WO2009049476A1

WO2009049476A1 - Process for the manufacture of (+)-biotin

Info

Publication number: WO2009049476A1
Application number: PCT/CN2008/001635
Authority: WO
Inventors: Fen-er CHEN; Hui-fang DAI; Jian Huang; Fei Xiong; Shu-Ping Jing
Original assignee: Dsm Ip Assets B.V.; Fudan University
Priority date: 2007-09-20
Filing date: 2008-09-22
Publication date: 2009-04-23
Also published as: CN102282149A

Abstract

Disclosed are processes for preparing synthetic biotin intermediates and a process for preparing biotin using said intermediates. In particular, disclosed is a process for the stereoselective total synthesis of the natural product (+)-biotin of formula (I).

Description

Process for the manufacture of (+)-biotin

Technical field

The invention relates to processes for the preparation of synthetic biotin intermediates and to a process for the preparation of biotin using said obtained intermediate(s). hi particular, the present invention relates to a process for the stereoselective total synthesis of the natural product (+)-biotin of formula I.

I Background art

Biotin is a vitamin useful as an additive for feed, medicine, etc. (+)-Biotin (formula I), also called vitamin H or coenzyme R, is a water-soluble vitamin of the vitamin B families. As the prosthetic group of various carboxylases, (+)-biotin is critical to the generation of reversible carboxylic group and the transferring of CO₂.

In 1944, the full synthetic route of (±)-biotin was first reported by Harris (J. Am. Chem. Soc. 1944, 66, 1756.). In this route (±)-biotin was obtained through 13 steps including reduction, coupling, Claisen condensation, etc. with L-cystine as starting material. The total yield reached 10%. So far, there have been numerous reports about total synthesis routes (see the summary in Chem. Rev. 1997, 97, 1755 and Medicinal Research Reviews 2006, 26, 434.). However, the route of Sterribach (from the Swiss company Roche), in which the sulfur-containing lactone of formula VI with R¹ = benzyl

is used as critical intermediate, is widely recognized as the most industrialized synthetic route. US 2,489,238 describes the famous Goldberg-Sternbach route, in which first naphthenic acid of formula II with R¹ = benzyl

II was generated through brominutesation, benzylaminutesation and phosgene ring closure of fumaric acid (starting material). Then cyclic anhydride of formula III with R¹ = benzyl

III was formed through dehydration of acetic anhydride; the racemic sulfur-containing lactone of formula VI with R¹ = benzyl was obtained through reduction and vulcanization. Then a side chain was introduced through Grignard reaction and the cis configuration was generated through dehydration and catalytic hydrogenation. Finally, (+)-biotin was obtained through formation of a sulfonium salt intermediate, decomposition by d-silver camphor sulfonate and debenzylation by hydrobromic acid. Later there was a modification of this route made by Gerecke (HeIv. Chim. Acta. 1970, 53, 991), in which racemic naphthenic acid monoester was made through mono-esterification between cyclic anhydride of formula III with R¹ = benzyl and cyclohexanol. Then required (4S, 5R)- naphthenic acid monoester was generated through crystallization resolution of the diastereomer with pseudoephedrine. Then, the critical chiral building block - (3aS, 6&R)- lactone of formula V with R¹ = benzyl -

was obtained via reduction with lithium borohydride and ring closure. The synthesis was finished with an overall yield of 10%. However, the resolution procedure is a disadvantage of the Sternbach route, which dramatically reduces the yield.

Improved routes for the synthesis of the critical chiral building block (3a5^*, 6a/?)-lactone of formula V with R¹ = benzyl have been described in many later methods. In the method described by EP-A 173 185, first the racemic naphthenic acid monoester is obtained through mono-esterifϊcation between cyclic anhydride of formula III with R¹ = benzyl and a primary alcohol. Then by use of dehydrogenated rosin aminutese as resolving agent, (4S, 5i?)-naphthenic acid monoester is obtained. Afterwards (3aS, 6ai?)-lactone of formula V with R¹ = benzyl is generated via reduction with sodium borohydride and ring closure.

In the method described by EP-A 092 194, ((5)-2-aminuteso- 1 , 1 -diphenylpropanol or (-)- ephedrine) is adopted as resolving agent in the resolution of racemic ethyl ester, however, resolution rate in the single time is only 30%. According to the process reported by Chen Fener in {ChemicalJournal of Chinese Universities, 2001, 12, 1141.), (IS, 2_JS^r)-threo-l-(p- nitrophenyl)-l, 3 -propanediols (chloramphenicol by-product) can be used as resolving agent to resolute racemic naphthenic acid monoester and prepare the compound of formula V with R¹ = benzyl. Though this resolving agent is inexpensive with wide resources, its single-time resolution rate is only 37%. And complex operation and higher cost are the common disadvantages of these resolution methods.

According to the description of EP-A 044 158, the chiral semi-amide can be obtained through non-enantioselective ring-opening of cyclic anhydride III with R¹ = benzyl by use of (S)-N-methyl-α-phenylethylaminutese as chiral auxiliary agent. The yield is 95% and the de value is 100%. Though providing agreeable stereoselectivity and yield, its disadvantages are complex steps and lower yield in the following preparation Of (Sa₁S¹, 6ai?)-lactone V with R¹ = benzyl.

WO2001/25215 describes asymmetric ring-opening method of cyclic anhydride III with R¹ = benzyl by using N-methyl ephedrine as chiral adjuvant, through which the de value of the obtained (4S, 5i?)-semi-ester of formula IV can reach 82%.

IV

WO 2004/094 367 describes an asymmetric ring-opening method using various chiral alcohols as chiral auxiliary agents. Among these chiral alcohols, (S)-I, 1-diphenyl-l, 2- propanediol has the highest ring-opening stereoselectivity and the (4S, 5i?)-semi-ester of formula IV can be obtained with a de value of 100% and a yield of 89%. However, the expensive chiral reagent and the difficulty in recovery of chiral reagent are disadvantages of these methods.

EP-A 084 892 describes the method of hydrolyzing meso dimethyl ester, diethyl ester and dipropyl ester with pig liver esterase, in which optical pure product can be obtained with a yield of 48% through recrystallization of the hydrolysate. F. Chen (Adv. Synth. Catal. 2005, 347, 549) has applied the asymmetric hydrolysis of meso dimethyl ester with polymer- loaded pig liver esterase and obtained (4S, 5Z?)-semi-ester IV with R¹ = benzyl and R² = methyl with a yield of 90% and an ee value of 91%. Though the enzyme resolution method provides relatively better optical selectivity, the variability and the low content of the enzyme, as well as the difficulties in extraction and separation limit its industrial application.

According to the report of Deng Li (Synthesis 2001, 11, 1737), (3aS, 6ai?)-lactone V with R¹ = benzyl can be prepared through asymmetric ring-opening with quinine derivative DHQD-PHN (9-O-(9 -phenanthryl) dihydroquinidine) as catalyst. Though this method provides high enantioselectivity, the high price of the catalyst and the complex reaction steps inhibit its application.

CN 1 183 137 describes a method for the preparation Of(SaS¹, 6a/?)-lactoneV with R¹ = benzyl by asymmetric alcoholysis of naphthenic hydride III with the chiral aminutese (IS, 2S)- 1 -(4- nitrophenyl)-2-Λζ, iV-dimethylaminuteso-3-tribenzyloxy-l-propanol as catalyst. This method can provide high yield and stereoselectivity, however, the complex preparation of the catalyst is its disadvantage.

Seki (Synthesis 2002, 361-364) has reported a synthetic route Of(SaO¹, 6aΛ)-lactone V with R¹ = benzyl using aspartic acid as chiral pool.

Deshmukh (Synthesis 2007, 1159-1164) has obtained (3aS, 6ai?)-lactoneV with R¹ = benzyl with the easy-to-prepare /3-lactam through 7 reaction steps.

Seki (Chem. Eur. J. 2004, 10, 6102) has also produced (3aS, 6ai?)-lactoneV with R¹ = benzyl using Z-cys cysteine as starting material and then synthesized (+)-biotin I by introducing the side chain via Pd/C catalyzed Fukuyama coupling. In 2007, F. Chen reported "Chiral pool" synthesis of I using D-mannose as starting material (Carbonhydr. Res. 2007, 342, 2461). The complex synthetic procedure is the normal disadvantage that inhibits the application of these methods.

This invention is to overcome the shortcomings of the available technology and provide a convenient total synthesis of (+)-biotin of formula I with high yield and high stereoselectivity.

Disclosure of the invention

To solve the problem, the present inventors have found a process for preparing biotin via compounds II, III, IV, V, VI, VII or VIII which is cost-efficient. It is therefore an industrially excellent preparation process. The present invention relates to a process for preparing the compound of formula I,

which comprises a) reacting a compound of formula II with acyl chloride to prepare meso-CYCLIC

ANHYDRIDE of formula III

D^Iπ wherein R¹ is benzyl, Gf-phenylethyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, allyl, 1-furyl, 2-furyl, 1-thienyl or 2-thienyl,

b) subjecting the compound of formula III to enantioselective alcoholysis with alcohol in the presence of a cinchona alkaloid to prepare the (4S,5R)-semiester of formula IV;

IV wherein R² is Cr₆ alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, hexyl etc.), C₃-₈ cycloalkyl (e.g. cyclopropyl, cyclobutyl, cycloamyl, cyclohexyl, cycloheptyl, cyclooctyl etc.), C₃-₆ alkenyl, C₃-₆ alkynyl, aralkyl (e.g. benzyl, substituted benzyl, phenethyl, hydrocmnamyl, 1-naρhthylmethyl, 2-naρhthylmethyl etc.) or aralkenyl (e.g. cinnamyl, substituted cinnamyl etc.); c) subjecting the compound of formula IV to ring closure by use of an acidic catalyst to prepare the (3aS, 6aR)-lactone of formula V;

V d) Subjecting the compound of formula V with a thio agent to prepare the (3aS, 6aR)- thiolactone of formula VI;

VI wherein R¹ has the same meaning as defined above, e) Subjecting the compound of formula VI with a zinc-containing agent in the presence of a nano-palladium catalyst to Fukuyama coupling to prepare the diastereomeric mixture of formula VII;

VII wherein R³ is carbalkoxy (e.g. Cr₆ carbalkoxy such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec- butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl etc.), aralkyloxycarbonyl (e.g. carbobenzoxy, substituted carbobenzoxy, naphthyloxycarbonyl, substituted naphthyloxycarbonyl etc.), cyan, or oxazolinyl.

f) reducing the compound of formula VII to (3aS, 4S, 6aR)-dibenzyl-biotin and its derivative of formula VIII via ionic hydrogenation with silane in the presence of an organic acid or a Lewis acid; or de-hydrating the compound of formula VII in the presence of an acid to obtain the compound of formula IX, then reducing the obtained compound of formula IX to (3aS, 4S, 6aR)-dibenzyl-biotin and its derivative of formula VIII via ionic hydrogenation with silane in the presence of an organic acid or a Lewis acid;

g) hydrolyzing the compound of formula VIII in the presence of an inorganic acid, then opening the ring, removing the protecting group, closing the ring using trichloromethyl chloroformate (diphosgene) or bis (trichloromethyl) carbonate (triphosgene) in the presence of activated carbon as catalyst to obtain (+)-biotin of formula

I.

Second, the present invention relates to a process for preparing a compound of formula III, comprising reacting the compound of formula II with acyl chloride,

wherein R¹ is benzyl, α-phenylethyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, allyl, 1-furyl,

2-furyl, 1-thienyl or 2-thienyl.

Third, the present invention relates to a method of preparing a (4S,5R)-semiester of formular IV, wherein the compound of formula III is subjected to enantioselective alcoholysis with alcohol in the presence of a cinchona alkaloid,

rv wherein R¹ is benzyl, ophenylethyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, allyl, 1-furyl, 2-furyl, 1-thienyl or 2-thienyl; R² is Cr₆ alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, hexyl etc.), C₃-₈ cycloalkyl (e.g. cyclopropyl, cyclobutyl, cycloamyl, cyclohexyl, cycloheptyl, cyclooctyl etc.), C₃-₆ alkenyl, C₃-₆ alkynyl, aralkyl (e.g. benzyl, substituted benzyl, phenethyl, hydrocinnamyl, 1-naphthylmethyl, 2- naphthylmethyl etc.) or aralkenyl (e.g. cinnamyl, substituted cinnamyl etc.).

Fourth, the present invention relates to a method of preparing a (3aS, 6aR)-lactone of formula V, wherein the compound of formula IV is selectively reduced at the ester group and then subjected to ring closure in the presence of an acidic catalyst

V wherein R¹ is benzyl, α-phenyl ethyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, allyl, 1-furyl, 2-furyl, 1-thienyl or 2-thienyl.

Fifth, the present invention relates to a method of preparing a (3aS, 6aR)-thiolactone of formula VI, wherein the compound of formula V is reacted with a thio-reagent

wherein R¹ is benzyl, α-phenylethyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, allyl, 1-furyl, 2-furyl, 1-thienyl or 2-thienyl.

Sixth, the present invention relates a method of preparing the diastereomeric mixture of formula VII, wherein the compound of formula VI is subjected to Fukuyama coupling with a zinc-agent in the presence of a nano-palladium catalyst,

VII wherein R¹ is benzyl, o«-phenyl ethyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, allyl, 1-furyl, 2-furyl, 1-thienyl or 2-thienyl; R³ is carbalkoxy (e.g. Cr₆ carbalkoxy such as methoxy- carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl etc.), aralkyloxycarbonyl (e.g. carbobenzoxy, substituted carbobenzoxy, naphthyloxycarbonyl, substituted naphthyloxycarbonyl etc.), cyan or oxazolinyl.

Seventh, the present invention relates to a method of preparing (3aS, 4S, 6aR)-dibenzyl- biotin and its derivative of formula VIII, wherein the compound of formula VII is reduced via ionic hydrogenation with silane in the presence of an organic acid or a Lewis acid; Or, wherein the compound of formula VII is subjected to de-hydration under action of acid to obtain the compound of formula IX, which is then reduced to (3aS, 4S, 6aR)-dibenzyl- biotin and its derivative of formula VIII via ionic hydrogenation with silane in the presence of an organic acid or a Lewis acid;

wherein R¹ is benzyl, α-phenyl ethyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, allyl, 1-furyl, 2-furyl, 1-thienyl or 2-thienyl; R³ is carbalkoxy (e.g. C^₆ carbalkoxy such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl etc.), aralkyloxycarbonyl (e.g. carbobenzoxy, substituted carbobenzoxy, naphthyloxycarbonyl, substituted naphthyloxycarbonyl etc.), cyan or oxazolinyl.

Eighth, the present invention relates to a method of preparing (+)-biotin (compound of formula I), wherein, the compound of formula VIII is hydrolyzed using an inorganic acid, followed by ring opening, removing of the protecting group, and ring closure using trichloromethyl chloroformate (diphosgene) or bis (trichloromethyl) carbonate (triphosgene) in the presence of activated carbon as catalyst to obtain biotin of formula I

Detailed description of the invention

1,3-di-substituted benzyl imidazolinyl-2-ketone-cis-4,5-dicarboxylic acid and various acyl halides are subject to dehydration/ring-closing reaction in the presence of an organic solvent or in the absence of solvent so as to give cis-1.3-di-substituted benzyl imidazolinyl-2-ketone-2/i-furano [3A-d\ imidazolyl-2,4,6-triketone (naphthenic anhydride, I). This reaction is characterized by mild reaction conditions and a product with a high grade of purity (>99.5%). The route of reaction is:

( I/ In the present invention, said acyl halide is a Cr₆ aliphatic acyl halide, an aromatic acyl halide or a substituted aromatic acyl halide, the halide being Cl or Br. Preferably the acyl halide is acetyl chloride, propionyl chloride or benzoyl chloride.

