WO2017219917A1 - Method for preparing trabectedin and intermediates thereof - Google Patents

Abstract

Provided in the present invention is a new method for preparing a trabectedin, using safracin B as the starting material and through a series of reactions synthesizing trabectedin. The method easily obtains raw materials, has fewer synthesis steps, does not use highly toxic organotin reagents, is safe and low-cost, and has high value in industrial applications.

Description

Preparation method of trimetidine and intermediate thereof

This application claims priority to Chinese Patent Application No. 201610446335.5, entitled "Preparation of a Curbeitidine and Its Intermediates", filed on June 20, 2016, the entire contents of which are hereby incorporated by reference. The citations are incorporated herein by reference.

Technical field

The invention relates to the field of chemistry, in particular to a preparation method of trobeidine and a synthetic intermediate thereof.

Background technique

Trabexidine, also known as ascidin 743, Ecteinascidin 743, ET-743, is a tetrahydroisoquinoline derivative with high antitumor activity isolated from the Caribbean sea sheath in 1969 and was launched in Europe in 2007. It is used to treat ovarian cancer and soft tissue sarcoma. It was listed in the United States as an orphan drug for the treatment of ovarian cancer in October 2015. It is the first anti-tumor drug of marine origin.

At present, the preparation methods of trobeidine are mainly as follows:

1. Biological extraction: The highest acquisition amount of trobeidine is 0.0001% (ACS Chem. Biol. 2011, 6, 1244), which is not conducive to the large-scale preparation of trobeidine.

2. Total synthesis: The synthetic routes of the total synthesis are mainly as follows: 1) The total synthesis reported by Corey et al., the synthesis of trobeidine by a 36-step reaction, yield 0.5%, which requires expensive chiral ligands and Precious metal ruthenium, and harsh reaction conditions such as reaction at -78 ° C (J. Am. Chem. Soc. 1996, 118, 9202-9203); 2) Full synthesis by Fukuyama et al., 50 steps, yield 0.56% It is also necessary to use expensive chiral ligands and precious metal ruthenium. In addition, n-butyl lithium is used as a flammable hazardous reagent (J. Am. Chem. Soc. 2002, 124, 6552-6554); 3) The total synthetic route reported by Zhu et al., in a 31-step reaction, yields 1.7%, requiring the use of highly toxic hydrofluoric acid and dangerous n-butyllithium (J. Am. Chem. Soc. 2006, 128, 87-89); 4) A new total synthesis route reported by Fukuyama et al., after a 30-step reaction, the total yield is 1.3%. The synthesis uses iodobenzene acetate repeatedly, as well as expensive osmium tetroxide and palladium catalysts (J.Am.Chem .Soc. 2013, 135, 13684-13687). It can be seen from the route reported above that the current synthetic route is too long, the operation is complicated, the expensive reagent is used in a large amount, and the yield is low, which is not conducive to mass production of ET-743.

3, semi-synthesis: Pharmamarin, Spain, reported that cyanobacterin B (Caynosafracin B) was used as a starting material to synthesize trebezidine (Compound I) in a 21-step reaction in a yield of 1% (Org. Lett., 2000, 16, 2545-2548). The semi-synthesis is relatively short in the synthetic route, and is a synthetic route currently in industrialization, but the route is still long and the yield is low.

In the above semi-synthesis, there is a key intermediate Xa-1. The preparation of Xa-1 from cyanobacterin B requires a 15 step reaction, the reaction route is long, and the yield is only 4.8%, and V Preparation of VI requires the use of highly toxic organotin reagents, all of which pose significant challenges for the industrial production of ET-743.

Summary of the invention

The technical problem to be solved by the present invention is that the preparation of trobeidine in the prior art, especially the preparation of the key intermediate Xa-1 of trometidine, has a long route, low yield, high cost, harsh reaction conditions, and operation. Complex and other defects.

The invention provides a safe, simple and inexpensive method for preparing trimetidine and its intermediates IIa, Va, VIa, VIIa, VIIIa and Xa-1, which does not use highly toxic organotin reagents. The synthesis of Xa-1 by safracin B greatly simplifies the synthesis of trobeidine and Xa-1 through a nine-step reaction, and has great industrial application value.

In a first aspect of the invention, there is provided a method of preparing trobeidine and Xa, the method comprising the steps of:

Wherein R ₁ is O and S; and R ₂ and R ₃ are a hydroxy protecting group.

The synthesis method comprises the following steps:

(1) The reaction of Safracin B with an isocyanate derivative gives a compound of formula IIa:

Wherein R ₁ is O or S.

In a preferred embodiment, in the step (1), the isocyanate derivative is preferably phenyl isothiocyanate, phenyl isocyanate, more preferably phenyl isothiocyanate; Safracin B and isocyanate derivatives The molar ratio is preferably 1:1 to 10, more preferably 1:6; the temperature of the reaction is preferably 0 to 40 ° C, more preferably 25 ° C; and the reaction time is preferably 2 to 48 h, more preferably 24 h.

(2) reacting compound IIa with cyanide to give a compound of formula IIIa:

Wherein R ₁ is O or S.

In a preferred embodiment, in the step (2), the cyanide is preferably sodium cyanide, potassium cyanide, more preferably sodium cyanide; the molar ratio of the compound IIa to cyanide is preferably 1:1 to 10 More preferably 1:2.5; the reaction temperature is preferably -20 to 20 ° C, more preferably -10 to -5 ° C; the reaction solvent is preferably tetrahydrofuran / water (v / v) = 4 to 2: 1, more preferably tetrahydrofuran / water ( v/v)=4:1.

(3) Edman degradation reaction of compound IIIa with trimethylchlorosilane gives a compound of formula IVa-1:

Wherein R ₁ is O or S.

In a preferred embodiment, the molar ratio of the compound IIIa to the trimethylchlorosilane in the step (3) is preferably 1:3 to 20, more preferably 1:5.5; the reaction solvent is preferably an organic solvent, the organic The solvent may be any suitable, including but not limited to, preferably methanol, ethanol, 1,4-dioxane, tetrahydrofuran; and the reaction temperature is preferably -20 to 50 ° C, more preferably 0 to 5 ° C.

