 414.2290;

Anal. _Calcd . for _C22H39O5NS : C, 61.51; H, 9.15; N, 3.26 _; S, 7.46; Found: C, 61.60; H, 9.37;

Example 4c (1R 2S, 5'R)-N, N-diisopropyl-{2-spiro-2'-[5'-methyl-5'-(prop-2"-enyl)-1 ',3'-dioxolane-4'-one]-7,7-dimethylbicyclo[2.2.1]hept-1-yl]methanesulfonamide

According to the conventional procedure, from (1R, 2S, 5′S)-N, N-diisopropyl-[2-spiro-2′-(5′-methyl-1′, 3′-dioxolane- The title compound was prepared by reaction of 4'-keto)-7,7-dimethyl-bicyclo[2.2.1]hept-1-yl]methanesulfonamide with allyl halide. The diastereoselectivity of the product was >98%.

78% yield;

mp=177,7-177.8°C;

[α] _D ²⁵ +18.65 (c1.00, CHCl ₃ );

IR (KBr) 3007, 2971, 1798, 1645, 1332, 1247, 1185, 1146, 984, 919, 774, 660cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ5.87-5.76(m, 1H), 5.21-5.14(m, 2H), 3.69(septet, J=6.8Hz, 2H), 3.27(d, J=14.0Hz , 1H), 2.57(d, J=14.0Hz, 1H), 2.51-2.29(m, 4H), 2.06-1.98(m, 1H), 1.85-1.77(m, 3H), 1.55(s, 3H), 1.38-1.23(m, 1H), 1.28(d, J=6.8Hz, 6H), 1.27(d, J=6.8Hz, 6H), 1.01(s, 3H), 0.91(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ174.3, 131.1, 119.7, 115.5, 80.1, 54.3, 51.9, 50.5, 48.1, 46.6, 44.2, 41.9, 26.4, 25.7, 22.6, 21.8, 20.6, 20.5, 20.1;

MS(EI) m/z (relative intensity) 427(M ⁺ , 0.13), 316(3), 300(2), 263(16), 215(16), 151(100), 123(40), 109 (67), 81(36), 67(25);

HRMS calculated for C ₂₂ H ₃₇ O ₅ NS(M ⁺ -Me) m/z 412.2174, found 412.2147;

Anal. _Calcd . for _C22H37O5NS : C, 61.80; H, 8.72; N, 3.28 _; S, 7.50; Found: C, 61.57; H, 8.52;

Example 4d (1R.2S, 5'R)-N, N-diisopropyl-[2-spiro-2'-(5'-methyl-5'-butyl-1', 3'-two Oxolane-4'-one)-7,7-dimethylbicyclo[2.2.1]hept-1-yl]methanesulfonamide

According to the conventional procedure, from (1R, 2S, 5′S)-N, N-diisopropyl-[2-spiro-2′-(5′-methyl-1′, 3′-dioxolane- The title compound was prepared by reaction of 4'-keto)-7,7-dimethyl-bicyclo[2.2.1]hept-1-yl]methanesulfonamide with butyl halide. The diastereoselectivity of the product was >98%.

74% yield;

mp=148.3-148.5°C;

[α] D ²⁵ +5.13 (c1.0, CHCl ₃ );

IR (KBr) 2963, 2939, 2876, 1794, 1338, 1148, 1137, 978, 778, 661cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ3.69 (septet, J=6.4Hz, 2H), 3, 27 (d, J=13.6Hz, 1H), 2.58 (d, J=13.6Hz, 1H), 2.35-2.23(m, 2H), 2.06-1.99(m, 1H), 1.82-1.75(m, 3H), 1.71-1.64(m, 2H), 1.49(s, 3H), 1.39-1.27(m, 3H ), 1.29(d, J=6.4Hz, 6H), 1.27(d, J=6.4Hz, 6H), 1.02(s, 3H), 0.92-0.88(m, 5H), 0.91(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ175.0, 115.3, 80.6, 54.3, 52.0, 50.6, 48.2, 46.6, 44.3, 37.3, 26.5, 25.8, 25.1, 22.7, 22.6, 22.0, 20.6, 20.5, 20.2, 13.6;

MS(EI) m/z (relative intensity) 443(M ⁺ , 0.3), 279(12), 215(14), 151(100), 123(42), 86(46).81(35), 67 (20);

HRMS calculated for C ₂₃ H ₄₁ O ₅ NS(m ^- -Me) m/z 428.2464, found 428.2476;