In the present invention, the molar ratio of the 1,3-di-substituted benzyl imidazolinyl-2- ketone-cis-4,5-dicarboxylic acid (naphthenic acid) (the compound of formula II) to the acyl halide is preferably in the range of 1 to 1-5.

The said organic solvent is an aromatic hydrocarbon (an arene or a substituted arene) or a halohydrocarbon. Preferably the aromatic hydrocarbon is selected from the group consisting of benzene, toluene and xylene. Preferred examples of the halohydrocarbon are 1,1,2-trichloroethane, 1,2,3-trichloropropane, tetrachloroethylene and 1,2,3- trichloropropylene. Toluene and 1 ,2-dichloroethane are especially preferred.

The mass/volume ratio of 1,3-di-substituted benzyl imidazolinyl-2-ketone-cis-4,5- dicarboxylic acid (compound of the formula II) to the organic solvent is preferably in the range of 1 to 6-20 g/mL, showing a better solubility in the reaction. Said reaction could also be carried out under a solvent- free condition.

In the present invention, the reaction temperature is preferably in the range between 20- 135⁰C and the reaction time is in the range of 0.5-5 hours (preferably 0.5-2 hours).

The optimum conditions for the reaction are as follows:

1) When the molar ratio of 1, 3-di-substituted benzyl imidazolinyl- 2-ketone-cis-4,5- dicarboxylic acid (naphthenic acid) (compound of formula II) to acetyl chloride is in the range of 1 to 1.5-5, the reaction can be successfully completed.

2) It can lower cost and environmental pollution if the organic solvent is avoided in the reaction.

3) The reaction is preferably carried out in the range of temperature between 45-60°C for 1-2 hours.

The present invention uses xanthate (A) as thio-reagent and conducts the thio-reaction of (3aS, 6aR)-l,3-dibenzyl-tetrahydro-4H-furan-[3,4-d] imidazol-2,4-(lH)-dione in an organic solvent. After completion of the reaction, the raw product is treated with 5% hydrochloric acid, abstract and extracted with toluene. After the removal of toluene (which can be recovered) the product crystallizes out solidly. Refining with ethyl acetate to give yields thio-ketone (I) with 90% yield and a chemical purity >98.5%. The thio-reagent used in the invention is xanthate A. For instance, potassium methyl thioxanthate or potassium dodecyl thioxanthate.

A

In the invention, the molar ratio between (3aS, 6aR)-l,3-dibenzyl-tetrahydro -4H-thieno- [3,4-d] imidazol-2,4-(lH)-dione and the thio-reagent is in the range of 1 to 1-5. This invention adopts N, N-dimethylacetamide or either of the following as organic solvent: N, N-dimethylformamide, N-methylketopyrrolidine, cyclobutylsulfone, dimethyl - sulfoxide, which can give rather good results. The better solvent is N, N- dimethylacetamide.

The reaction temperature of this invention is in the range of 100-140⁰C.

The better reaction conditions for this invention are:

The thio-reagent is potassium ethyl thioxanthate to get especially high product purity.

The molar ratio between reactant and thio-reagent is in the range of 1 to 1-2, to get better reaction results and lower costs. The organic solvent is N,N-dimethylacetamide, which gives good results with lower price and easy availability.

The optimal reaction temperature is in the range of 120-125°C.

hi the present invention, (3aS, 6aR)-l, 3-dibenzyl -4H-4H-thieno[3 , 4-d]miidazolyl-2, 4(lH)-diketone (II) (also named as sulphur lactone) and a halozinc reagent formed by zinc powder and halogenated carboxylate are subjected to a Fukuyama coupling reaction in the presence of a nano palladium catalyst dispersed in an anionic exchange resin. The multi- carbon side chain should be introduced in a single step, then water shall be added for filtration to give (3aS, 6aR)-l, 3-substituted aryl-tetrahydro-4H-lH-thieno [3, 4-d] imidazole derivative (I) with a yield > 85%. In the coupling reaction of the present invention of sulphur lactone and side chain, the strong alkali anionic exchange resin with -NMe₃Cl, NMe₂ functional groups available on the market is selected as a carrier and its particle size is in the range of 50-180 mesh containing 0.08-0.3mmol/g of nano palladium. The anionic exchange resin is initially subjected to swelling in methanol, then the metallic complex ion PdCl₄ ^2" is exchanged onto the ion exchange resin to give metallic nano Pd granules with the help OfNaBH₄ as a reducing agent. As its structure is shown in A, this catalyst presents a good catalytic effect with mild reaction conditions and simple operation and the catalyst itself can be quantitatively recoverable.

In the Fukuyama coupling reaction in the presence of a polymer dispersing Pd catalyst, the halogenated carboxylate is any one of the group consisting of 5-bromopentanoate, 5- iodopentanoate, 4-bromobutyrate, 4-iodobutyrate, which is used to prepare the halozinc reagent wherein the halogen is Cl, Br or I. The molar ratio of the compound of formula Il/the zinc powder/the halogenated carboxylate is in the range of 1 :(2-6.5)(2-12) upon which the reaction can be completed, hi the halozinc reagent, the organic solvent is tetrahydrofuran, N, N-dimethyl formamide or N, N-dimethyl acetamide, or tetrahydrofuran, N, N-dimethyl formamide and aromatic hydrocarbons with a volume ratio in the range of (10-20):(1.5-5):(10-30). These solvents are easily available, they have a low price, they are safe and recoverable. The molar ratio of the compound of formula Il/nano Pd catalyst is in the range of 1 :(0.002-l). The Fukuyama coupling reaction is carried out at a temperature in the range between 10-70°C for 5-20 hours upon which the good effect of reaction can be achieved. The organic solvent involved in the Fukuyama coupling reaction is a component solvent comprising tetrahydrofuran, N, N-dimethyl formamide, N, N-dimethyl acetamide or tetrahydrofuran, N, N-dimethyl formamide and aromatic hydrocarbons.

hi the Fukuyama reaction in the presence of the polymer-dispersing Pd catalyst according to the present invention, a bromozinc reagent formed from bromopentanoate induced by iodine is preferred due to its availability of preparation and reasonable price, such as 5- bromopentanoate, 5-iodopentanoate.

In the Fukuyama reactions in the presence of polymer-dispersing Pd catalyst according to the present invention, the molar ratio of compound II/zinc powder/halogenated carboxylate is preferably in the range of 1 :2-4:3-8.

In the Fukuyama reaction in the presence of polymer-dispersing Pd catalyst according to the present invention, the preferable organic solvent is tetrahydrofuran, N, N-dimethyl formamide and toluene with its volume ratio in the range of 15:(1.5-3):(20-25). This solvent is easily available in a low price; it is safe, non-toxic and recoverable.

In the preparation of the bromozinc reagent, the reaction is carried out at a temperature in the range between 10-70⁰C, preferably a temperature in the range between 30-50°C.

In the Fukuyama reaction in the presence of polymer-dispersing Pd catalyst, the reaction is preferably carried out at temperature in the range between 30-45°C for 5-15 hours.

hi the present invention, the molar ratio of compound (II)/nano Pd catalyst is preferably in the range of 1 :0.005-0.005.

The Fukuyama coupling reaction is conducted in the presence of a nano Pd catalyst dispersed in an anionic exchange resin. The side carbon chain of Biotin having a plurality of carbon atoms is introduced in a single step, and then be added with water and be simply filtered to give (3aS, 6aR)-l, 3-substituted aryl-tetrahydro-4H-lH-thieno [3, 4-d] imidazole derivative (I) which is cheap, safe, recoverable, of a high yield, and thus has a promising application prospect.

In the present invention, the said acid is a variety of aliphatic acids or substituted aliphatic acids, such as formic acid, acetic acid, propanoic acid, trifluoroacetic acid, trichloroacetic acid or tribromoacetic acid, sulfonic acid or substituted sulfonic acid, such as methane sulfonic acid or trifluoromethane sulfonic acid, and said Lewis acid is ZnCl₂, BF₃, AlCl₃, TiCl₄, or SnCl₄, etc. In the present invention, when preparing the compound of formula VIII, the said substituted silicane is trimethyl silicane, triethyl silicane, triphenyl silicane, dimethyl silicane, diethyl silicane or diphenyl silicane, etc.

In the present invention, the said organic solvent comprises halohydrocarbon (such as dichloromethane, chloroform, 1,2-dichloroethane, tetrachloromethane); aromatic hydrocarbon (such as benzene, toluene, xylene, nitrobenzene, and various benzene halides, etc.), or ether type of solvents (such as diethyl ether, dioxane or tetrahydrofuran, etc.). The reaction can be implemented either in a single solvent or in a mixture of solvents, and the the two-component-mixture is in a range of 1 :0.1-10 by volume. These solvents are easily available, cost effective and easily recoverable.

In the present invention, the molar ratio of tertiary alcohol II or alkene III /acid or Lewis acid/substituted silicane is in the range of 1 : 1-40 : 1-20. The reaction is carried out at a temperature between -80-50°C for 3-50 hours.

hi the present invention, the molar ratio of tertiary alcohol II or alkene III /acid or Lewis acid/substituted silicane is preferably 1 : 10-20 : 3-10.

In the present invention, the reaction is preferably carried out at a temperature in the range between -75 -25°C.

hi the present invention, the reaction is preferably carried out for 8 -24 hours.

In the present invention, said organic solvent is preferably dichloromethane.

The present invention is characterized by mild reaction conditions, easy operation, high yield and high optical purity, and is suitable to industrial production.

In the present invention, the cyclization reagent involved in the ring-closing reaction is diphosgene or triphosgene, and the molar ratio of the compound II to the cyclization reagent is in the range of 1 : 1.1 -8. The catalyst involved in the ring-closing reaction is an activated carbon, and the molar ratio of the compound II to the catalyst is in the range of 1- 2:1. The inorganic alkali solution involved in ring-closing reaction is 5-30% NaOH or KOH solution. The organic solvent involved in the ring-closing reaction is tetrahydrofuran, dioxane, anisole, toluene or xylene, etc. The ring-closing reaction is carried out at temperature between 5-50°C for 3-12 hours.

The present invention is characterized by mild reaction conditions, easy operation, and high yield, and is suitable to industrial production.

Hereinafter the present invention will be explained by referring to the examples, but the present invention is not limited only to these examples.

Examples

Example 1 : Preparation of the compound of formula III with R¹ = benzyl

In dry flask add CAC II with R¹ = benzyl (5.Og, 14.1 mmol) and acetyl chloride (4.0 mL, 56.4 mmol), stir the mixture at 60°C and react for lhr, adsorb the released acid fog with alkaline, then add 70 mL of toluene, heat and reflux for 4 hours, cool down to room temperature, filter and separate out solid, rinse the filter cake with toluene, vacuum dry to get 4.5g white solid III with R¹ = benzyl with 95% yield and m.p. (melting point) 239.2-

239.7°C.

IR(KBr): 3029, 2945, 1809, 1695, 1463, 1358, 1222, 1090, 919, 740, 700 cm^"1;

¹H NMR (CDCl₃, 400 MHz) δ 7.37 - 7.26 (m, 10H), 5.10 (d, J= 14.8 Hz, 2H), 4.21 (s,

2H), 4.19 (d, J= 14.8 Hz, 2H);

¹³C NMR (CDCl₃, 100 MHz) δ 166.3, 156.7, 134.6, 129.0, 128.8, 128.3, 54.3, 46.2; EI-MS m/z 336 (M⁺).

Example 2: Preparation of the compound of formula HI with R¹ = benzyl Transfer CAC II with R¹ = benzyl (5.0 g, 14.1 mmol), acetyl chloride (2.0 mL, 28.2 mmol) and 1,2-dichloroethane (90 mL) into a flask, heat, stir and reflux for 15 hours, cool down for crystallization, filter, rinse and vacuum dry to get 4.2 g of a white powder III with R¹ = benzyl with 90% yield and m.p. 238.5-239.7°C.

Diagrams of IR, ¹H NMR, ¹³C NMR and MS are identical to those described in Example 1. Example 3: Preparation of the compound of formula HI with R¹ = benzyl Transfer CAC II with R¹ = benzyl (35.5 g, 0.10 mol), propionyl chloride (17.4 mL, 0.20 mol) and toluene (710 mL) into a flask, heat, stir and reflux for 8 hours, cool down to room temperature, separate out solid, filter, rinse and dry to get a white powder III (33 g, 98%) and m.p. 238.2-239.5°C.

Diagrams of IR, ¹H NMR, ¹³C NMR and MS are identical to those described in Example 1.

Example 4 1,3-dibasic benzyl imidazolinyl-2-ketone-cis-4,5-dicarboxylic acid (35.5 g, 0.10 mol), acetyl chloride (8.56 mL, 0.12 mol) and toluene (355mL) are fed into a reaction flask, heated with agitation for circulation reflux for Ih. Then residual acetyl chloride and acetic acid are removed by reduced pressure to finally give white powder in formula I (33.7g,

99%), mp 23ό-237°C with content of 99.5% (by HPLC).

IR (KBr): v = 1805, 1740, 1687, 1227cm- 1.

IH NMR (CDCl₃): δ = 4.21 (s, 2H, C3a-H and C6a-H), 4.19, 5.10 (dd, 4H, J = 15Hz,

2XCH₂C₆H₅), 7.26-7.39 (m, 1OH, 2xArH) ppm.

EI-MS: (m/z, %) = 336(M+, 13.6), 264 (15.6), 173(5.8), 132 (10.9), 91(100).

Example 5

1,3-dibasic benzyl imidazolinyl-2-ketone-cis-4,5-dicarboxylic acid (35.5 g, 0.10 mol), acetyl chloride (14.3 mL, 0.20 mol) and 1,2-dichloroethane (650 mL) are fed into a reaction flask, heated with agitation for circulation reflux for 15 hours. After the temperature is returned to room temperature, a solid is precipitated out, then filtered, dried to give white powder in formula I (32 g, 95%), mp 235-237°C. IR, ¹H NMR and MS are the same to Example 4.

Example 6 1,3-dibasic benzyl imidazolinyl-2-ketone-cis-4,5-dicarboxylic acid (35.5 g, 0.10 mol), propionyl chloride (17.4 mL, 0.20 mol) and toluene (710 mL) are fed into a reaction flask, heated with agitation for circulation reflux for 8 hours. After the temperature is returned to room temperature, a solid is precipitated out, then filtered, dried to give white powder in formula I (33 g, 98%), mp 236-236.5⁰C. IR, ¹H NMR and MS are the same to Example 4. Example 7

1,3 -dibasic benzyl imidazolinyl-2-ketone-cis-4,5-dicarboxylic acid (35.5 g, 0.10 mol), benzoyl chloride (29.3 mL, 0.25 mol) and toluene (710 mL) are fed into a reaction flask, heated with agitation for circulation reflux for 8 hours. After the temperature is returned to room temperature, a solid is precipitated out, then filtered, dried to give white powder in formula I (32 g, 95%), mp 236-237°C. IR, ¹H NMR and MS are the same to Example 4.