(4) Compound IVa-1 undergoes diazotization and nucleophilic reaction with sodium nitrite and a nucleophile to obtain a compound of formula Va:

Wherein R ₂ is a hydroxy protecting group.

In a preferred embodiment, in step (4), the nucleophile is preferably sodium acetate, sodium formate, sodium propionate, more preferably sodium acetate; compound IVa-1 and sodium nitrite, the nucleophile The molar ratio is preferably 1:1 to 20:1 to 2, more preferably 1:7.9:1.4; the reaction solvent is preferably an organic solvent or a mixed organic solvent, and the organic solvent or mixed solvent may be any suitable, including However, it is not limited to dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, or a mixed solvent of methanol and water, ethanol and water, tetrahydrofuran and water; the reaction temperature is preferably -10 to 30 ° C, more preferably -5 to 0. °C.

(5) Compound Va is reacted with a hydroxy protecting agent to give a compound of formula VIa:

Wherein R ₂ is a hydroxy protecting group; and R ₃ is a hydroxy protecting group.

In a preferred embodiment, in the step (5), the hydroxy protecting agent is preferably bromomethyl methyl ether, chloromethyl methyl ether, 2-methoxyethoxymethyl chloride, more preferably bromine The methyl ether; the molar ratio of Va to the hydroxy protecting agent is preferably 1:1 to 20, more preferably 1:15; the base used for the reaction is preferably N,N-diisopropylethylamine, triethylamine, sodium hydride, More preferably, N,N-diisopropylethylamine; the molar ratio of the compound Va to the base is preferably 1:1 to 30, more preferably 1:20; and the reaction temperature is preferably -20 to 60 ° C, more preferably 0 to 5 ° C.

(6) Compound VIa is hydrolyzed to give a compound of formula VIIa:

Wherein R ₂ is a hydroxy protecting group; and R ₃ is a hydroxy protecting group.

In a preferred embodiment, in step (6), the hydrolysis reaction is preferably carried out under base catalysis, the base preferably being an inorganic base, which may be any suitable, including but not limited to, preferably hydrogen. Lithium oxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate; the molar ratio of the compound VIa to the base is preferably 1:1 to 20, more preferably 1:5.5.

(7) Compound VIIa is subjected to reduction and cyclization to give a compound of formula VIIIa:

Wherein R ₃ is a hydroxy protecting group.

In a preferred embodiment, in the step (7), the reduction reaction is preferably carried out under palladium carbon catalysis, wherein the mass ratio of the compound VIIa to the palladium carbon is preferably 1:0.1 to 1, more preferably 1:0.2; The reduction reaction temperature is preferably 10 to 30 ° C, more preferably 20 to 25 ° C; the cyclization reaction is preferably carried out by a base catalyzed cyclization reaction, wherein the base is preferably cesium carbonate, cesium fluoride, sodium carbonate, Potassium carbonate, more preferably cesium carbonate, the molar ratio of VIIa to base is preferably 1:15 to 5, more preferably 1:3; the solvent for the cyclization reaction is preferably N,N-dimethylformamide, dimethyl Sulfone, N,N-dimethylacetamide, acetonitrile, N-methylpyrrolidone, more preferably N,N-dimethylformamide; the cyclization reaction temperature is preferably from 50 to 110 ° C, more preferably 95 ~110 °C.

(8) Compound VIIIa is oxidized to give a compound of formula IXa:

Wherein R ₃ is a hydroxy protecting group.

In a preferred embodiment, in the step (8), the oxidizing agent of the oxidation reaction is preferably benzene selenate anhydride, 2-iodobenzoic acid, more preferably benzene selenate anhydride, and the molar ratio of the compound VIIIa to the oxidizing agent is preferably The reaction solvent is preferably an organic solvent, and the organic solvent may be any suitable, including but not limited to, preferably dichloromethane, tetrahydrofuran, ethyl acetate, methanol, ethanol. , acetonitrile.

(9) Compound IXa is reacted with compound XV by ester condensation to give a compound of formula Xa:

Wherein R ₃ is a hydroxy protecting group.

This reaction is described in the preparation of J. Am. Chem. Soc. 1996, 118, 9202-9203.

(10) Compound Xa is subjected to a ring reaction to give a compound of formula XIa:

Wherein R ₃ is a hydroxy protecting group.

This reaction is described in the preparation of J. Am. Chem. Soc. 1996, 118, 9202-9203.

(11) Compound XIa is subjected to acid-catalyzed deprotection to give a compound of the formula XIIa-1:

Wherein R ₃ is a hydroxy protecting group.

In a preferred embodiment, in the step (11), the acid is preferably trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, more preferably p-toluenesulfonic acid; and the reaction temperature is preferably -10. ～30 ° C, more preferably 20 to 30 ° C; the molar ratio of the compound XIa to the acid is preferably 1:4 to 15, more preferably 1:5.

(12) Conversion of the amino group of compound XIIa-1 to a ketone carbonyl group to give a compound of formula XIIIa-1:

This reaction is described in the preparation of J. Am. Chem. Soc. 1996, 118, 9202-9203.

(13) Compound XIIIa-1 is reacted with a compound of formula XVI to give a compound of formula XIVa-1:

This reaction is described in the preparation method of J. Am. Chem. Soc. 2006, 128, 87-89.

(14) Compound XIVa-1 is catalyzed by a copper salt to convert a cyano group to a hydroxy group to give a compound of formula I:

In a preferred embodiment, in the step (14), the copper salt catalyst is preferably cuprous chloride, cuprous bromide, cuprous iodide, cuprous sulfate, more preferably cuprous chloride; reaction temperature It is preferably 0 to 45 ° C, more preferably 25 to 30 ° C; and the reaction solvent is preferably an aqueous acetonitrile solution, an aqueous tetrahydrofuran solution, an aqueous methanol solution or an aqueous dichloromethane solution, more preferably an aqueous tetrahydrofuran solution.

In a preferred embodiment of the invention, R ₁ is preferably S, R ₂ is preferably acetyl, and R ₃ is preferably methoxymethyl (MOM).