Anal. _Calcd . for _C23H41O5NS : C, 62.27; H _, 9.32; N, 3.16.S, 7.23; Found: C, 62.15; H, 9.37; N, 3.34;

Example 4e (1R, 2S, 5'R)-N, N-diisopropyl-[2-spiro-2'-(5'-methyl-5'-phenylmethyl-1', 3 '-dioxolane-4'-one)-7,7-dimethylbicyclo[2.2.1]hept-1-yl]methanesulfonamide

According to the conventional procedure, from (1R, 2S, 5′S)-N, N-diisopropyl-[2-spiro-2′-(5′-methyl-1′, 3′-dioxolane- The title compound was prepared by reaction of 4'-keto)-7,7-dimethyl-bicyclo[2.2.1]hept-1-yl]methanesulfonamide with benzyl halide. The diastereoselectivity of the product was >98%.

82% yield;

mp=130.4-130.6°C;

[α] D ²⁵ +32.33 (c1.0, CHCl ₃ );

IR (KBr) 3061, 3027, 2997, 2973, 2944, 2881, 1790, 1333, 1179, 1146, 1119, 797cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ7.32-7.22(m, 5H), 3.66(septet, J=6.8Hz, 2H), 3.22(d, J=14.0Hz, 1H), 3.14(d, J =14.8Hz, 1H), 2.88(d, J=14.8Hz, 1H), 2.60(d, J=14.0Hz, 1H), 2.28-2.20(m, 2H), 2.13-2.06(m, 1H), 1.83 -1.76(m, 2H), 1.56(d, J=13.2Hz) 1H), 1.44(s, 3H), 1.41-1.42(m, 1H), 1.26(d, J=6.8Hz, 6H), 1.25( d, J=6.8Hz, 6H), 1.02(s, 3H), 0.92(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ174.6, 135.3, 130.4, 128.3, 127.1, 116.5, 81.4, 54.6, 51.9, 50.6, 48.2, 46.1, 44.4, 43.8, 26.4, 25.7, 22.9, 21.9, 21.6, 20.8, 20.2;

MS (ED m/z (relative intensity) 447(M ⁺ , 1.4), 313(100), 300(17), 215(56), 151(61), 123(12), 109(10);

HRMS calcd for C ₂₆ H ₃₉ O ₅ NS(M ⁺ -Me) m/z 477.2584, found 477.2517;

Anal. _Calcd . for _C26H39O5NS : C, 65.38; H, 6.71; _N , 2.93; S, 6.71; Found: C, 65.42; H, 6.85;

Example 4f (1R, 2S, 5'S)-N, N-diisopropyl-[2-spiro-2'-(5'-methyl-5'-phenyl-1', 3'-two Oxolane-4'-one)-7,7-dimethylbicyclo[2.2.1]hept-1-yl]methanesulfonamide

According to the conventional procedure, from (1R, 2S, 5′S)-N, N-diisopropyl-[2-spiro-2′-(5′-phenyl-1′, 3′-dioxolane- The title compound was prepared by reaction of 4'-keto)-7,7-dimethyl-bicyclo[2.2.1]hept-1-yl]methanesulfonamide with methyl halide. The diastereoselectivity of the product was >98%.

76% yield;

mp=142.2-142.4°C;

[α] _D ²⁵ -18.55 (c1.0, CHCl ₃ );

IR (KBr) 3060, 2982, 2880, 1791, 1639, 1394cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ7.69-7.71(m, 2H), 7.35-7.23(m, 3H), 3.09(d, J=14Hz, 1H, 2.95(b, 2H), 2.50-2.45( m, 1H), 2.45(d, J=14Hz, 1H), 2.30-2.23(m, 1H), 2.11-2.04(m, 1H), 1.94-1.78(m, 3H), 1.70(m, 3H), 1.42-1.36(m, 1H), 1.15(s, 3H), 1.02(d, J=6.4Hz, 6H), 0.94(d, J=6.4Hz, 6H, 0.93(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ 172.7, 140.6, 128.0, 127.1, 124.1, 115.9, 79.8, 54.2 51.2, 50.4, 47.5, 46.6, 44.2, 30.5, 26.5, 25.3, 22.8, 21.0, 20.0; 20.