Example 8: Preparation of compound IV with R¹ = benzyl and R² = methyl Transfer CYCLIC ANHYDRIDE III with R¹ = benzyl (33.6 g, 0.10 mol), quinine (32.4 g, 0.10 mol) and toluene (1000 mL) into dry flask, at -4O⁰C drop anhydrous methanol (12.2 mL, 0.3 mol), then stir at -40⁰C and react for 24 hours. Upon reaction completion, recover solvent under reduced pressure, cool down to room temperature, add ethyl acetate (500 mL) into remnant and stir for 15 minutes, then add 2M hydrochloric acid (400 mL), stir at 10- 15⁰C for 10 minutes, stay still, separate out organic layer and dry with anhydrous sodium sulphate. Filter, recover solvent ex filtrate under vacuum, recrystallize the remnant with benzene to get 31.3 g white crystal powder IV with R¹ = benzyl and R² = methyl) with 85% yield, m.p. 148-150⁰C, e.e. = 99.4% (HPLC, chiral column: Chiralcel AD-H), [α]_D ²² = +2.70 (c 1.0, CHCl₃).

IR(KBr): 3258, 2943, 1756, 1713, 1449, 1411, 1252, 968, 799, 598, 458 cm^"1;

¹R NMR (CDCl₃, 400 MHz) δ 7.36 - 7.19 (m, 10H), 6.85 (br s, IH), 5.09 (d, J= 14.8 Hz,

IH), 4.98 (d, J= 14.8 Hz, IH), 4.13 - 4.04 (m, 4H), 3.63 (s, 3H);

¹³C NMR (CDCl₃, 100 MHz) δ 171.7, 168.5, 159.5, 135.57, 135.52, 128.85, 128.79, 128.64, 128.56, 127.98, 127.93, 57.3, 56.7, 52.6, 46.89, 46.80; ESI-MS m/z 391.1 [M+Na]⁺

Example 9: Preparation of compound IV with R¹ = benzyl and R² = -CH₂CH = CHPh) Transfer CYCLIC ANHYDRIDE III with R¹ = benzyl (33.6g, O.lOmol), 9-propargyloxo- quinine (36.2g, O.lOmol) and toluene (50OmL) into dry flask, at -40⁰C drop cinnamyl alcohol (38.5mL, 0.30mol), then stir at -4O⁰C and react for 24 hours. Upon reaction completion, recover solvent under reduced pressure, cool down to room temperature, add ethyl acetate (500 mL) into remnant and stir for 15 minutes, then add 2M hydrochloric acid (400 mL), stir at 10-15⁰C for 10 minutes, stay still, separate out organic layer, extract with saturated aqueous solution OfNa₂CO₃, combine extracts, adjust to pH = 1 with concentrated hydrochloric acid, extract with ethyl acetate, combine extracts and dry with anhydrous sodium sulphate. Filter, recover solvent ex filtrate under vacuum, recrystallize the remnant with ethyl acetate to get 38.5g white crystal powder IV with R¹ = benzyl and R² = methyl) with 82% yield, m.p. 122.0-122.8°C, e.e. = 99% (HPLC, chiral column: Chiralcel AD-H), [α]_D ²² = +7.58 (c 1.0, MeOH).

IR (KBr): 3028, 2941, 1752, 1665, 1450, 1239, 1198, 966, 747, 700 crn ¹;

¹H NMR (CDCl₃, 400 MHz) δ 10.39 (br s, IH), 7.42 - 7.27 (m, 15H), 6.63 (d, J= 16.0 Hz, IH), 6.24 (dt, J = 16.0, 6.4 Hz, IH), 5.18 (d, J= 15.2 Hz, IH), 5.09 (d, J= 15.2 Hz, IH), 4.81 - 4.67 (m, 2H), 4.27 - 4.12 (m, 4H);

¹³C NMR (CDCl₃, 100 MHz) δ 169.3, 167.4, 159.7, 135.56, 135.13, 135.05, 134.47, 128.38, 128.19, 127.78, 127.52, 126.30, 121.59, 65.9, 60.2, 57.1, 56.6, 46.4, 46.3; ESI-MS m/z 493.4 [MH-Na]⁺

Example 10: Preparation of compound IV with R¹ = benzyl and R² = -CH?C ≡€H) Transfer CYCLIC ANHYDRIDE III with R¹ = benzyl (33.6 g, 0.10 mol), dihydroquinine (32.6 g, 0.10 mol), carbon tetrachloride (60OmL) and toluene (400 mL) into dry flask, at - 50°C drop propargyl alcohol (17.7 mL, 0.3 mol), then stir at -50°C and react for 60 hours. Upon reaction completion, recover solvent under reduced pressure, cool down to room temperature, add ethyl acetate (500 mL) into remnant and stir for 15minutes, then add 2M hydrochloric acid (400 mL), stir at 10-15⁰C for lOminutes, stay still, separate out organic layer and dry with anhydrous sodium sulphate. Filter, recover solvent ex filtrate under vacuum, recrystallize the remnant with ethyl acetate/cyclohexane (1 :1) to get 32.5 g white crystal powder IV (R¹ = -Bn, R² = -CH₂C ≡€H) with 83% yield, e.e. = 97% (HPLC, chiral column: Chiralcel AD-H), [a]_D ²⁵ = +15.6 (c 1.0, CHCl₃), m.p. 135.8-137.8⁰C.

IR (KBr): 3299, 3026, 2919, 1751, 1652, 1464, 1440, 1203, 978, 704 cm^"1; 1EL NMR (CDCl₃, 400 MHz) δ 7.33 - 7.20 (m, 10H), 6.62 (br s, IH), 5.08 (d, J= 14.8 Hz, IH), 5.00 (d, J= 14.8 Hz, IH), 4.66 - 4.56 (m, 2H), 4.12 - 4.06 (rn, 4H), 2.50 (t, J = 2.8 Hz, IH);

¹³C NMR (CDCl₃, 100 MHz) δ 171.5, 167.3, 159.5, 135.48, 135.36, 128.87, 128.84, 128.67, 128.60, 128.02, 128.00, 76.43, 75.97, 57.04, 56.51, 53.1, 46.85, 46.78; ESI-MS m/z 393.3 [M+H]⁺, 415.3 [M+Naf Example 11 : Preparation of compound IV (R¹ = -Bn, R² = -CHO Transfer CYCLIC ANHYDRIDE III (33.6 g, 0.10 mol), 9-propargyloxo-cinchonidine (29.4 g, 0.10 mol), carbon tetrachloride (500 mL) and toluene (500 mL) into dry flask, at 25°C drop anhydrous methanol (40.5 mL, 1.0 mol), then stir at 25°C and react for 18 hours. Upon reaction completion, recover solvent under reduced pressure, cool down to room temperature, add ethyl acetate (500 mL) into remnant and stir for 15 minutes, then add 2M hydrochloric acid (400 mL), stir at 10-15°C for 10 minutesutes, stay still, separate out organic layer and dry with anhydrous sodium sulphate. Filter, recover solvent ex filtrate under vacuum, recrystallize the remnant with benzene to get 32.2 g white crystal powder IV (R¹ = -Bn, R² = -CH₃) with 87% yield, e.e. = 67%, [α]_D ²² = +1.83 (c 1.0, CHCl₃), m.p. 140-142°C.

Diagrams of IR, ¹H NMR, ¹³C NMR and MS are identical to those described in Example 8.

Example 12: Preparation of compound IV TR¹ = -Bn, R² = - CH₂CsH₄NI Transfer CYCLIC ANHYDRIDE III (R¹ = -Bn) (33.6 g, 0.10 mol), quinine (32.4 g, 0.10 mol) and toluene (1250 mL) into dry flask, at -15°C drop 3-pyridmemethanol (14.6 mL, 0.15 mol), then stir at -15°C and react for 18 hours. Upon reaction completion, recover solvent under reduced pressure, cool down to room temperature, add 2M hydrochloric acid (400 mL), stir at 10-15⁰C for 30 minutesutes. Filter, solid was purified by chromatography column (Petroleum ester: Ethyl acetate = 1:1) to get 35.6g white powder IV (R¹ = -Bn, R² = -CH₂C₅H₄N) with 80% yield, [α]_D ¹⁵ = +2.30 (c 1.0, CHCl₃).

¹H NMR (DMSO, 400 MHz) δ 8.89 - 7.98 (m, 4H), 7.37 - 7.19 (m, 10H), 5.27 (d, J= 13.2 Hz, IH), 5.19 (d, J= 13.2 Hz, IH), 4.79 (d, J= 15.4 Hz, IH), 4.69 (d, J= 15.4 Hz, IH), 4.45(4 J= 9.7 Hz, IH), 4.26 (d, J= 9.7 Hz, IH), 4.09 (d, J= 15.4 Hz, IH), 4.03 (d, J= 15.4 Hz₅ IH)

Example 13: Preparation of compound IV (Rl = -Bn. R2 = — CH3)

To the solution of P-propargylquinine (32.4 g, 0.10 mol) in CCl₄ (600 ml) and toluene (400 ml) was added cz5-l,3-Dibenzyl-tetrahydro-2H-furo[3,4-d]imidazole-2,4,6-trione (33.6 g, 0.10 mol). The mixture is cooled to -40 "C, then methanol (40.5 mL, 1.0 mol) is added dropwise. After being stirred at -40⁰C for 60 h, the mixture is concentrated under reduced pressure. In to the residue is added ethyl acetate (500 ml) and 2 M aq. HCl (400 ml) at 10- 15^°C. The resulting mixture is stirred at the same temperature for 10 minutes, then the organic phase is dried over Na₂SO₄ and concentrated. The residue is recrystallized from benzene to get compound IV (Rl = -Bn, R2 = — CH3, 35 g, 95%) as a white solid. M.p.: 149-15O⁰C , [α]_D ²² = +2.74° Cc 0.20, CHCl₃) .

IR (KBr) : v=2979, 2384, 2281 , 1742, 1463 , 1229, 1169, 767cm^"1.

¹H NMR (CDCl₃ ) :<5=3.54 (s, IH, OCH₃) , 4.00-4.04 (m, 2H, C_6a-H, C_3a- H) , 4.16-4.80 (dddd, 4H, 2xCH₂C₆H₅) , 7.19-7.53 (m, 1OH, 2xArH) ppm.

EI-MS: (m/z, %) = 368 (M⁺, 37) , 323 (46) , 309 (59) , 265 (44) , 154 (8 ) , 136 ( 18) , 91 ( 100) .

To recover the catalyst, the acidic aqueous phase was neutralized with Na₂CO₃ until the pH was 9. The resulting white precipitate is filtrated off and dried to afford the catalyst quantitatively.

Example 14: Preparation of compound IV (Rl = -Bn, R2 = —cyclohexyl )

To the solution of 9 -propargylquinine (32.4 g, 0.10 mol) in CCl₄ (600 ml) and toluene

(400 ml) was added c/5-l,3-Dibenzyl-tetrahydro-2H-furo[3,4-d]imidazole-2,4,6-trione (33.6 g, 0.10 mol). The mixture is cooled to -40°C then cyclohexanol (52.2 mL, 0.50 mol) is added dropwise. After being stirred at -40⁰C for 60 hours, the mixture is concentrated under reduced pressure. In to the residue is added ethyl acetate (500 ml) and 2 M aq. HCl (400 ml) at 10-15⁰C The resulting mixture is stirred at the same temperature for 10 minutes, then the organic phase is dried over Na₂SO₄ and concentrated. The residue is recrystallized from benzene to get compound IV (R = -Bn, R = —cyclohexyl, 37.4g, 87% ) as a white solid. M.p.: 172-175°C , [α]_D ²² = +2.70° (c 0.20, CHCl₃) , [α]_D ²⁵ = +10.8° (c 1.0, DMF)

Example 15: Preparation of compound IV (Rl = -Bn, R2 = -CHO To the solution of O-propargyldihydroquinine (32.6g, 0.10 mol) in CCl₄ (600 ml) and toluene (400 ml) was added c/s-l,3-Dibenzyl-tetrahydro-2H-furo[3,4-d]imidazole-2,4,6- trione (33.6 g, 0.10 mol). The mixture is cooled to -4O⁰C, then methanol (40.5 mL, 1.0 mol) is added dropwise. After being stirred at -40⁰C for 60 hours, the mixture is concentrated under reduced pressure. In to the residue is added ethyl acetate (500 ml) and 2 M aq. HCl (400 ml) at 10-15°C. The resulting mixture is stirred at the same temperature for 10 minutes, then the organic phase is dried over Na₂SO₄ and concentrated. The residue is recrystallized from toluene to get compound IV (Rl = -Bn, R2 = CH_?, 33.2g,

90%) as a white solid.

M.p.: 148-15O⁰C , [α]_D ²² = +2.70° Cc 0.20, CHCl₃) .

Example 16: Preparation of compound IV (Rl = -Bn. R2 = -CHV)

To the solution of 6-Qthoxy-9-proρargylquinine (33.8 g, 0.10 mol) in THF (1000 ml) was added cώ-l,3-Dibenzyl-tetrahydro-2H-furo[3,4-d]imidazole-2,4,6-trione (33.6 g, 0.10 mol). The mixture is cooled to -40⁰C, then methanol (40.5 mL, 1.0 mol) is added dropwise. After being stirred at -40⁰C for 48 h, the mixture is concentrated under reduced pressure. In to the residue is added ethyl acetate (500 ml) and 2 M aq. HCl (400 ml) at 10-15°C. The resulting mixture is stirred at the same temperature for 10 minutes, then the organic phase is dried over Na₂SO₄ and concentrated. The residue is recrystallized from benzene to get compound IV (R¹ = -Bn, R² = — CH₃ , 32.5 g, 88%) as a white solid. M.p.: 147-150O , [α]_D ²² = +2.69° (c 0.20, CHCl₃) .

Example 17: Preparation of compound IV (Rl = -Bn, R2 = -CHV)

To the solution of 6-ethoxy-O-propargyldihydroquinine (33.8 g, 0.10 mol) in CCl₄ (OOO ml) and toluene (400 ml) was added cw-l,3-Dibenzyl-tetrahydro-2H-furo[3,4-d]imidazole- 2,4,6-trione (33.6 g, 0.10 mol). The mixture is cooled to -4O⁰C, then methanol (40.5 mL, 1.0 mol) is added dropwise. After being stirred at -4O⁰C for 60 h, the mixture is concentrated under reduced pressure. In to the residue is added ethyl acetate (500 ml) and 2 M aq. HCl (400 ml) at 10-15⁰C. The resulting mixture is stirred at the same temperature for 10 minutesutes, then the organic phase is dried over Na₂SO₄ and concentrated. The residue is recrystallized from benzene to get compound IV (R = -Bn, R = - CH ₃, 33.9 g, 92%) as a white solid.