The raw material Safracin B of the present invention can be prepared by a mature fermentation technique of the literature (JP59225189, J. Antibiot. 1983, 36, 1279-1283), and a raw material of kilograms can be obtained; the compound XV of the present invention can be referred to by reference ( The synthesis of the compound XVI of the present invention is commercially available from the method of synthesis, 1990, 119, 119-122).

In a particularly preferred embodiment, the invention provides the following synthetic route for a compound of formula I:

The present invention also provides a compound of formula IIa,

Wherein R ₁ is O or S, preferably S.

The present invention also provides a compound of the formula Va,

Wherein R ₂ is a hydroxy protecting group, preferably an acetyl group.

The present invention also provides a compound of the formula VIa,

Wherein R ₂ is a hydroxy protecting group, preferably an acetyl group; and R ₃ is a hydroxy protecting group, preferably a methoxymethyl group (MOM).

The present invention also provides a compound of formula VIIa,

Wherein R ₃ is a hydroxy protecting group, preferably methoxymethyl (MOM).

The invention also provides a compound of formula VIIIa,

Wherein R ₃ is a hydroxy protecting group, preferably methoxymethyl (MOM).

The invention has the advantages that the synthesis process provided by the invention is ingeniously conceived, and IVa-1 converts the amino group into the hydroxyl-protected Va by one step reaction with sodium nitrite and a nucleophilic reagent, thereby reducing the reaction step and improving the phenolic hydroxyl group in Va. The selectivity of VIa is synthesized during protection. When VIa synthesizes VIIa, the protective groups of the methyl group and the hydroxyl group are removed by a one-step reaction, and the operation of the reaction is reduced. In the present invention, the highly toxic organotin reagent is not used, the use of the protecting group is reduced, and the safety and simplicity of the reaction are greatly improved. The present invention synthesizes trobezidine (Compound I) by a fourteen-step reaction using Safracin B as a starting material, and compared with the literature (Org. Lett., 2000, 16, 2545-2548), the Canyosarcin B is passed through twenty-one. The step reaction synthesis of trobestatin shortens the seven-step reaction and has greater industrial application value.

The terminology used in the present invention has the following meanings, unless stated to the contrary:

"Alkyl" means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 10 carbon atoms, preferably including 1 to 6 carbon atoms. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-B 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, light, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, Heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo.

"Hydroxy protecting group" is a suitable group for hydroxyl protection known in the art, see literature

A hydroxy protecting group in ("Protective Groups in Organic Synthesis", 5 ^Th Ed. TW Greene & P. GM Wuts). As an example, preferred hydroxy protecting groups may be C _1-10 alkyl or substituted alkyl groups such as methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxylated Base, 2-tetrahydropyranyl (THP), etc.; may be (C _1-10 alkyl or aryl) ₃ silyl, for example: triethylsilyl, triisopropylsilyl, tert-butyl Methylsilyl, tert-butyldiphenylsilyl or the like; may be a (C _1-10 alkyl or aryl) acyl group, for example, formyl, acetyl, benzoyl, etc.; may be (C _1-6 Alkyl or C _6-10 aryl)sulfonyl; may also be (C _1-6 alkoxy or C _6-10 aryloxy)carbonyl.

detailed description

The invention will be explained in detail below with reference to specific examples, which are intended to provide a more complete understanding of the invention.

Example 1: Preparation of Compound IIa-1

Safracin B (51 g) was added to the reaction flask at room temperature, dichloromethane (100 ml) was added to dissolve, and phenyl isothiocyanate (76 g) was added dropwise. The reaction was stirred for 24 h. 150g. (no purification followed by next reaction)

¹ H NMR (400 MHZ, DMSO) δ: 9.94 (s, 1H), 8.66 (s, 1H) 7.46-7.40 (m, 3H), 7.36 (t, J = 8 Hz, 3H), 7.15 (t, J = 7.6) Hz, 1H), 6.20 (s, 1H), 4.47 (s, 1H), 4.36 (t, J = 7.2 Hz, 1H), 3.99-3.63 (m, 5H), 3.52 (s, 1H), 3.33 (s) , 3H), 2.99 (d, J = 2.8 Hz, 1H), 2.96-2.73 (m, 4H), 2.16 (s, 3H), 1.98 (s, 3H), 1.84 (s, 3H), 1.59 (m, 1H), 1.15 (d, J = 6.1 Hz, 2H), 0.46 (d, J = 2.8 Hz, 3H). MS: m/z (675), Found: 658 (MH ₂ O + H)

Example 2: Preparation of Compound IIIa-1

To the oil obtained in Example 1, tetrahydrofuran (250 ml), acetic acid (56 ml) was added, and the mixture was cooled to -10 ° C, and an aqueous solution of sodium cyanide (12 g of sodium cyanide, 100 ml of water) was added dropwise with stirring, and the reaction was carried out for 0.5 h. . Add the saturated sodium carbonate to adjust the pH to 10, add ethyl acetate (200 ml), separate the organic layer, and wash the organic layer twice with anhydrous sodium sulfate. Ether: ethyl acetate = 4:1, 3:1, 2:1, 1:1) yielded 54.9 g of a yellow solid.

¹ H NMR (400 MHZ, DMSO) δ: 9.87 (s, 1H), 8.55 (s, 1H) 7.45-7.43 (m, 3H), 7.36-7.32 (m, 2H), 7.15-7.05 (m, 2H), 6.22(s,1H),4.88(d,J=5.2Hz 1H), 4.42(m,1H), 4.39(m,1H), 4.28(m,1H), 4.13(s,1H),3.90(d, J=2.4 Hz, 1H), 3.89 (s, 3H), 3.87 (m, 1H), 3.53 (m, 4H), 3.11-2.96 (m, 3H), 2.85-2.55 (m, 3H), 2.11 (s) , 3H), 2.02 (s, 3H), 1.82 (s, 3H), 1.70-1.52 (m, 1H), 0.55 (d, J = 6.8 Hz, 3H). MS: m/z (684), Found: 685 (M+H)

Example 3: Preparation of Compound IVa-1

Take compound IIIa-1 (25g), add 70ml of methanol, cool to 0 ° C in ice bath, add trimethyl chloride The silane (25 ml) was added, and the reaction was kept for 3 hours. The filter cake was washed with dichloromethane (20 ml × 2) and dried to give a yellow solid (13.8 g).