MS(EI) m/z (relative intensity) 464(M ^- +1, 1.08), 448(11), 316(27), 299(46), 271(28), 151(100), 70(50) ;

HRMS calculated value for C ₂₅ H ₃₇ NO ₅ S (M ⁺ ) m/z 463.2392, found value 463.2400;

Anal. Calcd. for _C25H37NO5S : C, 64.76; _{H ,} 8.04; N, 3.02; S, 6.92; Found: C, 64.76; H, 8.07;

Example 4g (1R, 2S, 5'S)-N, N-diisopropyl-{2-spiro-2'-(5'-phenyl-5'-(prop-2"-enyl)- 1',3'-dioxolane-4'-one)-7,7-dimethyl-bicyclo[2.2.1]hept-1-yl}methanesulfonamide

According to the conventional procedure, from (1R,2S,5'S)-N,N-diisopropyl-[2-spiro-2'-(5'-phenyl-1',3'-dioxolane 4 The title compound was prepared by reaction of '-keto)-7,7-dimethyl-bicyclo[2.2.1]hept-1-yl]methanesulfonamide with allyl halide. The diastereoselectivity of the product was 98%.

84% yield;

mp=147.5-147.7°C;

[α] _D ²⁵ -19.64 (c1.0, CHCl ₃ );

IR (KBr) 2958, 2880, 1793, 1640, 1615, 1338, 1120, 977, 936, 702, 664cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ7.69-7.67(m, 2H), 7.35-7.22(m, 3H), 5.63-5.53(m, 1H), 5.08-4.97(m, 2H), 3.07(d , J=13.2Hz, 1H), 2.91(b, 2H), 2.66(d, J=7.2Hz, 2H), 2.49-2.44(m, 1H), 2.45(d, J=13.2Hz, 1H), 2.27 -2, 20(m, 1H), 2.14-2.06(m, 1H), 1.90-1.78(m, 1H), 1.40-1.33(m, 1H), 1.15(s, 3H), 1.02(d, J= 6.4Hz, 6H), 0.94(d, J=6.4Hz, 6H), 0.93(s, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ171.0, 138.2, 130.1, 127.4, 126.7, 124.1, 119.4, 115.9, 81.6, 53.9, 51.0, 49.9, 46.9, 46.5, 46.4, 43.5, 26.0, 24.9, 22.4, 20.4, 20.0, 19.5;

MS(EI) m/z (relative intensity) 490(M ⁺⁺ 1, 4.52), 420(54), 316(55), 215(32), 151(71), 105(100), 77(68) , 43(29);

HRMS calculated value for C ₂₇ H ₃₉ NO ₅ S (M ⁺ ) m/z 489.2549, found value 489.2556;

Anal. _Calcd . for _C27H39NO5S : C, 66.23; H, 8.03; N, 2.82; S, 6.55. Found: C, 66.25 _; H, 8.08; N, 2.87;

Example 5

Example 5 illustrates the alcoholysis of alkylated 1,3-dioxolanones of formula IV to form alpha-hydroxy acid derivatives of formula VI and 10-camphorsulfonamides of formula I. (2R)-2-Hydroxy-3-phenylpropanoic acid ethyl ester

Bubble anhydrous hydrogen chloride through (1R,2S,5'R)-N,N-diisopropyl-[2-spiro-2'-(5'phenylmethyl-1',-3'-di A solution of oxolane-4'-one)-7,7-dimethylbicyclo[2.2.1]hept-1-yl]methanesulfonamide (464 mg, 1 mmol) in absolute ethanol (4 mL) for 10 minutes. After reflux for 6 hours, the solution was cooled, poured into saturated sodium bicarbonate (aq), and extracted twice with ether. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (SiO ₂ , hexane-ethyl acetate, 6:1) to give 161 mg (83%) of the title compound and recover (1S)-(+)-N,N-diisopropyl - 1-camphorsulfonamide (287 mg, 91%).

[α] _D ²⁵ +22.21 (c3.85, CHCl ₃ );

IR (net) 3471(b), 3085, 3060, 3030, 2982, 2939, 1733, 1604, 1497, 1455, 1370, 1201, 1096, 1031cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ7.19-7,30(m, 5H), 4.42(dd, J=6.4, J=4.4Hz, 1H), 4.2(quartet, J=7.2Hz, 2H ), 3.11(dd, J=13.6, J=4.4Hz, 1H), 2.95(dd, J=13.6, J=6.4Hz, 1H), 1.26(t, J=7.2Hz, 3H);

¹³ C NMR (CDCl ₃ , 100.6 MHz) δ 174.1, 136.3, 129.4, 128.2, 126.7, 71.1, 61.5, 40.4, 14.0.