M.p.: 148-149⁰C , [α]_D ²² = +2.67° (c 0.20, CHCl₃ ) Example 18: Preparation of compound IV (^"Rl = -Bn. R2 = -CH_j) To the solution of 6-acQtoxy-9-propargylquinine (35.2 g, 0.10 mol) in toluene (1000 ml) was added cw-l,3-Dibenzyl-tetrahydro-2H-furo[3,4-d]imidazole-2,4,6-trione (33.6 g, 0.10 mol). The mixture is cooled to -50°C, then methanol (40.5 mL, 1.0 mol) is added dropwise. After being stirred at -50°C for 72 h, the mixture is concentrated under reduced pressure. In to the residue is added ethyl acetate (500 ml) and 2 M aq. HCl (400 ml) at 10-15⁰C. The resulting mixture is stirred at the same temperature for 10 minutes, then the organic phase is dried over Na₂SO₄ and concentrated. The residue is recrystallized from benzene to get compound IV (R¹ = -Bn, R² = -CH₃, 34 g, 92%) as a white solid. Mp.: 148-15O⁰C , [α]_D ²² = +2.72° (c 0.20, CHCl₃) .

Example 19: Preparation of compound IV (R¹ = -Bn, R² = -CHV)

To the solution of (9-propargylcinchonidine (29.4 g, 0.10 mol) in CCl₄ (500 ml) and toluene (500 ml) was added cw-l,3-Dibenzyl-tetrahydro-2H-furo[3,4-d]imidazole-2,4,6- trione (33.6 g, 0.10 mol). The mixture is cooled to -50°C, then methanol (40.5 mL, 1.0 mol) is added dropwise. After being stirred at -50°C for 60 h, the mixture is concentrated under reduced pressure. In to the residue is added ethyl acetate (500 ml) and 2 M aq. HCl (400 ml) at 10-15⁰C. The resulting mixture is stirred at the same temperature for 10 minutesutes, then the organic phase is dried over Na₂SO₄ and concentrated. The residue is recrystallized from benzene to get compound IV (Rl = -Bn, R2 = — CH₃ , 32.2 g, 87%) as a white solid. M.p.: 148-149O , [α]_D ²² = +2.70° (c O.20, CHCl₃) .

Example 20: Preparation of compound V (R¹ = -Bn) Dissolve semi-ester IV (R¹ = -Bn, R² = -CH₃) (3.68 g, 10 mmol) and milled anhydrous calcium chloride (1.11 g, 10 mmol) into 4OmL anhydrous ethanol, at 0⁰C add sodium borohydride (1.14 g, 30 mmol) via three times into such solution, stir the obtained mixture at O⁰C for lhr, then raise temperature to 25⁰C and continue agitation for 18 hours, recover solvent under reduced pressure, add 30 mL 2M hydrochloric acid, raise temperature to 55- 60°C and react for 0.5 hours, cool down to room temperature, extract with ethyl acetate, combine organic phases, rinse to neutral with 5% sodium bicarbonate solution, then rinse with saturated saline solution, dry with anhydrous sodium sulphate and vacuum concentrate to get 3.12 g V (R¹ = -Bn) with 97% yield, m.p. 119.2-120.5⁰C; [α]_D ²⁵ = +60.2 (c 1.0, CHCl₃).

IR(KBr, cm^"1): 3031, 2919, 1775, 1706, 1444, 1415, 1365, 1237, 1209, 1146, 997, 970, 754, 700, 639, 527;

¹H-NMR (400 MHz, CDCl₃) δ 7.24 - 7.36 (m, 10H), 5.05 (d, J= 15.2 Hz, IH), 4.63 (d, J = 15.2 Hz, IH), 4.37 (dd, J = 10.4 Hz, 15.2 Hz, 2H), 4.09 - 4.16 (m, 3H), 3.92 (d, J= 8.0 Hz, IH);

¹³C-NMR (IOO MHz, CDCl₃) S 172.7, 158.1,136.0, 135.9, 129.0, 128.8, 128.7, 128.2, 128.0, 127.8, 70.1, 54.3, 52.4, 46.9, 45.2;

Experiment 21 : Preparation of compound V (R¹ = -Bn)

Dissolve semi-ester IV (R¹ = -Bn, R² = -CH₃) (3.68 g, 10 mmol) into 50 mL tetrahydrofuran, cool down to O⁰C, add 5 mL tetrahydrofuran solution of sodium borohydride (0.76 g, 20 mmol), raise the temperature of obtained mixture to room temperature and stir for 3 hours, add 2M hydrochloric acid (30 mL), stir for 2 hours, recover solvent under reduced pressure, add water (5 mL) and ethyl acetate (10 mL), after stirring for 2 hours, separate out organic layer, extract aqueous phase with ethyl acetate (3*10 mL), combine organic phases, dry with sodium sulphate, concentrate under reduced pressure to get 2.6 g white solid V (R¹ = -Bn) with 80.7% yield, m.p. 118-119°C, [α]_D ²² = +61.3 (c 1.02, CHCl₃).

Diagrams of IR, ¹H NMR, ¹³C NMR and MS are identical to those described in Example 20.

Example 22: Preparation of compound V (R¹ - -Bn)

Dissolve semi-ester IV (R¹ = -Bn, R² = -CH₂CH = CHPh) (4.54 g, 10 mmol) into 60 mL tetrahydrofuran, cool down to 0⁰C, add 5 mL tetrahydrofuran solution of potassium borohydride (1.08 g, 20 mmol), raise to room temperature and react for 5 hours, add 2M hydrochloric acid (30 mL) to terminutesate reaction, stir for 2.5 hours, recover solvent under reduced pressure, add water (5 mL) and ethyl acetate (1OmL), after stirring for 2 hours, separate out organic layer, extract aqueous phase with ethyl acetate (3* 1OmL), combine organic phases, dry with sodium sulphate, remove solvent under reduced pressure to get 2.9 g white solid V (R¹ = -Bn) with 90.0% yield, m.p. 117-119°C, [α]_D ²² = +60.3 (c 1.02, CHCl₃).

Example 23: Preparation of compound VI (R¹ = -Bn)

Transfer lactone V (R¹ = -Bn) (5 g, 15.5 mmol) and dry N,N-dimethylacetamide (5 mL) into flask, under nitrogen blanket heat up to 140⁰C, add sodium thioacetate (1.8 g, 18.3 mmol), stir the obtained mixture at 150°C for 45 minutesutes, cool down to room temperature, recover solvent under reduced pressure, add dichloromethane (30 mL) and water (30 mL), extract the aqueous phase with dichloromethane, combine organic phases, dry with anhydrous magnesium sulphate, concentrate, recrystallize the remnant with isopropanol to get 3.75 g white crystal powder with 72% yield, m.p. 124-126⁰C, [α]_D ²⁵ = +90.5 (c 1.0, CHCl₃).

IR (KBr): 3030, 2934, 2889, 1703, 1697, 1453, 1412, 1361, 1218, 1148, 1051, 997, 903,

808, 66698, 647, 581, 485 cm^"1;

¹H-NMR (CDCl₃, 400 MHz) δ 7.37 - 7.25 (m, 10H), 5.03 (d, J= 14.8 Hz, IH), 4.68 (d, J = 15.6 Hz, IH), 4.37 tø J = 15.6 Hz, IH), 4.36 (J, J - 14.8 Hz, IH), 4.15 - 4.11 (m, IH),

3.81 (d, J= 8.0 Hz, IH), 3.37 (dd, J= 12.4, 5.6 Hz, IH), 3.28 (dd, J= 12.4, 2.0 Hz, IH);

¹³C-NMR (CDCl₃, 100 MHz) δ 203.4, 158.2, 136.4, 136.2, 128.87, 128.78, 128.66, 128.0,

127.91, 127.73, 62.1, 55.8, 46.5, 45.2, 33.0;

ESI-MS m/z 361.1 [M+Na]⁺

Example 24: Preparation of compound VI (R¹ = -BnI

Under nitrogen blanket, transfer V (R¹ = -Bn) (3.2 g, 10 mmol), sodium thio-benzoate (2.5 g, 13 mmol) and N,N-dimethylacetamide (50 mL) into dry flask, heat up to 15O⁰C and react for 2.0 hours, cool down to room temperature, recover solvent under reduced pressure, add adequate amount of water, extract with toluene (3*25mL), combine organic phases, rinse in turn with saturated sodium bicarbonate solution and saturated saline solution and dry with anhydrous sodium sulphate. Filter, recover solvent under reduced pressure, recrystallize the remnant with ethyl acetate to get 2.8 g white crystal powder with

82.8% yield, m.p. 123-126°C, [α]_D ²² = +90.1 (c 1.05, CHCl₃). Diagrams of IR, ¹H NMR, ¹³C NMR and MS are identical to those described in Example 23.

Example 25: Preparation of compound VI (^"R¹ = -Bn)

Under nitrogen blanket, transfer V (R¹ = -Bn) (3.2 g, 10 mmol), ammonium thioacetate (1.21 g, 12 mmol) and N-methylpyrrolidone (50 mL) into dry flask, heat up to 170⁰C and react for 4 hours, cool down to room temperature, add adequate amount of water, extract with toluene (3*25mL), combine organic phases, rinse in turn with saturated sodium bicarbonate solution and saturated saline solution and dry with anhydrous sodium sulphate. Filter, recover solvent under reduced pressure, recrystallize the remnant with ethyl acetate to get 3.0g white crystal powder with 88% yield, m.p. 124-125°C, [a]_D ²² = +91.1 (c 1.04, CHCl₃).

Diagrams of IR, ¹H NMR, ¹³C NMR and MS are identical to those described in Example 23.

Example 26: Preparation of compound VII (R¹ = -Bn₁ R³ = -CO_?Bn)

Under argon blanket, add zinc powder (0.528 g, 8.07 mmol), tetrahydrofuran (2.0 mL) and toluene (1.5 mL) into dry flask, at 10-20⁰C drop liquid brominutese (0.33 g, 2.06 mmol) into obtained mixture, after addition, raise temperature to 50°C, drop 5-benzyliodovalerate (1.31 g, 4.13 mmol). Keep reaction temperature during dropping at 50-60⁰C, then stir at same temperature for 1 hour, cool down the obtained mixture to 30⁰C, then add thiolactone Vl (R¹ = -Bn) (1.0 g, 2.95 mmol), tetrahydrofuran (2 mL), toluene (5 mL), DMF (0.5 mL) and anion exchange resin D₂₉₀ dispersed nano-palladium (1.5 g, 0.15 mmol) into the obtained mixture, then stir at 30⁰C for 24 hours, add saturated aqueous solution of ammonium chloride (15 mL), stir at room temperature for 0.5hr, filter, extract the filtrate with ethyl acetate, combine organic phases, rinse with saturated saline solution, dry with anhydrous sodium sulphate, concentrate and purify the remnant via column chromatography to get 1.17 g oily substance with 75% yield.

IR (neat): 3340, 2938, 1730, 1684, 1451, 1240, 1158, 963, 738, 701 cm^"1;

¹H-NMR (CDCl₃, 400 MHz) δ 7.34 - 7.13 (m, 15H), 5.13 (d, J= 15.2 Hz, 0.6H), 5.10 (s,

0.5H), 5.07 (s, 1.5H), 5.07 id, J= 15.6 Hz, 0.3H), 4.86 (d, J= 15.2 Hz, 0.6H), 4.81 (d, J = 15.2 Hz, 0.2H), 4.36 (s, 0.6H), 4.12 - 3.89 (m, 3.0H), 3.68 (d, J = 8.4 Hz, 0.2H), 3.60 (d, J = 10.0 Hz, 0.6H), 3.33 (s, 0.2H), 2.99 - 2.95 (m, 0.8H), 2.81 - 2.77 (m, 0.8H), 2.33 - 2.25 (m, 2.5H), 2.01 (s, 0.7H), 1.90 - 1.85 (m, 0.7H), 1.67 - 1.36 Qn, 4.5H), 1.25 - 1.21 (t, J= 6.8 Hz, 0.5H); 1³C-NMR (CDCl₃, 100 MHz) δ 173.11, 173.05, 161.16, 160.22, 136.85, 136.55, 136.36, 135.88, 128.66, 128.60, 128.55, 128.48, 128.45, 128.39, 128.35, 128.07, 128.03, 127.99, 127.90, 127.86, 127.73, 127.57, 127.52, 127.38, 127.35, 98.9, 95.5, 68.8, 66.0, 65.9, 61.3, 60.5, 60.1, 48.6, 47.1, 46.0, 45.8, 41.2, 36.8, 34.1, 33.89, 33.85, 33.71, 33.65, 25.36, 25.14, 24.96, 24.80, 23.95, 20.83, 14.0;

Example 27: Preparation of compound VII (R¹ = -Bn, R³ = -COjEf)

Under nitrogen blanket, add zinc powder (0.8 g, 12.4 mmol), iodine (39 mg, 0.15 mmol), tetrahydrofuran (1.3 niL) and toluene (0.8 mL) into dry flask, heat up to 40⁰C, stir till disappearance of purple red color, then at 5O⁰C drop ethyl bromo valerate (1.3 g, 6.2 mmol) into reactant. Complete dropping in ca 1.0-1.5 hours, continue agitation at same temperature for 2.5-3 hours, cool down to 30⁰C, add anion exchange resin D₂₉₆ dispersed nano-palladium (9 g, 0.9 mmol), thiolactone VI (R¹ = -Bn) (1.0 g, 2.95 mmol), toluene (6 mL) and N,N-dimethylformamide (0.8 mL) into reactant, react at 30-35⁰C for 12 hours, quench the reaction with water, filter, separate out organic phase, extract the aqueous phase with toluene (3*30 mL), combine organic phases, dry with anhydrous sodium sulphate, concentrate, isolate the remnant with silica gel to get 1.2 g slightly yellow oily substance VII (R¹ = -Bn, R³ = -CO₂Et) with 87% yield.

IR(neat): 2961 , 2930, 1670, 1387, 1256, 665 cm^"1;

¹H-NMR (CDCl₃, 400 MHz) δ 1.23 - 1.27(m, 3H), 1.44 - 1.45(m, 2H), 1.60 - 1.62 (m, 2H), 2.24 - 2.33(m, 4H), 2.72 (m, 2H), 3.65 (m, IH), 3.94 (d, J= 22.4, IH), 4.02 (d, J= 22.4 Hz, IH), 4.10 - 4.20 (m, 4H), 4.88 (d, J= 15.6Hz, IH), 5.10 (d, J= 15.6 Hz, IH), 7.24 - 7.32 (m, 10H); ESI-MS m/z 469 [M+H]⁺

Example 28: Preparation of compound VII (R¹ = -Bn. R³ = -CQ₇Et) Under nitrogen blanket, add zinc powder (0.8 g, 12.4 mmol), iodine (39 mg, 0.15 mmol), tetrahydrofuran (1.5 mL) and toluene (2 mL) into dry flask, stir at room temperature till disappearance of purple red color, then raise temperature to 50°C, slowly drop ethyl bromovalerate (1.3 g, 6.2 mmol). Complete dropping in ca 2.0-2.5 hours, continue agitation at same temperature for 2.5-3 hours, cool down to 30°C, add anion exchange resin D290 dispersed nano-palladium (8 g, 0.8 mmol), thiolactone VI (R¹ = -Bn) (1.0 g, 2.95 mmol), toluene (10 mL) and N,N-dimethylformarnide (2 mL) into reactant, react at 35-40°C for 24 hours, quench the reaction with water, filter, separate out organic phase, extract the aqueous phase with toluene (3*30 mL), combine organic phases, dry with anhydrous sodium sulphate, recover solvent under reduced pressure, isolate the remnant with silica gel to get 1.2 g slightly yellow oily substance VII (R¹ = -Bn, R³ = -CO₂Et) with 85.7% yield.