^{1 H NMR (400MHz, DMSO)} δ9.35 (s, 1H), 7.53 (s, 3H), 6.52 (s, 1H), 5.06 (s, 1H), 4.53 (s, 2H), 4.14 (d, J = 14.6 Hz, 3H), 3.97 (s, 4H), 3.64 (s, 3H), 3.28 (s, 1H), 3.19 - 2.84 (m, 5H), 2.20 (s, 3H), 1.85 (s, 3H) , 1.74 (dt, J = 23.8, 11.9 Hz, 1H). MS: m/z (514), Found: 479 (M-Cl)

Example 4: Preparation of Compound Va-1

Sodium acetate (15g), acetic acid (91ml), dichloromethane (245ml), water (120ml), compound IVa-1 (15g) was added to the reaction flask, cooled to 0 ° C in an ice bath, protected with nitrogen, nitrous acid was added dropwise An aqueous solution of sodium (2.9 g of sodium nitrite, 200 ml of water) is added, and the reaction is kept for 3 hours. The pH is adjusted to 8 with saturated sodium hydrogencarbonate. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, column chromatography (petroleum ether: ethyl acetate = 6:1, 5:1, 4:1) gave Compound Va-1 (7.3 g).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ6.48 (s, 1H), 4.71 (dd, J = 11.5,3.1Hz, 1H), 4.21 (d, J = 1.6Hz, 1H), 4.13 (s, 1H) , 4.01 (s, 3H), 3.95 (d, J = 1.9 Hz, 1H), 3.76 (s, 3H), 3.71 - 3.65 (m, 1H), 3.47 (d, J = 6.9 Hz, 1H), 3.21 ( d, J = 11.1 Hz, 1H), 3.13 (dd, J = 17.6, 2.2 Hz, 1H), 3.03 (dd, J = 18.1, 7.9 Hz, 1H), 2.61 (d, J = 18.1 Hz, 1H), 2.38 (s, 3H), 2.26 (s, 3H), 1.96 (s, 3H), 1.63 (m, 1H), 1.40 (s, 3H), 1.15 (d, J = 6.1 Hz, 1H). MS: m /z(521),Found:522(M+H)

Example 5: Preparation of Compound VIa-1

Take compound Va-1 (1g), acetonitrile (10ml), N,N-diisopropylethylamine (4.8g), cool to 0 ° C in ice bath, add bromomethyl methyl ether (3.6g) in acetonitrile solution (10 ml), after the addition, the mixture was warmed to room temperature for 24 h, the pH was adjusted to 1 with 1M hydrochloric acid, dichloromethane was evaporated, and the organic layer was dried over anhydrous sodium sulfate.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ6.73 (s, 1H), 5.16 (q, J = 6.0Hz, 2H), 4.67 (dd, J = 11.5,3.0Hz, 1H), 4.42 (d, J = 2.3 Hz, 1H), 4.19 (s, 1H), 4.01 (s, 3H), 3.96 (d, J = 1.9 Hz, 1H), 3.77 - 3.69 (m, 3H), 3.67 (dd, J = 7.4, 5.0) Hz, 2H), 3.59 (s, 3H), 3.35 - 3.22 (m, 1H), 3.19 - 3.01 (m, 2H), 2.69 (d, J = 18.2 Hz, 1H), 2.45 (s, 3H), 2.24 (d, J = 8.4 Hz, 3H), 1.97 (s, 3H), 1.67 - 1.49 (m, 1H), 1.47 - 1.38 (m, 3H), .MS: m/z (565), Found: 566 ( M+H)

Example 6: Preparation of Compound VIIa-1

The compound VIa-1 (1.1 g) was added to tetrahydrofuran (22 ml), the temperature was lowered to 0 ° C, and 22 ml of a 0.5 M aqueous lithium hydroxide solution was added dropwise thereto. After the addition, the reaction was kept for 12 hours, and the pH was adjusted to 2 with 0.5 M hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give compound VI (0.94 g).

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.72 (s, 1H), 5.32 - 5.05 (m, 2H), 4.31 (d, J = 2.1 Hz, 1H), 4.08 (d, J = 2.1 Hz, 1H) , 3.85 (s, 1H), 3.79 - 3.66 (m, 4H), 3.60 (s, 3H), 3.48 (dd, J = 11.6, 1.4 Hz, 1H), 3.42 (d, J = 7.0 Hz, 1H), 3.29 (dt, J = 11.2, 2.8 Hz, 1H), 3.15 (dt, J = 18.1, 5.8 Hz, 2H), 2.50 (d, J = 18.1 Hz, 1H), 2.38 (s, 3H), 2.22 (s) , 3H), 1.92 (s, 3H), 1.64 (m, 1H). MS: m/z (509), Found: 510 (M+H)

Example 7: Preparation of Compound VIIIa-1

Compound VIIa-1 (0.7 g), N,N-dimethylformamide (14 ml) was added to a hydrogenation vessel, 10% palladium carbon (0.14 g) was added, and the reaction was stirred at 1 M hydrogen pressure for 5 h at room temperature. Filtration, adding cesium carbonate (0.5g), bromochloromethane (4ml), under nitrogen, heating to 100 ° C, reaction 1h, suction filtration, adding saturated brine (100ml), ethyl acetate (40ml), liquid separation, The organic layer was dried over anhydrous sodium sulfate, filtered, evaporated

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.71 (s, 1H), 5.91 (d, J = 1.3 Hz, 1H), 5.84 (d, J = 1.3 Hz, 1H), 5.45 (d, J = 16.6 Hz) , 1H), 5.36 - 5.30 (m, 1H), 5.19 (t, J = 6.5 Hz, 1H), 4.28 (d, J = 2.3 Hz, 1H), 4.10 (d, J = 2.5 Hz, 1H), 4.05 –3.98(m,1H), 3.70 (dd, J=15.8, 5.3 Hz, 7H), 3.56 (m, 1H), 3.44–3.36 (m, 2H), 3.18–3.07 (m, 2H), 2.54 (d) , J = 2.0 Hz, 1H), 2.38 (d, J = 5.7 Hz, 3H), 2.25 (d, J = 11.3 Hz, 3H), 2.10 (s, 3H), 1.84 (dd, J = 15.2, 11.8 Hz) , 2H).MS: m/z (523), Found: 524 (M+H)