Example 6a-c

Examples 6a-c illustrate the hydrolysis of alkylated 1,3-dioxolanones of general formula IV to form alpha-hydroxy acids of general formula V and 10-camphorsulfonamides of general formula I. The general process of hydrolysis is as follows:

A solution of 1 g of the alkylated 1,3-dioxolanone in 4 mL of methanol and 1 mL of 1 N sodium hydroxide (aq) was heated at 60° C. for 4 hours. After cooling the solution, methanol was distilled off in vacuo. The residue was diluted with water (5 mL), extracted with ethyl acetate (2 x 10 mL). The organic phase was dried over sodium sulfate and concentrated to recover 10-camphorsulfonamide. The pH of the aqueous layer was adjusted to 2 with concentrated aqueous hydrochloric acid, and the solvent was distilled off under reduced pressure. The residue was dissolved in 10 mL of ether, and the salt (NaCl) was removed by filtration. The resulting solution was dried over sodium sulfate and concentrated to give the desired alpha-hydroxy acid.

Embodiment 6a (2R)-2-hydroxyl-2-methylbutanoic acid

By hydrolysis of (1R,2S,5'R)-N,N-diisopropyl-[2-spiro-2'-(5'-ethyl-5'-methyl-1',-3'-di Oxolane-4'-one)-7,7-dimethylbicyclo[2.2.1]hept-1-yl]methanesulfonamide to give the title compound. The yield of the title compound was 97% (1S)-(+)-N, the recovery of N-diisopropyl-10-camphorsulfonamide was 96%;

mp=72.4-72.6°C;

[α] _D ²⁵ -7.03 (c1.4, 0.2N NaOH);

IR(KBr) 3447, 3343, 2981-2583(b), 1737cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ7.02(b, 1H), 1.84-1.66(m, 2H), 1.43(s, 3H), 0.90(t, J=7.3Hz, 3H);

¹³ C NMR (CDCl ₃ , 100.6MHz) δ181.8, 75.2, 32.9, 25.4, 7.8;

MS (EI) m/z (relative intensity) 118 (M ⁺ , 2), 73 (100), 71 (14), 57 (42), 55 (90).

Embodiment 6b(2R)-2-hydroxyl-2-methylhexanoic acid

By hydrolysis of (1R,2S,5'R)-N,N-diisopropyl-[2-spiro-2'-(5'-methyl-5'-butyl-1',3'-dioxo Pentane-4'-one)-7,7-dimethylbicyclo[2.2.1]hept-1-yl]methanesulfonamide to give the title compound.

The yield of the title compound was 98% (1S)-(+)-N, the recovery of N-diisopropyl-10-camphorsulfonamide was 92%;

mp=67.8-67.9°C;

[α] _D ²³ -8.12 (c0.85, H ₂ O);

IR (net) 3457, 3421, 2961-2578(b), 1735cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ7.10(b, 1H), 1.78-1.62(m, 2, H), 1.43(s, 3H), 1.31-1.13(m, 4H), 0.86(t, J =6.96Hz, 3H);

¹³ C NMP, (CDCl ₃ , 100.6MHz) δ161.8, 74.9, 39.7, 25.8, 25.7, 22.7, 13.8;

MS (EI) m/z (relative intensity) 146 (M ⁺ , 39.51), 128 (44), 122 (42), 85 (59), 55 (100).

Embodiment 6c (2S)-2-hydroxyl-2-phenyl-4-pentenoic acid By hydrolysis of (1R,2S,5′S)-N,N-diisopropyl-{2-spiro-2′-(5′-phenyl-5′-(prop-2″-enyl)-1 ',3'-dioxolan-4'-one)-7,7-dimethylbicyclo[2.2.1]hept-1-yl}methanesulfonamide to give the title compound.

The yield of the title compound was 94%, and the recovery of (1S)-(+)-N,N-diisopropyl-10-camphorsulfonamide was 93%;

mp=132.1-132.3°C;

[α] _D ²⁶ +29.54 (c1.0, CHCl ₃ );

IR (net value) 3423, 3080, 2915, 1725, 1640cm ^-1 ;

¹ H NMR (CDCl ₃ , 400MHz) δ7.61-7.60(m, 2H), 7.37-7.24(m, 3H), 5.81-5.71(m, 2H), 5.25-5.81(m, 2H), 3.02(dd J=14, J=7.2Hz, 1H), 2.79(dd, J=14, J=7.2Hz, 1H);

¹³ C NMR (CDCl ₃ , 100.6 MHz) δ 178.5, 140.2, 131.7, 128.4, 128.2, 125.5, 120.4, 77.8, 44.1.