Diagrams of IR, ¹H NMR, ¹³C NMR and MS are identical to those described in Example 27.

Example 29: Preparation of compound VII (R¹ = -Bn, R³ = -CO₂Bn)

Under nitrogen blanket, add zinc powder (0.528 g, 8.07 mmol), iodine (39 mg, 0.15 mmol) and N,N-dimethylformamide (4.0 mL) into dry flask, heat up to 80°C and react for 3 hours, drop 5-benzyliodovalerate (1.31 g, 4.13 mmol). After dropping, stir at same termperature for lhr, cool down the obtained mixture to 30⁰C, then add thiolactone VI (R¹ = -Bn) (1.0 g, 2.95 mmol), tetrahydrofuran (4 mL), toluene (7 mL) and anion exchange resin D₂Q₆ dispersed nano-palladium (1.5 g, 0.15 mmol) into the obtained mixture, then stir at 30⁰C for 24 hours, add saturated aqueous solution of ammonium chloride (15 mL), stir at room temperature for 0.5 hours, filter, extract the filtrate with ethyl acetate, combine organic phases, rinse with saturated saline solution, dry with anhydrous sodium sulphate, concentrate and purify the remnant via column chromatography to get 1.17 g oily substance VII (R¹ = -Bn, R³ = -CO₂Bn) with 75% yield.

Diagrams of IR, ¹H NMR, ¹³C NMR and MS are identical to those described in Example 26.

Example 30: Preparation of compound VII Put zinc powder (0.8 g, 12.4 mmol) and iodine (39 nig) with tetrahydrofuran (1.3 ml), toluene (0.8 ml) into a dry reaction flask, heat at 40°C and agitate the mixture until purplish red color disappeared, raise the temperature to 50°C, slowly drop bromopentanoate (1.3 g, 6.2 mmol) into the mixed solution within 1.0-1.5 hours, and keep heating with agitation until the bromopentanoate fully reacted (about 2.5-3 hours). The mixture is then transferred to a mixture system of Pa Pd-dispersed ion exchange resin (9 g, 0.9 mmol) and the compound (II) (1.0 g, 3.0 mmol). Then dissolve the mixture in toluene (6 ml) and N, N-dimethyl formamide (0.8 ml), adjust the temperature to 35-40⁰C for reaction for 10 hours, add with water and filter to, separate the organic phase. The aqueous phase is extracted with toluene (3 x 30 ml). Combine the organic phase, recover the solvent by reducing pressure to give a yellowish oily substance I (1.2 g, 85%) after the mixture runs through a silica gel column (mobile phase: ethyl acetate/petroleum ether = 2/1).

IR (KBr): v = 2961, 2930, 1670, 1387, 1256, 665cm^"1.

IH NMR (CDC13) : δ = 1.24 (t, 3H, CH3), 1.50 (t, 2H, CH2), 1.65 (t, 2H, CH2), 2.25 (m, 2H, CH2), 2.38 (m, 2H, CH2), 2.78 (m, 2H, SCH2), 3.97 (m, 2H, OCH2), 4.16-4.22 (dddd, 4H, 2xCH2Ph, 4.86 (d, J = 14.8 Hz, IH), 5.17 (d, J = 14.8 Hz, 1 H), 7.22-7.38 (m, 1OH, 2xArH), ESI-MS: (m/z, %) = 469 (M+, 11.3), 375 (40.3), 225 (100), 266 (50).

Example 31 : Preparation of compound VII

Put zinc powder (0.8 g, 12.4 mmol) and iodine (39 mg) with tetrahydrofuran (2 ml) into a dry reaction flask, heat at 25⁰C and agitate the mixture until purplish red color disappeared, raise the temperature to 50°C, slowly drop bromopentanoate (1.8 g, 8.6 mmol) into the mixed solution within 1.5 hours, and keep heating with agitation until the bromopentanoate fully reacted (about 3-3.5 hours). The mixture is, then, transferred to a mixture system of P-a-Pd-dispersed ion exchange resin (9 g, 0.76 mmol) and compound II (1.0 g, 3.0 mmol). Then dissolve the mixture in N₅ N-dimethyl formamide (1.5ml), reduce the temperature to 40-45⁰C for reaction for 8 hours, add with water and filter to separate the organic phase. The aqueous phase is extracted with toluene (3x30 ml). Combine the organic phase, recover the solvent by reducing pressure to give a yellowish oily substance I (1.3 g, 92.8%) after the mixture runs through a silica gel column (mobile phase: ethyl acetate/petroleum ether = 2/l).IR, IH NMR and MS spectrums are in accordance with Example 30.

Example 32 Put zinc powder (0.8 g, 12.4 mmol) and iodine (39 mg) with tetrahydrofuran (2 ml), toluene (2 ml) into a dry reaction flask, heat at 30⁰C and agitate the mixture until purplish red color disappeared, raise the temperature to 4O⁰C, slowly drop bromopentanoate (1.3 g, 6.2 mmol) into the mixed solution within 1.5 hours, and keep heating with agitation until the bromopentanoate fully reacted (about 3.5-4 hours). The mixture is, then, transferred to a mixture system of the Pa-dispersed ion exchange resin (1O g, 1.2 mmol) and the compound (II) (1.Og, 3.0mmol). Then dissolve the mixture in toluene (10 ml) and N₅ N- dimethyl formamide (0.8ml), reduce the temperature to 35-40⁰C for reaction for 10 hours, add with water, and filter to separate the organic phase. The aqueous phase is extracted with toluene (3x30 ml). Combine the organic phase, recover the solvent by reducing pressure to give a yellowish oily substance I (1.1 g, 78.5%) after the mixture runs through a silica gel column (mobile phase: ethyl acetate/petroleum ether = 2/1). IR, IH NMR and MS spectrums are in accordance with Example 30.

Example 33 Put zinc powder (0.8 g, 12.4 mmol)and iodine (39 mg) with tetrahydrofuran (1.5 ml), toluene (2 ml) into a dry reaction flask, heat at 20⁰C and agitate the mixture until purplish red color disappeared, raise the temperature to 50⁰C, slowly drop bromopentanoate (1.3 g, 6.2 mmol) into the mixed solution within 2.0-2.5 hours, and keep heating with agitation until the bromopentanoate fully reacted (about 2.5-3 hours). The mixture is, then, transferred to a mixture system of the Pa-dispersed ion exchange resin (8 g, 0.7 mmol) and the compound (II) (1.0 g, 3.0 mmol). Then dissolve the mixture in toluene (10ml) and N, N-dimethyl formamide (2 ml), bringing the temperature back to 35-40⁰C for reaction for 12 hours, added with water, filtered to separate the organic phase. The aqueous phase is extracted with toluene (3x30 ml). Combine the organic phase, recover the solvent by reduced pressure to give a yellowish oily substance I (1.2 g, 85.7%) after the mixture runs through a silica gel column (mobile phase: ethyl acetate/petroleum ether = 2/1). IR, IH NMR and MS spectrums are in accordance with Example 30.

Example 34: Preparation of compound IX (R¹ = -Bn. R³ = -CN) Under nitrogen blanket, add activated zinc powder (2.3 g, 35.4 mmol) and tetrahydrofuran (5 niL) into dry flask, then drop 1,2-dibromoethane (80 μL, 0.92 mmol), heat and reflux for 3minutes, cool down to room temperature, drop timethylchlorosilane (80 μL, 0.64 mmol), stir for 15minutes, drop 5-iodovaleronitril (3.75 g, 8.98 mmol), after addition, stir at 30°C for 30 minutes, then add thiolactone VI (R¹ = -Bn) (1.5 g, 4.43 mmol), benzene (5.5 mL), N,N-dimethylformamide (0.2 mL) and anion exchange resin D₂₉₆ dispersed nano-palladium (4.4 g, 0.44 mmol). After addition, stir at room temperature for 35 hours, determinutese reaction completion via TLC, then filter, recover solvent ex filtrate under reduced pressure, add ethyl acetate (35 mL) in reactant, in turn rinse with IM hydrochloric acid, saturated aqueous solution of sodium bicarbonate and saturated saline solution, dry with anhydrous sodium sulphate, filter, recover solvent under reduced pressure and purify the remnant via column chromatography to get 1.3 Ig viscous oily substance IX (R¹ = -Bn, R³ = -CN) with 73% yield. [a]_O ²⁰ = +27.4 (c 0.1, CH₂Cl₂).

IR(neat): 2224 (C -=N) cm^"1;

¹H-NMR (CDCl₃, 400 MHz) δ 1.39-1.86 (m, 4H, 2*CH₂), 2.03(t, 2H, CH₂CN), 2.8l(dd, IH, J= 5.5, 12.2Hz, CH_exoS), 2.95(d, IH, J= 12.3Hz, CH_endoS), 4.13(m, IH, C₆₈-H), 4.67(d, IH, J= 7.9 Hz, C₃₈-H). 4.05, 4.34, 4.51, 4.96 (Ad, 4H, J = 15.5, 16.8, Hz, 2XArCH₂); EI-MS m/z(%) 404(M⁺, 7), 313(62), 106(10), 91(100)

Example 35: Preparation of compound IX (R¹ = -Bn, R³ = -CO₂Bn) Mix VII (R¹ = -Bn, R³ = -CO₂Bn) (5 g, 9.4 mmol), toluene (30 mL) and 18% hydrochloric acid (20 mL), stir at 6O⁰C for 5 hours, cool down to room temperature, separate out organic phase, extract the aquesous phase with toluene, combine organic phases, respectively rinse with saturated aqueous solution of sodium bicarbonate and saturated saline solution, dry with anhydrous sodium sulphate, concentrate to get 4.57 g oily substance IX (R¹ = -Bn, R³ = -CO₂Bn) with 95% yield, [α]_D ²⁵ = +154.4, (c 1.0, MeOH).

IR (neat): 3029, 2930, 1732, 1696, 1449, 1236, 1158, 1027, 746, 700 cm^"1;

¹H-NMR (CDCl₃, 400 MHz) δ 7.33 - 7.19 (m, 15H), 5.39 (t, J= 6.8 Hz, IH), 5.07 (s, 2H), 4.83 (d, J= 16.0 Hz, IH), 4.75 (d, J= 15.2 Hz, IH), 4.23 - 4.17 (m, 2H), 4.05 - 3.99 (m, 2H), 3.59 - 3.46 (m, IH), 2.92 (dd, J = 12.0, 3.2 Hz, IH), 2.86 (dd, J = 12.0, 5.6 Hz, IH), 2.29 (t, J= 7.2 Hz, 2H), 2.13 - 2.01 (m, 2H), 1.81 - 1.60 (m, 3H); ¹³C-NMR (CDCl₃, 100 MHz) δ 172.3, 158.3, 137.4, 136.57, 136.49, 135.38, 128.06, 128.00, 127.87, 127.52, 127.40, 127.14, 126.97, 126.66, 124.88, 65.48, 64.04, 60.93, 58.41, 45.80, 44.36, 44.30, 36.47, 32.91, 30.37, 29.30, 28.52, 23.50; ESI-MS m/z 513.4 [M+H]⁺

Example 36: Preparation of compound VIII (R¹ = -Bn, R³ = -COjBn) Add VII (R¹ = -Bn, R³ = -CO₂Bn) (5 g, 9.4 mmol), triethylsilane (3.29 g, 28.3 mmol) and dichloromethane (50 mL) into dry flask, cool down to 0°C, drop trifluoroactic acid (6.45 g, 56.6 mmol), after addition, raise to room temperature and stir for 12 hours, quench the reaction with saturated aqueous solution of sodium bicarbonate, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate to get 4.45 g viscous oily liquor VIII (R¹ = -Bn, R³ = -CO₂Bn) with 92% yield. [αfo²⁵ = -20.7 (c 1.0, MeOH).

IR (neat): 3030, 2930, 1731, 1698, 1449, 1237, 1160, 968, 745, 700 cm^'1; 1H-NMR (CDCl₃, 400 MHz) δ 7.36 - 7.22 (m, 15H), 5.12 (s, 2H), 5.05 (d, J= 15.2 Hz,

IH), 4.73 (d, J= 15.2 Hz, IH), 4.14 (d, J= 15.2 Hz, IH), 3.98 - 3.93 (m, 2H), 3.84 (dd, J

= 9.6, 5.6 Hz, IH), 3.08 - 3.03 (m, IH), 2.72 (dd, J = 12.4, 4.0 Hz, IH), 2.66 (dd, J= 12.4,

6.0 Hz, IH), 2.35 (t, J= 6.8 Hz, 2H), 1.69 - 1.30 (m, 6H);

¹³C-NMR (CDCl₃, 100 MHz) δ 173.1, 160.9, 136.94, 136.83, 136.00, 128.65, 128.59, 128.49, 128.19, 128.12, 127.57, 127.55, 66.09, 62.6, 61.1, 54.1, 47.9, 46.5, 34.6, 34.0, 28.5,

28.3, 24.6;

ESI-MS m/z 515.2 [M+H]⁺

Example 37: Preparation of compound VIII (R¹ = -Bn, R³ = -COJD Add VII (R¹ = -Bn, R³ = -CO₂H) (10.0 g, 22.7 mmol), triethylsilane (26.4 g, 0.227 mol) and dichloromethane (100 mL) into dry flask, cool down to 0°C, drop trifluoroactic acid (51.7 g, 0.454 mol), after addition, raise temperature to 25°C and stir for 8 hours. Recover solvent under reduced pressure, dilute the remnant with ethyl acetate (250 mL), rinse to neutral with saturated saline solution, separate out organic phase, dry with anhydrous sodium sulfate. Filter, recover solvent ex filtrate under reduced pressure to get 9.2 g colorless oily liquor VIII (R¹ = -Bn, R³ = -CO₂H) with 95% yield. [α]_D ²⁵ = -27.5 (c 1.0, MeOH).

IR (neat): 3029, 2932, 1698, 1451, 1239, 1076, 962, 911, 732 cm^"1; ¹H-NMR (CDCl₃, 400 MHz) δ 1.26 - 1.66 (m, 6H, 3xCH₂), 2.32 (t, 2H, -CH₂CO₂H), 2.68 (ddd, 2H, -CH₂S), 3.04-3.08 (m, IH, C₄-H), 3.85 (dd, IH, C_3a-H), 3.94-3.98 (m, 2H, C_6a-H, N₃-CHPh), 4.14 (d, IH, N₁-CHPh), 4.73 (d, IH, N₁-CHPh), 5.05 (d, IH, N₃-CHPh), 7.22- 7.33 (m, 1OH, 2xArH), 10.25 (br. S₃IH₅-CO₂H); 1³C-NMR (CDCl₃, 100 MHz) δ 178, 161, 136.8, 136.7, 128.77, 128.71, 128.29, 128.26, 127.71, 127.66, 62.7, 61.3, 54, 48, 46, 34.7, 33.9, 28.5, 28.4, 24; ESI-MS m/z 425 [M+H]⁺,447 [M+Naf

Example 38: Preparation of compound VIII (R¹ = -Bn. R³ = -CO₂Bn) Transfer compoud IX (R¹ = -Bn, R³ = -CO₂Bn) (10.0 g, 19.5 mmol), triethylsilane (11.3 g, 0.097 mol) and dichloromethane (100 mL) into dry flask, cool down to O⁰C, drop formic acid (8.97 g, 0.195 mol), after addition, raise temperature to 25°C, stir and react for 8 hours. Recover solvent at reduced pressure, dilute the remnant with ethyl acetate (250 mL), respectively rinse the remnant with saturated aqueous solution of sodium bicarbonate and saturated saline solution, separate out organic phase, dry with anhydrous sodium sulfate. Filter, recover solvent ex filtrate under reduced pressure to get 9.7g colorless oily liquor VIII (R¹ = -Bn, R³ = -CO₂Bn) with 97% yield. [α]_D ²⁵ - -20.5 (c 1.0, MeOH).