Example 8: Preparation of Compound IXa-1

The compound VIIIa-1 (0.25 g) was taken, dissolved in dichloromethane (15 ml), cooled to -10 ° C, 70% phenyl selenic anhydride (0.25 g) was added, stirred for 0.5 h, and quenched by adding water (20 ml). , liquid, no The organic layer was dried with sodium sulfate and evaporated to dryness.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ6.71 (s, 1H), 5.84 (s, 1H), 5.16 (s, 2H), 4.10 (m, 2H), 3.92 (s, 3H), 3.83 (m, 1H), 3.75 (m, 1H), 3.58 (m, 1H), 3.52 (s, 3H), 3.34 (m, 1H), 3.04 (m, 1H), 2.73-2.65 (m, 1H), 2.62 (d) , J=18 Hz, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 2.25-2.19 (m, 1H), 2.02 (m, 2H), 1.80 (s, 3H). MS: m/z (539), Found: 540 (M+H)

Example 9: Preparation of Compound Xa-1

Compound IXa-1 (0.20 g), XV (0.24 g) was added to dichloromethane (10 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.17 g) , 4-dimethylaminopyridine (0.11g), reacted at room temperature for 5h, the reaction was stopped, washed with sodium hydrogencarbonate, separated, dried over anhydrous sodium sulfate, filtered, concentrated, : ethyl acetate = 5:1, 4:1, 3:1, 2:1, 1:1) Xa-1 (0.23 g) was obtained in a yield of 70%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.73-7.63 (m, 4H), 7.42-7.30 (m, 4H), 6.65-6.56 (m, 1H), 5.74 (s, 1H), 5.65 (s, 1H ), 5.31 (s, 1H), 5.05 (m, 1H), 4.70-4.30 (m, 2H), 4.30-4.12 (m, 3H), 4.08-3.70 (m, 3H), 3.64 (s, 3H), 3.52 (m, 3H), 3.34 (s, 1H), 3.19 (s, 2H), 3.17-2.90 (m, 3H), 2.60-2.05 (m, 8H), 2.38 (d, J = 5.7 Hz, 3H) , 1.79 (s, 3H), 1.45 (s, 8H). MS: m / z (920), Found: 921 (M + H)

Example 10: Preparation of Compound XIa-1

Dimethyl sulfoxide (1.6 ml) was added to dichloromethane (88 ml), the internal temperature was lowered to -78 ° C, and a mixed solution of trifluoromethanesulfonic anhydride (1.53 ml) and dichloromethane (1 ml) was added dropwise. The temperature is lower than -74 ° C, after the addition, the reaction is kept for 20 min, and a solution of Xa-1 (4.18 g) in dichloromethane (58 ml) is added dropwise. The temperature control during the dropwise addition is less than -76 ° C, and the temperature is raised to -40. The reaction was carried out at ° C, the color changed from yellow to dark green, and the reaction was carried out for 40 min. A mixed solution of N,N-diisopropylethylamine (6.3 ml) and dichloromethane (4 ml) was added dropwise, and the temperature was slowly raised to 0 ° C. The reaction liquid changed from dark green to yellow, and the reaction was carried out for 40 min. A mixed solution of t-butanol (1.7 ml) and dichloromethane (1 ml) was added, and the reaction was kept for 20 min, and 1,1,3,3-tetramethyl group was added dropwise. A mixed solution of 2-tert-butylhydrazine (5.4 ml) and dichloromethane (4 ml) was added to a temperature of 23 ° C for 40 min, and a mixed solution of acetic anhydride (4.2 ml) and dichloromethane (4 ml) was added dropwise. After the addition, the reaction was carried out at room temperature for 1 h, and the reaction was completed by TLC. The reaction was stopped, washed twice with saturated aqueous ammonium chloride, twice with saturated brine, dried over anhydrous sodium sulfate, filtered, filtered and evaporated. Petroleum ether = 10:1, 8:1, 6:1, 5 : 1, 4: 1), the product was obtained in an amount of 1.54 g, yield 44%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ6.79 (s, 1H), 6.09 (s, 1H), 5.99 (s, 1H), 5.20 (d, J = 5.2Hz, 2H), 5.14 (d, J = 5.2 Hz, 1H), 5.02 (d, J = 11.6 Hz, 1H), 4.63 (d, J = 9.1 Hz, 1H), 4.49 (s, 1H), 4.29 (m, 3H), 4.16 (t, J = 12.6 Hz, 2H), 3.78 (s, 3H), 3.57 (s, 3H), 3.42 (s, 2H), 2.93 (s, 2H), 2.80 (s, 1H), 2.37-2.29 (m, 6H), 2.25-2.14 (m, 4H), 2.05 (m, 4H), 1.45 (s, 9H). MS: m/z (766), Found: 767 (M+H)

Example 11: Preparation of Compound XIIa-1

Take XIa-1 (0.34g), add p-toluenesulfonic acid (0.68g), dichloromethane (18ml), stir the reaction at room temperature for 4h, stop the reaction, add the reaction droplets to the aqueous solution of sodium bicarbonate, and separate. The aqueous layer was extracted with dichloromethane (10 mL×2). EtOAcjjjjjj

_{^{1 H NMR (400MHz, CDCl 3}} ) δ6.51 (s, 1H), 6.05 (m, 2H), 5.75 (s, 1H), 5.01 (d, J = 11.6Hz, 2H), 4.52 (m, 1H) , 4.27 (m, 2H), 4.14 (m, 2H), 3.78 (s, 3H), 3.40 (m, 2H), 3.24 (t, J = 6.4 Hz, 1H), 2.89 (s, 2H), 2.80 ( m, 2H), 2.30-2.10 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 2.17 (s, 3H), 2.02 (s, 3H). MS: m/z (622) ,Found:623(M+H)

Example 12: Preparation of Compound XIIIa-1

XIIa-1 (100 mg) was added, and a mixed solvent of anhydrous pyridinium salt (450 mg), dichloromethane (5 ml) and N,N-dimethylformamide (5 ml) was added, and the mixture was stirred at room temperature for 1 hour, and the temperature was lowered to 0. °C, adding a mixed solution of DBU and dichloromethane (5ml dichloromethane), adding to warm to room temperature for 0.5h, cooling to 0 ° C, adding 5ml of saturated oxalic acid solution, warming to room temperature, stirring for 1h, layering, use The methylene chloride was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered (ethyl acetate: petroleum ether = 6:1, 5:1, 4:1, 3:1, 2:1, 1:1). XIIIa-150 mg was obtained in a yield of 50%.