The description of the above specification teaches the principles of the present invention, and these examples are for illustrative purposes only, and it can be understood that the present invention will include all useful changes, changes and modifications, as defined in the claims.

Claims (12)

1. the preparation method of an alpha hydroxy acid and its derivative, this method comprise the steps: to make the alkylating 1 of general formula I V, and 3-dioxolane ketone carries out

Wherein, R ₁And R ₂Can be identical or different, be H or C independently of one another _1-6Alkyl; R ₅Be H, C _1-6Alkyl or the phenyl that does not replace or replace; R ₆Be C _1-8Alkyl, C _2-7Alkenyl or the benzyl that does not replace or replace;

(i) work as R ₅During for hydrogen, alcoholysis, the alpha hydroxy acid derivative of formation general formula V

Wherein, R ₆Be C _1-8Alkyl, C _2-7Alkenyl or the benzyl that does not replace or replace, R ₇Be C _1-6Alkyl, and separate the product that forms;

Perhaps

(ii) work as R ₅Be C _1-6When alkyl or the phenyl that do not replace or replace, hydrolysis forms the alpha hydroxy acid of general formula VI

Wherein, R ₅Be H, C _1-6Alkyl or the phenyl that does not replace or replace, R ₆Be C _1-8Alkyl, C _2-7Alkenyl or the benzyl that does not replace or replace, and separate the product (V) that forms and (VI).

2. according to the method for claim 1, it also comprises the alkylation 1 of producing general formula I V, the step of 3-dioxolane ketone,

Wherein, R ₁And R ₂Can be identical or different, be H or C independently of one another _1-6Alkyl; R ₅Be H, C _1-6Alkyl or the phenyl that does not replace or replace; And R ₆Be C _1-8Alkyl, C _2-7Alkenyl or the benzyl that does not replace or replace, this step is to make 1 of general formula III, 3-dioxolane ketone

Wherein, R ₁And R ₂Can be identical or different, be H or C independently of one another _1-6Alkyl, R ₅Be hydrogen, C _1-16Alkyl or the phenyl that does not replace or replace,

With general formula R ₆The alkylating reagent reaction of X, wherein, R ₆Be C _1-8Alkyl, C _2-7Alkenyl or the benzyl that does not replace or replace, X is a leavings group, and separates the product (IV) that forms.

3. according to the method for claim 2, also comprise 1 of production general formula III, the step of 3-dioxolane ketone,

Wherein, R ₁And R ₂Can be identical or different, be H or C independently of one another _1-6Alkyl, R ₅Be hydrogen, C _1-16Alkyl or the phenyl that does not replace or replace, this step is the dialkoxy acetal that makes general formula I I

Wherein, R ₁And R ₂Can be identical or different, be H or C independently of one another _1-6Alkyl, R ₃And R ₄Can be identical or different, be C independently of one another _1-4Alkyl;

Alpha hydroxy acid reaction with following general formula

Wherein, R ₅Be H, C _1-6Alkyl or the phenyl that does not replace or replace, and separate the product (III) that forms.

4. according to the method for claim 3, also comprise the step of the dialkoxy acetal of producing general formula I I,

Wherein, R ₁And R ₂Can be identical or different, be H or C independently of one another _1-6Alkyl, R ₃And R ₄Can be identical or different, be C independently of one another _1-4Alkyl; This step is the 10-camphor sulfonamide that makes general formula I

Wherein, R ₁And R ₂Can be identical or different, be H or C independently of one another _1-6Alkyl,

With the alkane reaction of alkoxyl group replacement, and separate the product (II) that forms.

5. according to the process of claim 1 wherein, wherein produce the 10-camphor sulfonamide and the recovery of general formula I as product

Wherein, R ₁And R ₂Can be identical or different, be H or C independently of one another _1-6Alkyl.

6. according to the method for claim 2, wherein, wherein produce 1 of by product general formula III a, 3-dioxolane ketone separates this by product then

Wherein, R ₁And R ₂Can be identical or different, be H or C independently of one another _1-6Alkyl.

7. according to the process of claim 1 wherein that described product is selected from:

(2R)-2-hydroxyl-3-phenylpropionic acid ethyl ester,

(2R)-2-hydroxy-2-methyl butyric acid,

(2R)-2-hydroxy-2-methyl caproic acid and

(2S)-2-hydroxyl-2-phenyl-4-pentenoic acid.