Diagrams of IR, ¹H NMR, ¹³C NMR and MS are identical to those described in Example 36.

Example 39: Preparation of compound VIII (R¹ = -Bn. R³ = -CN)

Transfer compoud IX (R¹ = -Bn, R³ = -CN) (10.1 g, 25 mmol), triethylsilane (11.6g, lOOmmol) and toluene (80 mL) into dry flask, cool down to O⁰C, drop methanesulfonic acid (12.9mL, 0.2mol), after addition, raise temperature to 25°C, stir and react for 12 hours. Recover solvent under reduced pressure, dilute the remnant with ethyl acetate (15OmL), rinse to neutral with saturated aqueous solution of sodium bicarbonate and saturated saline solution, separate out organic phase, dry with anhydrous sodium sulfate. Filter, recover solvent ex filtrate under reduced pressure, recrystallize the remnant with isopropanol to get 9.13g white solid VIII (R¹ = -Bn, R³ = -CN) with 90% yield, m.p. 93-94°C, [α]_D ²⁵ = -67.3 (c 1.02, DMSO).

IR(KBr): 2270 (C ≡tsf) cm^"1; ¹H-NMR (CDCl₃, 400 MHz) δ 1.58 - 1.75(m, 6H₅ 3xCH₂), 2.34(7, 2H, J= 6.56Hz₅ CH₂CN), 2.1\(dd, 2H, J= 2.34, 4.39Hz, C_6α-H and C_6jS-H), 3.06(rø, IH₅ C₄-H), 3.89(d, IH₅ J= 5.56Hz₅ C_3crH ), 3.96(m, IH₅ C_6a-H ), 4.03, 4.15, 4.75, 5.00 (4 d, AB., J = 15.07, 15.0 Hz, 2XCH₂Ph)₅ 7.22 - 7.38 (m, 1OH, 2*ArH); EI-MS m/z(%) 405(M⁺, 18), 314(20), 277(48), 265(16), 187(21), 91(100).

Example 40: Preparation of the compound VIII (R¹ = -Bn. R³ = -CO₂Bn)

Transfer compound VII (R¹ = -Bn₅ R³ = -CO₂Bn) (10.0 g, 18.8 mmol), triethylsilane (43.7 g, 0.376 mol) and tetrahydrofuran (100 mL) into dry flask, cool down to -70°C, drop diethyl ether solution of boron triflroride (26.7 g, 0.188 mol), after addition, stir and react at -70⁰C for 24 hours. Slowly raise to room temperature, dilute with ethyl acetate (250 mL), rinse to neutral with saturated aqueous solution of sodium bicarbonate, separate out organic phase, dry with anhydrous sodium sulfate. Filter, recover solvent ex filtrate under reduced pressure to get 9.0 g colorless oily liquor VIII (R¹ = -Bn, R³ = -CO₂Bn) with 93% yield, [a]_O ²⁵ = -20.7 (c 1.0, MeOH).

Example 41

5-[(3aS, 4RS, 6aR)-l,3-dibenzyl-2-oxyhexahydro-4-hydroxy-lH-thieno [3, 4-d] imidazolyl-5-yl]benzyl pentanoate (10.0 g, 18.8 mmol), triethyl silicane (43.7 g, 0.376 mol) and tetrahydrofuran (100 ml) are fed into a dry reaction flask, cooled to -70°C, added drop by drop with boron trifluoride etherate (26.7 g, 0.188 mol), and then agitated at -7O⁰C for 24 hours. It is then raised to room temperature before added with ethyl acetate (250ml) for dilution, and washed with a saturated NaHCO3 solution to neutral so as to separate the organic phase, dried with anhydrous Na2SO4. It is then filtered to recover the solvent by reduced pressure so as to give colorless oily liquor I (R = -Bn₅ 9.0 g₅ 93%), [a]D25 = - 20.7°(c 1.0 MeOH).

IR (KBr):i> = 3030, 1731, 1696, 1449, 1337, 1169, 745, 700cm-l.

IH NMR (CDC13):δ = 1.30-1.69 (m, 6H₅ 3xCH2)₅ 2.35 (t, 2H, -CH2CO2Bn), 2.68 (ddd,

2H, -CH2S), 3.03-3.08 (m, IH, C4-H), 3.84 (dd, IH, C3a-H), 3.93-3.96 (m, 2H, C6a-H, N3-CHPh), 4.14 (d, IH, Nl-CHPh), 4.73 (d, IH₅ Nl-CHPh), 5.05 (d, IH, N3-CHPh), 5.12 (s, 2H, -CO2CH2Ph), 7.22-7.36 (m, 15H, 3 x ArH) ppm. ESI-MS: 537 (M+Na+).

Example 42: Preparation of compound VIII

5-[(3aS, 4RS, 6aR)-l,3-dibenzyl-2-oxyhexahydro-4-hydroxy-lH- thieno [3,4-d] imidazolyl-5-yl]valeric acid (10.0 g, 22.7 mol), triethyl silicane (26.4 g, 0.227 mol) and dichloromethane (100 ml) are fed into a dry reaction flask, cooled to O⁰C, added drop by drop with trifluoroacetic acid (51.7 g, 0.454 mol), and then agitated at 25°C for 8 hours. It then recovers the solvent by reduced pressure before added with ethyl acetate (250 ml) for dilution, and washed with a saturated table salt solution to neutral so as to separate the organic phase, dried with anhydrous Na₂SO₄. It is then filtered to recover the solvent by reduced pressure so as to give colorless oily liquor I (R = -H, 9.2g, 95%), [α]D 25 = -27.5° (c 1.0, MeOH).

IR (KBτ):v = 3029, 2932, 1698, 1451, 1239, 1076, 962, 911, 732cm-l. IH NMR (CDC13):δ = 1.26-1.66 (m, 6H, 3xCH2), 2.32 (t, 2H, -CH2CO2H), 2.68 (ddd, 2H, -CH2S), 3.04-3.08 (m, IH, C4-H), 3.85 (dd, IH, C3a-H), 3.94-3.98 (m, 2H, C6a-H, N3-CHPh), 4.14 (d, IH, Nl-CHPh), 4.73 (d, IH, Nl-CHPh), 5.05(d, IH, N3-CHPh), 7.22- 7.33 (m, 1OH, 2xArH), 10.25 (br.s, IH, -CO2H) ppm. ESI-MS: 425 (M+H+), 447 (M+Na+).

Example 43: Preparation of compound VIII

5-[(3aS, 4Z, 6aR)-l,3-dibenzyl-2-oxyhexahydro-lH- thieno [3,4-d] imidazolyl-5-enyl] benzyl pentanoate (10.0 g, 19.5mol), triethyl silicane (11.3 g, 0.097 mol) and dichloromethane (100ml) are fed into a dry reaction flask, cooled to 0⁰C, added drop by drop with formic acid (8.97 g, 0.195 mol), and then agitated at 25°C for 8 hours. It then recovers the solvent by reduced pressure before added with ethyl acetate (250 ml) for dilution, and washed with a saturated NaHCO₃ solution to neutral so as to separate the organic phase, dried with anhydrous Na₂SO₄. It is then filtered to recover the solvent by reduced pressure so as to give colorless oily liquor I (R = -Bn, 9.7 g, 97%), [α]D 25 = - 20.5° (c 1.0, MeOH). IR (KBr) : v = 3030, 1731, 1696, 1449, 1337, 1169, 745, 700cm-l. IH NMR (CDC13) : δ = 1.30-1.69 (m, 6H, 3xCH2), 2.35 (t, 2H, -CH2CO2Bn), 2.68 (ddd, 2H, -CH2S), 3.03-3.08 (m, IH, C4-H), 3.84 (dd, IH, C3a-H), 3.93-3.96 (m, 2H, C6a-H, N3-CHPh), 4.14 (d, IH, Nl-CHPh), 4.73 (d, IH, Nl-CHPh), 5.05 (d, IH, N3-CHPh), 5.12 (s, 2H, -CO2CH2Ph), 7.22-7.36 (m, 15H, 3 x ArH) ppm. ESI-MS: 537 (M+Na+)

Example 44: Preparation of biotin I

5-[(3aS,4S,6aR)-l ,3-dibenzyl-2-oxyhexahydro-lH-thieno [3,4-d] imidazolyl-5-yl]benzyl pentanoate (10. Og, 19.4mmol), 48% hydrobromic acid (5OmL) and xylene (5OmL) are fed into a reaction flask, with agitation for reflux for 24h. The temperature is then returned to room temperature so as to separate a supernatant organic phase. After the aqueous phase is condensed to 2OmL, 10% NaOH solution is added to adjust to pH = 12. The achieved solution is then added drop by drop to a mixture of diphosgene (2.28mL, 19.4mmol), activated carbon (O.lg) and anisole (3OmL), agitated at room temperature for 3h, filtered, and then anisole is recovered by reduced pressure. The aqueous phase is adjusted with concentrated HCl to pH = 1-2, such that a white solid is precipitated out, filtered, and re- crystallized with distilled water to give a while white powder I (a = 4, 4.7g, 90%), m.p.: 230-231°C, [α]D20 = +90.7 (c 1.0, 0. IM NaOH).

IR (KBr) : ^ = 3308, 2967, 1941, 1707, 1480, 1318, 1202, 1154, 1098cm-l. IH NMR (DMSO-d6):δ = 1.30-1.63 (m, 6H, 3xCH2), 2.20 (t, 2H, -CH2CO2H), 2.58 (d, IH, C6ce- H), 2.82 (dd, IH, C6β-H), 3.07-3.12 (m, IH, C4/3-H), 4.11-4.15 (m, IH, C3a-H), 4.28-4.32 (m, IH, C6a-H), 6.34 (s, IH, Nl-H), 6.41 (s, IH, N3-H), 11.96 (br s, IH, -CO2H) ppm. ESI-MS: 267(M+Na+).

Example 45: Preparation of biotin I

5-[(3aS,4S,6aR)-l,3-dibenzyl-2-oxyhexahydro-lH-thieno [3,4-d]imidazolyl-5-yl]valeric acid (10.0 g, 23.6 mmol), 48% hydrobromic acid (55 mL) and xylene (55mL) are fed into a reaction flask, with agitation for reflux for 20 hours. The temperature is then returned to room temperature so as to separate a supernatant organic phase. After the aqueous phase is condensate to 25 mL, 10% NaOH solution is added to adjust to pH = 12. The achieved solution is then added drop by drop to a mixture of triphosgene (5.6 g, 18.9 mmol), activated carbon (0.1 g) and toluene (30 mL), agitated at room temperature for 5h, filtered, and then toluene is recovered by reduced pressure. The aqueous phase is adjusted with concentrated HCl to pH = 1-2, such that a white solid is precipitated out, filtered, and re- crystallized with distilled water to give while powder I (a = 4, 5.3g, 92%), m.p.: 230.5- 231.5⁰C, [G!]D20 = +91 (c 1.0, 0.1M NaOH). IR, IH NMR and MS spectrums are the same as Example 44.

Example 46: Preparation of biotin I

Transfer VIII (R¹ = -Bn₅ R³ = -CO₂Bn) (10.0 g, 19.4 mmol), 48% hydrobromic acid (50 mL) and xylene (50 mL) into flask, stir and reflux for 24 hours, cool down to room temperature, separate the upper organic phase, concentrate the aqueous phase under reduced pressure to 20 mL, then add 10% aqueous solution of sodium hydroxide to adjust pH = 12, drop the obtained solution into mixture composed of diphosgene (2.28 mL, 19.4 mmol), activated carbon (0.1 g) and anisole (30 mL), sitr and react at room temperature for 3 hours. Filter, recover anisole under reduced pressure, adjust the aqueous phase with concentrated hydrochloric acid to pH = 1-2, separate out white solid, filter, recrystallize with distilled water to get 4.7 g white powder-type solid I with 90% yield, m.p. 230- 231⁰C, [α]_D ²⁰ = +90.7 (c 1.0, 0.1 M aq. NaOH).

IR(KBr): 3308, 2967, 1941, 1707, 1480, 1318, 1202, 1154,1098 cm^"1;

¹H-NMR (DMSO-J₆, 400 MHz) δ 11.9 (s, IH), 6.40 (s, IH), 6.33 (s, IH), 4.30 (dd, J= 7.6, 5.2 Hz, IH), 4.15 - 4.11 (m, IH), 3.12 - 3.07 (m, IH), 2.82 (dd, J= 12.4, 5.2 Hz), 2.57 (d, J = 12.4 Hz), 2.20 (t, J= 7.6 Hz, 2H), 1.62 - 1.41 (m, 4H), 1.37 - 1.30 (m, 2H); 1³C-NMR (CDCl₃, 100 MHz) δ 174.8, 163.1, 61.5, 59.6, 55.8, 40.0, 33.9, 28.57, 28.52, 25.0;

Example 47: Preparation of biotin I

Transfer VIII (R¹ = -Bn, R³ = -CO₂H) (10.0 g, 23.6 mmol), 48% hydrobromic acid (55 mL) and xylene (55 mL) into flask, stir and reflux for 20 hours, cool down to room temperature, separate the upper organic phase, concentrate the aqueous phase under reduced pressure to 25 mL, then add 10% aqueous solution of potassium hydroxide to adjust pH = 12, drop the obtained solution into mixture composed of triphosgene (5.6 g, 18.9 mmol), activated carbon (0.1 g) and toluene (30 mL), sitr and react at room temperature for 5 hours. Filter, recover solvent under reduced pressure, adjust the aqueous phase with concentrated hydrochloric acid to pH = 1-2, separate out white solid, filter, recrystallize with distilled water to get 5.3 g white powder-type solid I with 92% yield, m.p. 229.1- 230.9°C, [αjp²⁰ = +91.3 (c 1.0, 0.1 M aq. NaOH).

Diagrams of IR₅ ¹H NMR, ¹³C NMR and MS are identical to those described in Example 46.

Example 48: Preparation of biotin I

Transfer VIII (R¹ = -Bn, R³ = -CN) (10.0 g, 24.6 mmol), 48% hydrobromic acid (50 mL) and xylene (55 mL) into flask, stir and reflux for 20 hours, cool down to room temperature, separate the upper organic phase, concentrate the aqueous phase under reduced pressure to 25mL, then add 10% aqueous solution of sodium hydroxide to adjust pH = 12, drop the obtained solution into mixture composed of triphosgene (5.6 g, 18.9 mmol), activated carbon (0.1 g) and toluene (30 mL), sitr and react at room temperature for 8 hours. Filter, recover solvent under reduced pressure, adjust the aqueous phase with concentrated hydrochloric acid to pH = 1-2, separate out white solid, filter, recrystallize with distilled water to get 5.7 g white powder-type solid I with 95% yield, m.p. 230.2- 231.6⁰C, [α]_D ²⁰ = +91.2 (c 1.0, 0.1 M aq. NaOH).