¹ H NMR (400MHz, CDCl3)

(s, 1H), 6.10 (s, 1H), 6.03 (s, 1H), 5.70 (s, 1H), 5.09 (d, J = 11.6 Hz, 1H), 4.66 (br, 1H), 4.39 (s, 1H), 4.24 (d, J = 4.8 Hz, 1H), 4.22 (d, J = 11.6 Hz, 1H), 4.16 (s, 1H), 3.76 (s, 3H), 3.54 (d, J = 4.8 Hz, 1H), 3.43-3.40 (m, 1H), 2.90 (m, 1H), 2.83-2.56 (m, 2H), 2.33 (s, 3H), 2.24 (s, 3H), 2.13 (s, 3H), 2.04 (s, 3H) MS: m/z (621), Found: 622 (M+H)

Example 13: Preparation of Compound XIVa-1

Add XIIIa-1 (30 mg) to the reaction flask, add amine (75 mg), 4.5 ml of absolute ethanol, stir at room temperature for 1 h, add sodium acetate (39 mg), then react for 4 h, stop the reaction and add 20 ml of ethyl acetate and 10 ml of water. The organic layer was washed twice with water, and then dried over anhydrous sodium sulfate, filtered, and concentrated to give the product of XIVa-1 (35 mg).

¹ H NMR (400MHz, CDCl3)

(s, 1H), 6.48 (s, 1H), 6.45 (s, 1H), 6.05 (s, 1H), 5.98 (s, 1H), 5.70 (s, 1H), 5.36 (s, 1H), 5.02 ( d, J = 11.2 Hz, 1H), 4.58 (s, 1H), 4.33 (s, 1H), 4.28 (d, J = 5.6 Hz, 1H), 4.19 (d, J = 2.8 Hz, 1H), 4.12 ( m,1H), 3.79 (s, 3H), 3.63 (s, 3H), 3.50 (d, J = 5.0 Hz, 1H), 3.42 (m, 1H), 3.10 (m, 1H), 2.94 (m, 2H) ), 2.78 (m, 1H), 2.62 (m, 1H), 2.46 (m, 1H), 2.35 (m, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H) , 2.08 (m, 1H), 2.04 (s, 3H) MS: m/z (784), Found: 785 (M+H)

Example 14: Preparation of Compound I

Add XIVa-1 (30mg) to the reaction flask, add a solution of tetrahydrofuran (1.5ml) and water (0.5ml), cuprous chloride (38mg), protect with nitrogen, avoid light, stir at room temperature overnight, next day TLC Check After the reaction was completed, a saturated aqueous solution of ammonium chloride (20 ml) and ethyl acetate (20 ml) was added, and the organic layer was washed twice with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate, filtered, The yield is 100%.

¹ H NMR (400MHz, CDCl3)

(s, 1H), 6.47 (s, 1H), 6.44 (s, 1H), 6.02 (s, 1H), 5.93 (s, 1H), 5.70 (br, 1H), 5.39 (br, 1H), 5.13 ( d, J = 11.2 Hz, 1H), 4.80 (s, 1H), 4.48 (s, 1H), 4.46 (br, 1H), 4.16 (d, J = 4.2 Hz, 1H), 4.05 (dd, J = 11.2) , 2.2 Hz, 1H), 3.79 (s, 3H), 3.61 (s, 3H), 3.57 (d, J = 4.9 Hz, 1H), 3.22 (s, 1H), 3.12 (m, 1H), 2.82-2.95 (m, 2H), 2.80 (m, 1H), 2.60 (m, 1H), 2.48 (m, 1H), 2.33 (br, 1H), 2.32 (s, 3H), 2.25 (s, 3H), 2.20 ( s, 3H), 2.19 (br, 1H), 2.03 (s, 3H) MS: m/z (761), Found: 744 (MH ₂ O+H)

Since the present invention has been described in terms of its specific embodiments, certain modifications and equivalents are obvious to those skilled in the art and are included within the scope of the invention.

Claims (24)

1. A compound of the formula Va:

   

   Wherein R ₂ is a hydroxy protecting group, preferably an acetyl group.
2. A method of preparing a compound as shown in Formula Va, the method comprising the steps of:

   Step 1: Safracin B and an isocyanate derivative are reacted to give a compound of formula IIa:

   

   Wherein R ₁ is O or S;

   Step 2: Reaction of compound IIa with cyanide to give a compound of formula IIIa:

   

   Wherein R ₁ is O or S;

   Step 3: Edman degradation reaction of compound IIIa with trimethylchlorosilane gives the compound of formula IVa-1:

   

   Wherein R ₁ is O or S;

   Step 4: Compound IVa-1 undergoes diazotization and nucleophilic reaction with sodium nitrite and a nucleophile to give a compound of formula Va:

   

   Wherein R ₂ is a hydroxy protecting group.
3. The method of claim 2, wherein

   In the step 1, the isocyanate derivative is phenyl isothiocyanate or phenyl isocyanate, preferably phenyl isothiocyanate; the molar ratio of Safracin B to the isocyanate derivative is 1:1 to 10, preferably Is 1:6; the temperature of the reaction is 0-40 ° C, preferably 25 ° C; reaction time is 2 ~ 48h, preferably 24h;