8. according to the method for claim 2, wherein, the described alkylation 1 of general formula I V, 3-dioxolane ketone is selected from:

(1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl isophthalic acid ' ,-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin,

(1R, 2S, 5 ' S)-N, the N-di-isopropyl-2-spiral shell-2 '-[5 '-(the third-2 " thiazolinyl)-1 ' ,-3 '-dioxolane-4 '-ketone]-7,7-dimethyl two rings [2.2.1] heptan-1-yl } Toluidrin,

(1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-ethyl-1 ' ,-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin,

(1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 ' phenyl methyl-1 ' ,-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin,

(1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-ethyl-5 '-methyl isophthalic acid ' ,-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin,

(1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl-5 '-propyl group-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl) Toluidrin,

(1R, 2S, 5 ' R)-N, the N-di-isopropyl-2-spiral shell-2 '-[5 '-methyl-5 '-(the third-2 " thiazolinyl)-1 ', 3 '-dioxolane-4 '-ketone]-7,7-dimethyl two rings [2.2.1] heptan-1-yl } Toluidrin,

(1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl-5 '-butyl-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin,

(1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl-5 '-phenyl methyl-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin,

(1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl-5 '-phenyl-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin and

(1R, 2S, 5 ' S)-N, the N-di-isopropyl-2-spiral shell-2 '-(5 '-phenyl-5 '-(the third-2 " thiazolinyl)-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two rings [2.2.1] heptan-1-yl } Toluidrin.

9. according to the method for claim 3, wherein, 1 of general formula III, 3-dioxolane ketone is selected from:

(1R, 2S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(1 '-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two rings [2.2.1] heptan-1-yl] Toluidrin,

(1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl isophthalic acid ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin and

(1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-phenyl-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin.

10. according to the method for claim 4, wherein, the dialkoxy acetal of general formula I I is (1R)-N, N-di-isopropyl-(2,2-dimethoxy-7,7-dimethyl two ring [2.2.1] heptan-1-yl) Toluidrin.

11. according to the method for claim 2, wherein said being reflected at-100 ℃ carried out under-45 ℃.

12. the preparation method of an optically active alpha-hydroxy acids, this method may further comprise the steps:

(a) in the presence of pure and mild tosic acid, the 10-camphor sulfonamide of general formula I and the alkane of alkoxyl group replacement are reacted, form the dialkoxy acetal of general formula I I

Wherein, R ₁And R ₂Can be identical or different, be H or C independently of one another _1-6Alkyl

Wherein, R ₁And R ₂Can be identical or different, be H or C independently of one another _1-6Alkyl, R ₃And R ₄Can be identical or different, be C independently of one another _1-4Alkyl;

(b) in the presence of ether and Lewis acid, make the dialkoxy acetal and alpha hydroxy acid reaction of general formula I I with following general formula

Wherein, R ₅Be H, C _1-6Alkyl, or the phenyl that does not replace or replace form 1 of general formula III, 3-dioxolane ketone

Wherein, R ₁And R ₂Can be identical or different, be H or C independently of one another _1-6Alkyl, R ₅Be H, C _1-6Alkyl or the phenyl that does not replace or replace;

(c) at highly basic and optionally in the presence of the hexamethylphosphoramide ,-100 ℃ under 0 ℃, make 1 of general formula III, 3-dioxolane ketone reacts with alkylating reagent, the alkylation 1 of formation general formula I V, 3-dioxolane ketone

Wherein, R ₁And R ₂Can be identical or different, be H or C independently of one another _1-6Alkyl, R ₅Be H, C _1-6Alkyl or the phenyl that does not replace or replace, R ₆Be C _1-8Alkyl, C _2-7Alkenyl or the benzyl that does not replace or replace;

(d) make the alkylating 1 of general formula I V, 3-dioxolane ketone carries out

(i) work as R ₅During for hydrogen, alcoholysis, the alpha hydroxy acid derivative of formation general formula V

Wherein, R ₇Be C _1-6Alkyl, R ₆Be C _1-8Alkyl, C _2-7Alkenyl or not replacement

Or the benzyl that replaces,

Or

(ii) work as R ₅Be C _1-6When alkyl or the phenyl that do not replace or replace, hydrolysis, shape

Become the alpha hydroxy acid of general formula VI

Wherein, R ₅Be H, C _1-6Alkyl or the phenyl that does not replace or replace, R ₆Be C _1-8Alkyl, C _2-7Alkenyl or benzyl that does not replace or replace and the 10-camphor sulfonamide that reclaims general formula I.