Diagrams of IR, ¹H NMR, ¹³C NMR and MS are identical to those described in Example 46

Example 49: Preparation of biotin I

Transfer VIII (R¹ = -Bn, R³ = -CO₂Et) (10.0g, 22.1mmol), 48% hydrobromic acid (55mL) and xylene (55mL) into flask, stir and reflux for 24 hours, cool down to room temperature, separate the upper organic phase, concentrate the aqueous phase under reduced pressure to 25mL, then add 10% aqueous solution of potassium hydroxide to adjust pH = 12, drop the obtained solution into mixture composed of triphosgene (2.6mL, 22.1mmol), activated carbon (O.lg) and xylene (3OmL), sitr and react at room temperature for 12 hours. Filter, recover solvent under reduced pressure, adjust the aqueous phase with concentrated hydrochloric acid to pH = 1-2, separate out white solid, filter, recrystallize with distilled water to get 4.85g white powder-type solid I with 90% yield, m.p. 229.7- 231.2⁰C, [α]_D ²⁰ = +90.8 (c 1.0, 0.1 M aq. NaOH). Diagrams of IR, ¹H NMR, ¹³C NMR and MS are identical to those described in Example 46.

Claims

Claims 1. A process for preparing the compound of formula I,

I which comprises a) reacting a compound of formula II with acyl chloride to prepare meso-CYCLIC ANHYDRIDE of formula III

II III wherein R¹ is benzyl, α-phenylethyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, allyl, 1-furyl, 2-furyl, 1-thienyl or 2-thienyl, b) subjecting the compound of formula III to enantioselective alcoholysis with alcohol in the presence of a cinchona alkaloid to prepare the (4S,5R)-semiester of formula IV;

IV wherein R² is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, aralkyl or aralkenyl; c) subjecting the compound of formula IV to ring closure by use of an acidic catalyst to prepare the (3aS, 6ai?)-lactone of formula V;

V d) subjecting the compound of formula V with a thio-agent to prepare the (3aS, 6aR)- thiolactone of formula VI;

VI wherein R¹ has the same meaning as defined above, e) subjecting the compound of formula VI with a zinc-agent in the presence of a nano-palladium catalyst to Fukuyama coupling to prepare the diastereomeric mixture of formula VII;

VII wherein R³ is carbalkoxy, aralkyloxycarbonyl, cyan or oxazolinyl. f) reducing the compound of formula VII to (3aS, 4S, 6aR)-dibenzyl-biotin and its derivative of formula VIII via ionic hydrogenation with silane in the presence of an organic acid or a Lewis acid; or de-hydrating the compound of formula VII in the presence of an acid to obtain the compound of formula IX, then reducing the obtained compound of formula IX to (3aS, 4S, 6aR)-dibenzyl-biotin and its derivative of formula VIII via ionic hydrogenation with silane in the presence of an organic acid or a Lewis acid;

VIII IX g) hydrolyzing the compound of formula VIII in the presence of an inorganic acid, then opening the ring, removing the protecting group, closing the ring in the presence of a reagent and a catalyst to obtain (+)-biotin of formula I.

2. The process according to claim 1, wherein said acyl halide used in step (a) is a C₁- C₆ aliphatic acyl halide, an aromatic acyl halide or a substituted aromatic acyl halide; the halogen is chlorine or bromine.

3. The process according to claim 2, wherein the used acyl halide is acetyl chloride, propionyl chloride or benzoyl chloride.

4. The process according to claim 3, wherein the molar ratio between the compound represented by II and acyl halide is in the range between 1 :1-5.

5. The process according to claim 1, wherein step (a) can be carried out with or without solvent; wherein the solvent is selected from a halohydrocarbon, an arene or a substituted arene.

6. The process according to claim 5, wherein the solvent is toluene or 1,2- dichloroethane.

7. The process according to claim 5, wherein the mass volume ratio between the compound of formula II and the organic solvent is in the range between 1 to 6-20 g/mL.

8. The process according to claim 1, wherein the reaction temperature in step (a) is in the range of 20°C-135°C.

9. The process according to claim 1, wherein the reaction time in step (a) is in the range of 0.5 - 5 hours.

10. The process according to claim 1, wherein the cinchona alkaloid used in step (b) has the structure as of formula A:

A wherein R⁴ is hydroxyl or C₁-C₁₀ alkoxy; R⁵ is hydrogen or -OR⁷ with R⁷ being C₁- C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ acyl, benzyl, benzoyl, cinnamyl or a substituted derivative of any of the above-mentioned groups; and R⁶ is ethyl, vinyl or ethynyl.

11. The process according to claim 10, wherein R is hydroxyl, propargyloxyl or allyloxy.

12. The process according to claim 1, wherein the cinchona alkaloid is selected from quinine or quinine derivatives.

13. The process according to claim 1, wherein the alcohol used in step (b) is a Ci-C₆ alkanol, a C₃-C₈ cycloalkanol, a C₃-C₆ enol, a C₃-C₆ alkynol, an aralkyl alcohol, an aryl enol or a substituted derivative of any of the above-mentioned alcohols.

14. The process according to claim 13, when preparing the compound of formula IV via the compound of formula III, the alcohol used is methanol, ethanol, propanol, butanol, cyclopentanol, allyl alcohol, propargyl alcohol, benzalcohol or cinnamyl alcohol.

15. The process according to claim 14, wherein the alcohol used is methanol, allyl alcohol or cinnamyl alcohol.

16. The process as described in Claim 1, wherein step (b) is carried out in one or more than one organic solvent comprising a halohydro carbon such as dichloromethane, chloroform, 1,2-dichloroethane or carbon tetrachloride.; an aliphatic hydrocarbon such as hexane, heptane, octane, nonane, acetonitrile or ethyl acetate; an arene such as benzene, toluene, xylene, nitrobenzene or benzene halide ; an ether solvent such as diethyl ether, methyl tert-butyl ether, dioxane or tetrahydrofuran, and the reaction can be carried out in a single solvent, or in a mixture of the solvents.

17. The process according to claim 16, when preparing the compound of formula IV starting from the compound of formula III, the organic solvent is selected from the group consisting of benzene, toluene, xylene, methyl tert-butyl ether, t-amylmethylether and tetrahydrofuran or any combination thereof.

18. The process according to claim 1, wherein the molar ratio of CYCLIC ANHYDRIDE III : alcohol : cinchona alkaloid catalyst in step (b) is in the range of 1 : (3-

10) : (0.5-2).

19. The process according to claim 18, wherein the molar ratio of CYCLIC ANHYDRIDE III : alcohol : cinchona alkaloid catalyst is in the range of 1 : (3-5) : (0.5- 1.1).

20. The process according to claim 1, wherein said alcoholysis reaction temperature in step (b) is in the range of -6O⁰C to -15⁰C.

21. The process according to claim 20, wherein said alcoholysis reaction temperature is in the range of -50⁰C to -15°C.

22. The process according to claim 1, wherein said alcoholysis reaction time in step (b) is in the range of 10-80 hours.

23. The process according to claim 19, wherein said alcoholysis reaction time is in the range of 18-72 hours.

24. The process according to claim 1, wherein the reducing agent used in step (c) comprises borohydride, such as alkyl substituted potassium borohydride, alkyl substituted lithium borohydride, alkyl substituted sodium borohydride, or sodium borohydride, potassium borohydride, lithium borohydride, or cyano sodium borohydride.

25. The process according to claim 24, wherein the used reducing agent is sodium borohydride or potassium borohydride.

26. The process according to claim 24, wherein calcium chloride is added in step (c).

27. The process according to claim 1, wherein the solvent used in the reduction step (c) is one or more selected from the group consisting of alcohols and ethers.

28. The process according to claim 27, wherein the solvent is ethanol or tetrahydrofuran.

29. The process according to claim 1, when preparing compound of formula V ex compound of formula IV, the reducing agent used is sodium borohydride, and the solvent used is tetrahydrofuran.

30. The process according to claim 1, wherein the reaction temperature in the reduction step (c) is in the range of -20°C to 50°C.

31. The process according to claim 30, wherein the reaction temperature in the reduction step (c) is in the range of 0°C-25°C.

32. The process according to claim 1, wherein the reaction time in the reduction step (c) is in the range of 4-24 hours.

33. The process according to claim 1, wherein the acid used in the ring closure step (c) is one or more inorganic acids comprising hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and/or perchloric acid.

34. The process according to claim 33, when preparing compound of formula V starting from compound of formula IV, the acid used in the ring closure step is 1.0M-4.0M hydrochloric acid.

35. The process according to claim 1, wherein said reaction temperature in the ring closure step (c) is in the range of 50°C-60°C.

36. The process according to claim 1, wherein said reaction time in the ring closure step (c) is in the range of 0.5-4 hours.

37. The process according to claim 1, wherein said thio-reagent used in step (d) has the structure as of formula B:

B wherein R⁸ is C₁-C₆ alkyl, alkenyl, alkynyl, aryl or substituted aryl; R⁹ is Na⁺, Cs⁺ or NH₄ ⁺.

38. The process according to claim 37, wherein R⁸ is methyl or phenyl, R⁹ is Na⁺.

39. The process according to claim 1, wherein said organic solvent used in step (d) comprises an arene, an acylamide, a phosphamide a sulfoxide or a mixture thereof.

40. The process according to claim 39, wherein the solvent used is N₅N- dimethylacetamide or N-methylpyrrolidone.

41. The process according to claim 1, wherein the reaction temperature in step (d) is in the range of 100°C-200°C.

42. The process according to claim 4I₅ wherein the reaction temperature is in the range of 140°C-175°C.

43. The process according to claim 1, wherein the reaction time in step (d) is in the range of 0.5-7 hours.

44. The process according to claim 43, wherein the reaction time in step (d) is in the range of 0.5-5 hours.

45. The process according to claim 1, wherein the catalyst used in step (e) is the strong alkaline anion exchange resin D₂g₀, D₂g₆ dispersed nano-palladium with the structure as of formula C,

C wherein the carrier granularity is in the range of 50-180 mesh, the functional group is -

NMe₃Cl, -NMe₂, the palladium content is in the range of 0.08-0.3mmol/g.

46. The process according to claim 1, wherein the zinc-agent used in step (e) can be prepared by the combination of metal zinc and a halonitrile comprising 5-chlorovalerate,

5 -bromo valerate or 5 -iodo valerate.

47. The process according to claim 1, wherein the zinc-agent used in step (e) can be prepared by the combination of metal zinc and a halonitrile comprising 5- chlorovaleronitrile, 5-bromovaleronitrile or 5-iodovaleronitrile.

48. The process according to claim 1, wherein the zinc-agent used in step (e) can be prepared by the combination of metal zinc and a halooxazoline comprising (4- chlorobutyl)-2-oxazoline, (4-bromobutyl)-2-oxazoline or (4-iodobutyl)-2-oxazoline.

49. The process according to any one of claims 1, 46, 47, 48, wherein the molar ratio of the compound of formula VI : zinc powder : halogen in step (e) is in the range of 1 : (2- 5) : (1.3-3).

50. The process according to claim 1, wherein the organic solvent in step (e) is selected from tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone or any mixture thereof.

51. The process according to claim 1, wherein the molar ratio between the compound of formula VI : Pd catalyst in step (e) is in the range of 1 : (0.005-0.5).

52. The process according to any one of claims 1, 46, 47, or 48, wherein the zinc- agent formation temperature in step (e) is in the range of 15⁰C-IOO⁰C.

53. The process according to claim 1, wherein the Fukuyama coupling reaction temperature in step (e) is in the range of 10°C-50°C.

54. The process according to claim 1, wherein the Fukuyama coupling reaction time in step (e) is in the range of 5-50 hours.

55. The process according to claim 1, wherein the the organic acid used for the ionic hydrogenation in step (f) is an aliphatic acid or a substituted aliphatic acid, a sulfonic acid or a substituted sulfonic acid.

56. The process according to claim 55, wherein the organic acid used in step (f) for the ionic hydrogenation is selected from formic acid, acetic acid, propanoic acid, butyric acid, isobutyric acid, trifluoroactic acid, trichloroacetic acid, tribromoacetic acid, sulfonic acid or substituted sulfonic acid.

57. The process according to claim 1, wherein the Lewis acid used in step (f) for the ionic hydrogenation is zinc chloride, boron triflroride, aluminium trichloride, titanium tetrachloride or tin tetrachloride.

58. The process according to claim 56, wherein the organic acid is trifluoroactic acid, formic acid, methanesulfonic acid, or borontrifluoride etherate.

59. The process according to claim 1, wherein the acid used to dehydrate the compound of formula VII to obtain the compound of formula IX in step (f) is an inorganic acid comprising sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, perchloric acid, or an organic acid comprising formic acid, acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or a Lewis acid such as zinc chloride, tin tetrachloride, boron triflroride, titanium tetrachloride or aluminium trichloride.

60. The process according to claim 59, wherein the inorganic acid is hydrochloric acid.

61. The process according to claim 1, wherein the reaction temperature to dehydrate the compound of formula VII to obtain the compound of formula IX in step (f) is in the range of -50°C to 80°C.

62. The process according to claim 61, wherein the reaction temperature to dehydrate the compound of formula VII to obtain the compound of formula IX in step (f) is in the range of O°C to 60°C.

63. The process according to claim 1, wherein the silane used for the ionic hydrogenation in step (f) is trimethylsilane, triethylsilane, triphenylsilane, dimethylsilane, diethylsilane or diphenylsilane.

64. The process according to claim 56, wherein the silane used for the ionic hydrogenation in step (f) is triethylsilane.

65. The process according to claim 1, wherein the organic solvent used for the ionic hydrogenation in step (f) is a halohydrocarbon comprising dichloromethane, chloroform, 1 ,2-dichloroethane, carbon tetrachloride; an arene comprising benzene, toluene, xylene, nitrobenzene, one or more benzene halides; or an ether comprising diethyl ether, dioxane or tetrahydrofuran; or a mixture thereof.

66. The process according to claim 1, wherein the organic solvent used for the ionic hydrogenation in step (f) is dichloromethane.

67. The process according to claim 1, wherein the molar ratio in step (f) of the compound represented by VII : acid : silane is in the range of 1 : (1-40) : (1-20).

68. The process according to claim 1, wherein the molar ratio in step (f) of the compound represented by IX : acid : silane is in the range of 1 : (1-40) : (1-20).

69. The process according to claim 1, wherein the reaction temperature for the ionic hydrogenation in step (f) is in the range of -80°C to 10°C.

70. The process according to claim 1, wherein the reaction time for the ionic hydrogenation in step (f) is in the range of 3-24 hours.

71. The process according to claim 1, wherein the inorganic acid used in step (g) is one or more strong acid(s) comprising hydrobromic acid, hydroiodic acid, hydrochloric acid and/or perchloric acid.

72. The process according to claim 71, wherein the inorganic acid used in step (g) is hydrobromic acid.

73. The process according to claim 1, wherein the mass volume ratio between the compound represented by VIII and the acid used in step (g) is in the range of 1 : 4-15 (w/v).

74. The process according to claim 1, wherein the temperature for hydrolysis ring opening in step (g) is in the range of 120°C to 150°C.

75. The process according to claim 1, wherein the reaction time for hydrolysis ring opening in step (g) is in the range of 4 to 60 hours.