   In step 2, the cyanide is sodium cyanide, potassium cyanide, preferably sodium cyanide; the molar ratio of compound IIa to cyanide is 1:1 to 10, preferably 1:2.5; the reaction temperature is -20 ～20°C, preferably -10～-5°C; the reaction solvent is tetrahydrofuran/water (v/v)=4～2:1, preferably tetrahydrofuran/water (v/v)=4:1;

   In the step 3, the molar ratio of the compound IIIa to the trimethylchlorosilane is 1:3 to 20, preferably 1:5.5; the reaction solvent is an organic solvent, preferably methanol, ethanol, 1,4-dioxane, Tetrahydrofuran; reaction temperature is -20 to 50 ° C, preferably 0 to 5 ° C;

   In the step 4, the nucleophilic reagent is sodium acetate, sodium formate, sodium propionate, preferably sodium acetate; the molar ratio of the compound IVa-1 to sodium nitrite and the nucleophilic reagent is 1:1 to 20:1. ～2, preferably 1:7.9:1.4; the reaction solvent is an organic solvent or a mixed organic solvent, preferably dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, or a mixture of methanol and water, ethanol and water, tetrahydrofuran and water. Solvent; reaction temperature is -10 to 30 ° C, more preferably -5 to 0 ° C.
4. a compound of formula IIa:

   

   Wherein R ₁ is O or S.
5. A process for the preparation of a compound of formula IIa, which comprises reacting Safracin B with an isocyanate derivative to give a compound of formula IIa:

   

   Wherein R ₁ is O or S.
6. The method according to claim 5, wherein the isocyanate derivative is phenyl isothiocyanate, phenyl isocyanate, preferably phenyl isothiocyanate; and the molar ratio of Safracin B to isocyanate derivative is 1. : 1 to 10, preferably 1:6; the reaction temperature is 0 to 40 ° C, preferably 25 ° C; and the reaction time is 2 to 48 h, preferably 24 h.
7. A process for the preparation of compound VIa from compound Va, which comprises reacting compound Va with a hydroxy protecting agent to give a compound of formula VIa:

   

   Wherein R ₂ is a hydroxy protecting group; and R ₃ is a hydroxy protecting group.
8. The method according to claim 7, wherein said hydroxy protecting agent is bromomethyl methyl ether, chloromethyl methyl ether, 2-methoxyethoxymethyl chloride, preferably bromomethyl methyl ether; Va Hydroxyl protecting agent a molar ratio of 1:1 to 20, preferably 1:15; the base used for the reaction is N,N-diisopropylethylamine, triethylamine, sodium hydride, preferably N,N-diisopropylethylamine; The molar ratio of the compound Va to the base is 1:1 to 30, preferably 1:20; and the reaction temperature is -20 to 60 ° C, preferably 0 to 5 ° C.
9. A method of preparing compound VIIa from compound Va, the method comprising the steps of:

   Step 1: Compound Va is reacted with a hydroxy protecting agent to give a compound of formula VIa:

   

   Wherein R ₂ is a hydroxy protecting group; and R ₃ is a hydroxy protecting group;

   Step 2: Compound VIa is hydrolyzed to give a compound of formula VIIa:

   

   Wherein R ₂ is a hydroxy protecting group; and R ₃ is a hydroxy protecting group.
10. A method of preparing compound VIIIa from compound Va, the method comprising the steps of:

    Step 1: Compound Va is reacted with a hydroxy protecting agent to give a compound of formula VIa:

    

    Wherein R ₂ is a hydroxy protecting group; and R ₃ is a hydroxy protecting group;

    Step 2: Compound VIa is hydrolyzed to give a compound of formula VIIa:

    

    Wherein R ₂ is a hydroxy protecting group; and R ₃ is a hydroxy protecting group;

    Step 3: Compound VIIa is subjected to reduction and cyclization to give a compound of formula VIIIa:

    

    Wherein R ₃ is a hydroxy protecting group.
11. A method of preparing compound Xa from compound Va, the method comprising the steps of:

    Step 1: Compound Va is reacted with a hydroxy protecting agent to give a compound of formula VIa:

    

    Wherein R ₂ is a hydroxy protecting group; and R ₃ is a hydroxy protecting group;

    Step 2: Compound VIa is hydrolyzed to give a compound of formula VIIa:

    

    Wherein R ₂ is a hydroxy protecting group; and R ₃ is a hydroxy protecting group;

    Step 3: Compound VIIa is subjected to reduction and cyclization to give a compound of formula VIIIa:

    

    Wherein R ₃ is a hydroxy protecting group.

    Step 4: Compound VIIIa is oxidized to give a compound of formula IXa:

    

    Wherein R ₃ is a hydroxy protecting group.
12. A method of preparing trobeidine, the method comprising the steps of:

    Step 1: Compound Va is reacted with a hydroxy protecting agent to give a compound of formula VIa:

    

    Wherein R ₂ is a hydroxy protecting group; and R ₃ is a hydroxy protecting group;

    Step 2: Compound VIa is hydrolyzed to give a compound of formula VIIa:

    

    Wherein R ₂ is a hydroxy protecting group; and R ₃ is a hydroxy protecting group;

    Step 3: Compound VIIa is subjected to reduction and cyclization to give a compound of formula VIIIa:

    

    Wherein R ₃ is a hydroxy protecting group;

    Step 4: Compound VIIIa is oxidized to give a compound of formula IXa:

    

    Wherein R ₃ is a hydroxy protecting group;

    Step 5: Compound IXa is reacted with compound XV by ester condensation to give a compound of formula Xa:

    

    Wherein R ₃ is a hydroxy protecting group;

    Step 6: Compound Xa is cyclized to give a compound of formula XIa:

    

    Wherein R ₃ is a hydroxy protecting group;

    Step 7: Compound XIa is subjected to acid-catalyzed deprotection to give a compound of formula XIIa-1:

    Wherein R ₃ is a hydroxy protecting group;

    Step 8: Conversion of the amino group of compound XIIa-1 to a ketocarbonyl group gives the compound of formula XIIIa-1:

    

    Step 9: Compound XIIIa-1 is reacted with a compound of formula XVI to give a compound of formula XIVa-1:

    

    Step 10: Compound XIVa-1 is catalyzed by a copper salt to convert a cyano group to a hydroxy group to give a compound of formula I:

    
13. The method according to any one of claims 9 to 12, wherein in step 1, the hydroxyl group is protected The protective agent is bromomethyl methyl ether, chloromethyl methyl ether, 2-methoxyethoxymethyl chloride, preferably bromomethyl methyl ether; the molar ratio of Va to the hydroxy protecting agent is 1:1-20. Preferably, the base used for the reaction is N,N-diisopropylethylamine, triethylamine, sodium hydride, preferably N,N-diisopropylethylamine; the molar ratio of the compound Va to the base is 1 : 1 to 30, preferably 1:20; and the reaction temperature is -20 to 60 ° C, preferably 0 to 5 ° C.
14. A process according to any one of claims 9 to 12, wherein in step 2, the hydrolysis reaction is carried out under base catalysis, the base being an inorganic base, preferably lithium hydroxide, sodium hydroxide or potassium hydroxide Sodium carbonate, potassium carbonate, cesium carbonate; the molar ratio of the compound VIa to the base is 1:1 to 20, preferably 1:5.5.
15. The method according to any one of claims 10 to 12, wherein in the step 3, the reduction reaction is carried out under palladium-carbon catalysis, wherein the mass ratio of the compound VIIa to the palladium carbon is 1:0.1 to 1, preferably 1 :0.2; the reduction reaction temperature is 10 to 30 ° C, preferably 20 to 25 ° C; the cyclization reaction is carried out by a base catalyzed cyclization reaction, wherein the base is cesium carbonate, cesium fluoride, sodium carbonate, carbonic acid Potassium, preferably cesium carbonate, having a molar ratio of VIIa to base of 1:15 to 5, preferably 1:3; the solvent for the cyclization reaction is N,N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, acetonitrile, and N-methylpyrrolidone are preferably N,N-dimethylformamide; and the cyclization reaction temperature is preferably 50 to 110 ° C, and more preferably 95 to 110 ° C.
16. The method according to any one of claims 11 to 12, wherein in the step 4, the oxidizing agent is benzene selenate, 2-iodobenzoic acid, preferably benzene selenate, compound VIIIa and oxidizing agent. The molar ratio is 1:1 to 2, preferably 1:1; the reaction solvent is an organic solvent, preferably dichloromethane, tetrahydrofuran, ethyl acetate, methanol, ethanol, acetonitrile.
17. The method according to claim 12, wherein in the step 7, the acid is trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, preferably p-toluenesulfonic acid; and the reaction temperature is -10 to 30 °C, preferably 20 to 30 ° C; the molar ratio of the compound XIa to the acid is 1:4 to 15, preferably 1:5.
18. The method according to claim 12, wherein in the step 10, the copper salt catalyst is cuprous chloride, cuprous bromide, cuprous iodide, cuprous sulfate, preferably cuprous chloride; the reaction temperature is 0 to 45 ° C, preferably 25 to 30 ° C; the reaction solvent is an aqueous acetonitrile solution, an aqueous tetrahydrofuran solution, an aqueous methanol solution, an aqueous dichloromethane solution, preferably an aqueous tetrahydrofuran solution.
19. The method according to any one of claims 7 to 18, wherein the compound Va is produced by the following method, comprising:

    Step 1: Safracin B and an isocyanate derivative are reacted to give a compound of formula IIa:

    

    Wherein R ₁ is O or S;

    Step 2: Reaction of compound IIa with cyanide to give a compound of formula IIIa:

    

    Wherein R ₁ is O or S;

    Step 3: Edman degradation reaction of compound IIIa with trimethylchlorosilane gives the compound of formula IVa-1:

    

    Wherein R ₁ is O or S;

    Step 4: Compound IVa-1 undergoes diazotization and nucleophilic reaction with sodium nitrite and a nucleophile to give a compound of formula Va:

    

    Wherein R ₂ is a hydroxy protecting group.
20. The method of claim 19, wherein

    In the step 1, the isocyanate derivative is phenyl isothiocyanate or phenyl isocyanate, preferably phenyl isothiocyanate; the molar ratio of Safracin B to the isocyanate derivative is 1:1 to 10, preferably Is 1:6; the temperature of the reaction is 0-40 ° C, preferably 25 ° C; reaction time is 2 ~ 48h, preferably 24h;

    In step 2, the cyanide is sodium cyanide, potassium cyanide, preferably sodium cyanide; the molar ratio of compound IIa to cyanide is 1:1 to 10, preferably 1:2.5; the reaction temperature is -20 ～20°C, preferably -10～-5°C; the reaction solvent is tetrahydrofuran/water (v/v)=4～2:1, preferably tetrahydrofuran/water (v/v)=4:1;

    In the step 3, the molar ratio of the compound IIIa to the trimethylchlorosilane is 1:3 to 20, preferably 1:5.5; the reaction solvent is an organic solvent, preferably methanol, ethanol, 1,4-dioxane, Tetrahydrofuran; reaction temperature is -20 to 50 ° C, preferably 0 to 5 ° C;

    In the step 4, the nucleophilic reagent is sodium acetate, sodium formate, sodium propionate, preferably sodium acetate; the molar ratio of the compound IVa-1 to sodium nitrite and the nucleophilic reagent is 1:1 to 20:1. ～2, preferably 1:7.9:1.4; the reaction solvent is an organic solvent or a mixed organic solvent, preferably dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, or a mixture of methanol and water, ethanol and water, tetrahydrofuran and water. Solvent; reaction temperature is -10 to 30 ° C, more preferably -5 to 0 ° C.
21. The method according to any one of claims 7 to 20, wherein R ₁ is S, R ₂ is an acetyl group, and R ₃ is a methoxymethyl group (MOM).
22. a compound of formula VIa:

    

    Wherein R ₂ is a hydroxy protecting group, preferably an acetyl group; and R ₃ is a hydroxy protecting group, preferably a methoxymethyl group (MOM).
23. a compound of formula VIIa:

    

    Wherein R ₃ is a hydroxy protecting group, preferably methoxymethyl (MOM).
24. a compound of formula VIIIa,

    

    Wherein R ₃ is a hydroxy protecting group, preferably methoxymethyl (MOM).