76. The process according to claim 1, wherein the organic solvent used for hydrolysis ring opening in step (g) is one or more arene comprising dibasic benzene, tribasic benzene, nitrobenzene and/or a mixture thereof.

77. The process according to claim 1, wherein the reagent for ring closure in step (g) is diphosgene or triphosgene.

78. The process according to claim 1, wherein the molar ratio of the compound represented by VIII : ring closure reagent in step (g) is in the range of 1 : (1.0-3).

79. The process according to claim 1, wherein the catalyst used for the ring closure reaction in step (g) is activated carbon.

80. The process according to claim 1, wherein the molar ratio between the compound represented by VIII : activated carbon in step (g) is in the range of 5-3 : 1.

81. The process according to claim 1, wherein the inorganic alkaline solution for the ring closure reaction in step (g) is a 5-30 weight-% aqueous solution of lithium hydroxide, sodium hydroxide or potassium hydroxide.

82. The process according to claim 1, wherein the organic solvent for the ring closure reaction in step (g) is an ether comprising tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, anisole etc., or an arene comprising toluene and/or xylene.

83. The process according to claim 1, wherein the reaction temperature for the ring closure reaction in step (g) is in the range of 20°C-50°C.

84. A process for preparing a compound of formula III, comprising reacting the compound of formula II with acyl chloride,

II III wherein R¹ is benzyl, α-phenylethyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, allyl, 1-furyl, 2-furyl, 1-thienyl or 2-thienyl.

85. The process according to claim 84, wherein said acyl halide is a C₁-C₆ aliphatic acyl halide, an aromatic acyl halide or a substituted aromatic acyl halide, and wherein the halogene is chlorine or bromine.

86. The process according to claim 84, wherein the acyl halide used is acetyl chloride, propionyl chloride or benzoyl chloride.

87. The process according to claim 84, wherein the molar ratio between II and acyl halide is in the range of 1 : 1-5.

88. The process according to claim 84, which can be carried out without solvent or with solvent; when using solvent, a halohydrocarbon, an arene or a substituted arene are used.

89. The process according to claim 88, wherein the solvent used is toluene or 1,2- dichloroethane.

90. The process according to claim 88, the mass volume ratio between II and organic solvent is in the range of 1 : 6-20 g/mL.

91. The process according to claim 84, wherein the reaction temperature is in the range of 20°C-135°C.

92. The process according to claim 84, wherein the reaction time is in the range of 0.5-5 hours.

93. A process of preparing (4S,5R)-semiester of formular IV, wherein the compound of formula III is subjected to enantioselective alcoholysis with alcohol in the presence of cinchona alkaloid,

IV wherein R¹ is benzyl, α-phenylethyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, allyl, 1-furyl, 2-foryl, 1-thienyl or 2-thienyl; R² is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, aralkyl or aralkenyl.

94. The process according to claim 93, wherein the cinchona alkaloid used has the structure as of formula A:

A wherein R⁴ is hydroxyl, C₁-C₁₀ alkoxy; R⁵ is -H or -OR⁷, R⁷ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ acyl, benzyl, benzoyl, cinnamyl or a substituted derivative of any the above-mentioned groups; and R⁶ is ethyl, vinyl or ethynyl.

95. The process according to claim 94, wherein R⁴ is hydroxyl, propargyl-oxo or allyloxy.

96. The process according to claim 93, wherein the the cinchona alkaloid is selected from quinine or quinine derivatives.

97. The process according to claim 93, wherein the alcohol used is a C₁-C₆ alkanol, a C₃-Cg cycloalkanol, a C₃-C₆ enol, a C₃-C₆ alkynol, an aralkyl alcohol, an aryl enol or a substituted derivative of any of the above-mentioned alcohols.

98. The process according to claim 97, wherein the alcohol used is methanol, ethanol, propanol, butanol, cyclopentanol, allyl alcohol, propargyl alcohol, benzylalcohol, or cinnamyl alcohol.

99. The process according to claim 98, wherein the alcohol used is methanol, allyl alcohol or cinnamyl alcohol.

100. The process according to claim 93, which is carried out in an organic solvent selected from the group consisting of halohydrocarbons, aliphatic hydrocarbons, acetonitrile, ethyl acetate; arenes, nitrobenzene, benzene halides, ethers and mixtures thereof.

101. The process according to claim 100, wherein the organic solvent used is benzene, toluene, xylene, methyl tert-butyl ether, t-amylmethylether, tetrahydrofuran or any mixture thereof.

102. The process according to claim 93, wherein the molar ratio of CYCLIC ANHYDRIDE III: alcohol: cinchona alkaloid catalyst is in the range of 1 : (3-10) : (0.5-2).

103. The process according to claim 102, wherein the molar ratio of CYCLIC

ANHYDRIDE III: alcohol: cinchona alkaloid catalyst is in the range of 1 : (3-5) : (0.5- 1.1).

104. The process according to claim 93, wherein the alcoholysis reaction temperature is in the range of -6O⁰C to -15°C.

105. The process according to claim 104, wherein the alcoholysis reaction temperature is in the range of -50°C to -15°C.

106. The process according to claim 93, wherein the alcoholysis reaction time is 10-

80 hours.

107. The process according to claim 106, wherein the alcoholysis reaction time is 18- -72 hours.

108. A process of preparing a (3aS, 6aR)-lactone of formula V, wherein the compound of formula IV is selectively reduced at the ester group and then subjected to ring closure in the presence of an acidic catalyst

109. The process according to claim 108, wherein the reducing agent used is one borohydride or more borohydrides selected from the group consisting of alkyl substituted potassium borohydrides, alkyl substituted lithium borohydrides, alkyl substituted sodium borohydrides and sodium borohydride, potassium borohydride, lithium borohydride, cyano sodium borohydride.

110. The process according to claim 109, wherein the reducing agent used is sodium borohydride or potassium borohydride.

111. The process according to claim 109, wherein calcium chloride is added.

112. The process according to claim 108, wherein the solvent used in the reduction step is an alcohol, an ether or a mixture of these solvents.

113. The process according to claim 112, wherein the solvent used is ethanol or tetrahydrofuran.

114. The process according to claim 108, wherein the reducing agent used is sodium borohydride, the solvent used is tetrahydrofuran.

115. The process according to claim 108, wherein the reaction temperature in the reduction step is in the range of -20°C to 50°C.

116. The process according to claim 115, wherein the reaction temperature in the reduction step is in the range of 0°C to 25°C.

117. The process according to claim 108, wherein the reaction time in the reduction step is in the range of 4-24 hours.

118. The process according to claim 108, wherein the acid used in the ring closure reaction is an inorganic acid, preferably selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and perchloric acid.

119. The process according to claim 118, wherein the acid used in the ring closure step is 1.0M-4.0M hydrochloric acid.

120. The process according to claim 108, wherein the reaction temperature in the ring closure step is in the range of 50°C-60°C.

121. The process according to claim 108, wherein the reaction time for the ring closure step is in the range of 0.5-4 hours.

122. A process for preparing a (3aS, 6aR)-thiolactone of formula VI, wherein the compound of formula V is reacted with a thio-reagent

VI wherein R¹ is benzyl, α-phenylethyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, allyl, 1-furyl, 2-furyl, 1-thienyl or 2-thienyl.

123. The process according to claim 122, wherein the thio-reagent has the structure as of formula B:

124. The process according to claim 123, wherein R⁸ is methyl or phenyl, R⁹ is Na⁺.

125. The process according to claim 122, wherein the organic solvent is selected from the group consisting of arenes, acylamides, N-methylpyrrolidone, l,3-dimethyl-2- imidazolidinone, phosphamides, sulfoxides and mixtures thereof.

126. The process according to claim 125, wherein the solvent used is N₅N- dimethylacetamide or N-methylpyrrolidone.

127. The process according to claim 122, wherein the reaction temperature is in the range of 100°C-200°C.

128. The process according to claim 127, wherein the reaction temperature is in the range of 14O⁰C-175°C.

129. The process according to claim 122, wherein the reaction time is in the range of 0.5-7 hours.

130. The process according to claim 129, wherein the reaction time is in the range of 0.5-5 hours.

131. A process for preparing the diastereomeric mixture of formula VII,

VII wherein the compound of formula VI is subjected to Fukuyama coupling with a zinc-agent in the presence of a nano-palladium catalyst,

VI wherein R¹ is benzyl, α-phenyl ethyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, allyl, 1-furyl, 2-furyl, 1-thienyl or 2-thienyl; R³ is carbalkoxy, aralkyloxycarbonyl, cyan or oxazolinyl.

132. The process according to claim 131, wherein the catalyst used is the commercialized strong alkaline anion exchange resin D_2J0, D2₉₆ dispersed nano-palladium with the structure indicated in C; the carrier granularity is in the range of 50-180 mesh, the functional groups are -NMe₃Cl and -NMe₂, the palladium content is in the range of 0.08-

0.3mmol/g.

133. The process according to claim 131, wherein the zinc- agent used can be prepared by the combination of metal zinc and a halonitrile comprising 5-chlorovalerate, 5 -bromo valerate or 5-iodovalerate.

134. The process according to claim 131, wherein the zinc-agent used can be prepared by the combination of metal zinc and a halonitrile comprising 5- chlorovaleronitrile, 5-bromovaleronitrile or 5-iodovaleronitrile.

135. The process according to claim 131, wherein the zinc-agent used can be prepared by the combination of metal zinc and a halooxazoline comprising (4- chlorobutyi)-2-oxazoline, (4-bromobutyl)-2-oxazoline or (4-iodobutyl)-2-oxazoline.

136. The process according to any one of claims 131, 133, 134 or 135, wherein the molar ratio of the compound of formula VI:zinc powder: halogen in step (e) is in the range of 1:2-5: 1.3-3.

137. The process according to claim 131, wherein the organic solvent is selected from the group consisting of tetrahydrofuran, toluene, N,N-dimethylformamide, N₅N- dimethylacetamide, N-methylpyrrolidone and any mixture thereof.

138. The process according to claim 131, wherein the molar ratio between the compound of formula VI : Pd catalyst is in the range of 1 :0.005-0.5.

139. The process according to any one of claims 131, 133, 134, or 135, wherein the zinc-agent formation temperature is in the range of 15⁰C-IOO⁰C.

140. The process according to claim 131, wherein the Fukuyama coupling reaction temperature is in the range of 10°C-50°C.

141. The process according to claim 131, wherein the Fukuyama coupling reaction time is 5-50 hours.

142. A process for preparing (3aS, 4S, 6aR)-dibenzyl-biotin and its derivative of formula VIII, wherein said compound of formula VII is reduced via ionic hydrogenation with silane in the presence of organic acid or Lewis acid; or, subjecting the compound of formula VII to de-hydration under action of acid to yield the compound of formula IX, which is then reduced to (3aS, 4S, 6aR)-dibenzyl-biotin and its derivative of formula VIII via ionic hydrogenation with silane in the presence of an organic acid or a Lewis acid;

wherein R¹ is benzyl, ophenyl ethyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, allyl, 1-furyl, 2-furyl, 1-thienyl or 2-thienyl; R³ is carbalkoxy, aralkyloxycarbonyl, cyan or oxazolinyl.

143. The process according to claim 142, wherein the organic acid used for the ionic hydrogenation is an aliphatic acid or a substituted aliphatic acid, a sulfonic acid or a substituted sulfonic acid.

144. The process according to claim 143, wherein the organic acid used for the ionic hydrogenation is selected from the group consisting of formic acid, acetic acid, propanoic acid, butyric acid, isobutyric acid, trifluoroactic acid, trichloroacetic acid, tribromoacetic acid, sulfonic acid and substituted sulfonic acid.

145. The process according to claim 142, wherein the Lewis acid for the ionic hydrogenation is zinc chloride, boron triflroride, aluminium trichloride, titanium tetrachloride or tin tetrachloride.

146. The process according to claim 144, wherein the organic acid used for the ionic hydrogenation is trifluoroactic acid, formic acid, methanesulfonic acid and/or [???] borontrifluoride etherate.

147. The process according to claim 142, wherein the acid used to dehydrate the compound of formula VII is an inorganic acid or an organic acid or a Lewis acid.

148. The process according to claim 147, wherein the inorganic acid is hycrochloric acid.

149. The process according to claim 142, wherein the reaction temperature to dehydrate the compound of formula VII to obtain the compound of formula IX is in the range of-50°C to 80°C.

150. The process according to claim 149, wherein the reaction temperature to dehydrate the compound of formula VII to obtain the compound of formula IX is O⁰C- 60°C.

151. The process according to claim 142, wherein the silane used for the ionic hydro genation is trimethylsilane, triethylsilane, triphenylsilane, dimethylsilane, diethylsilane or diphenylsilane.

152. The process according to claim 152, wherein the silane used for the ionic hydrogenation is triethylsilane.

153. The process according to claim 142, wherein the organic solvent used for the ionic hydrogenation is selected from the group consisting of halohydrocarbons, arenes, nitrobenzene, benzene halides, ethers and any mixture thereof.

154. The process according to claim 142, wherein the organic solvent used for the ionic hydrogenation is dichloromethane.

155. The process according to claim 142, wherein the molar ratio of the compound of formula VII: acid: silane is in the range of 1 : 1 -40: 1 -20.

156. The process according to claim 142, wherein the molar ratio of the compound of formula IX: acid: silane is in the range of 1:1-40:1-20.

157. The process according to claim 142, wherein the reaction temperature for the ionic hydrogenation is in the range of -80°C to 10°C.

158. The process according to claim 142, wherein the reaction time for the ionic hydrogenation is in the range of 3-24 hours.

159. A process for preparing (+)-biotin I, wherein the compound of formula VIII is hydrolyzed by use of an inorganic acid, followed by ring opening, removing of the protecting group and ring closure in the presence of a catalyst to obtain biotin of formula I

I

160. The process according to claim 159, wherein the inorganic acid used is hydrobromic acid, hydroiodic acid, hydrochloric acid or perchloric acid.

161. The process according to claim 160, wherein the inorganic acid used is hydrobromic acid.

162. The process according to claim 159, wherein the mass volume ratio between the compound of formula VIII and the acid is in the range of 1 : 4-15 (w/v).

163. The process according to claim 159, wherein the temperature for the hydrolysis ring opening is in the range of 120°C-150°C.

164. The process according to claim 159, wherein the reaction time for the hydrolysis ring opening is in the range of 4-60 hours.

165. The process according to claim 159, wherein the organic solvent used for the hydrolysis ring opening is dibasic benzene, tribasic benzene, nitrobenzene and/or their mixture.

166. The process according to claim 159, wherein the reagent for ring closure is diphosgene or triphosgene.

167. The process according to claim 159, wherein the molar ratio between the compound of formula VIII: ring closure reagent is in the range of 1 :1.0-3.

168. The process according to claim 159, wherein the catalyst used for the ring closure is activated carbon.

169. The process according to claim 159, wherein the molar ratio between the compound of formula VIII: activated carbon is in the range of 5-3:1.

170. The process according to claim 159, wherein the inorganic alkaline solution for the ring closure is a 5-30 weight-% aqueous solution of lithium hydroxide, sodium hydroxide or potassium hydroxide.

171. The process according to claim 159, wherein the organic solvent used for the ring closure is an ether (preferably tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, anisole), or an arene (preferably toluene, xylene).

212. The process according to claim 159, wherein the reaction temperature for the ring closure is in the range of 20°C-50°C.