TWI378924B - Process for the manufacture of chroman derivatives,especially α-tocopherol and alkanoates thereof - Google Patents

Description

1378924 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel preparation method of a chroman derivative, in particular...tocopherol (TCP) and its alkanoate (TCPA), such as ~tocopherol acetate A novel process for the preparation of esters (TCPAc) wherein at least one step of the process is carried out under pressure in the presence of a Lewis acid as a catalyst or a mixture of Lewis acid and Bruce's acid. The preferred absolute pressure for the reaction is at least 丨1 bar, more preferably from about 1.1 bar to about 20 ‘0 bar, even more preferably from about U bar to about 6.0 bar. As a starting material for the preparation of TCP and its alkanoates, 2,3,5-trimethylhydroquinone (TMHQ) or 2,3,6-trimethylhydroindole-1-alkanoate (TMHQa) And a mixture of compounds selected from the group consisting of phytol (PH), isophytol (ip) and (iso) phytol derivatives, or "open-loop" compounds 2 - phytosyl-3, 5, 6_ Trimethylhydroquinone (PTMHQ), 3-phytyl-2,5,6-trimethylhydroquinone-i-alkanoate (PTMHQA) and/or its isomers. [Prior Art] As we know, '(full racem) _α_tocopherol (or tocopherol as it is usually referred to in the prior art) is 2,5,7,8-tetramethyl-2-( a mixture of four pairs of diastereomers of the enantiomer of 4,8,8,12,-dimethyl-tridecyl)-6-chromanol tocopherol, which is a vitamin Ε The biologically most active and industrially most important member of the family. It is described in the literature selected below by TMHQ/2,3,6-trimethylhydroquinone-1-acetate (TMHQAc) Prepared by reaction with IP or PH in the presence of a catalyst or catalyst system and in the presence of a solvent or solvent system, d,la-tocopherol is so referred to in the literature as described in 98122.doc 1378924) and many of its acetates The preparation of alpha-tocopherol by reacting TMHQ with PH or phytyl bromide in the presence of anhydrous ZnCl2 is described, for example, in US Pat. No. 2,41 1,967. According to DE 196 54 038 Al, TMHQ series with PH or IP The α-tocopherol and its acetate are prepared by reacting in the presence of ZnCl 2 and a proton donor, whereby in the method of US 3,708,505, a Lewis acid such as 211 (: 12 and at least one) is included. A combined acid condensing agent of a strong acid such as p-toluenesulfonic acid and sodium hydrogen sulfate is used as a catalyst. The reaction of TMHQ with IP or hydrazine described in ΕΡ-Α0 100 471 is in a Lewis acid as a catalyst system such as ZnCl2. In the presence of BF3 or A1C13, a strong acid such as HCl and an amine salt, IP or PH is pretreated with ammonia or an amine in the process of DE-OS 26 06 830 and US Pat. No. 4,191,692, and thereafter in the presence of ZnCl 2 and an acid. Reaction with TMHQ. Compounds of the formula in DE-OS 21 60 103 and US 3,789,086

R1 XO. wherein X is hydrogen, alkyl fluorenyl or aryl fluorenyl, and each of R1, R2 and R3 is hydrogen or methyl, which reacts with a compound of the formula

- Η where Υ is -CH2-CH(CH3)- or -CH=C(CH3)- and the oxime is halogen, hydroxy, sulfonate or esterified, the reaction is in the HC1 and 98122.doc as catalysts 1378924

For example, fermentation is carried out in the presence of Fe and/or FeCl2. According to ΕΡ-ΑΟ 694 541, TMHQ and IP, ruthenium or osmium derivatives are used as catalysts for inorganic acids, Lewis acids, acidic ion exchange resins or trifluorosulfonium sulfonate of sharp (Sc), y (Y) or lanthanides. The reaction is carried out in the presence of a salt, a nitrate or a sulfate. The ruthenium trifluorosulfonate (ruthenium) is also used as a catalyst for the condensation of tmhq with IP in Bull. Chem. Soc. Jpn. 1995, 68, 3569-3571. TCP can be converted to its acetate, succinate and further known forms of application by standard methods, for example in UIlmann, s Encyclopedia of

Industrial Chemistry, Vol. A27, 5th edition, pages 484 to 485, VCH Verlagsgesellschaft mbH, D-69451 Wein-heim, 1996. In contrast to TCP, which is not unstable under oxidizing conditions, these vinegars (TCPA) are more stable and easier to handle. Disclosure of the Invention An object of the present invention is to provide a process for preparing color-rich organisms such as tocols and tocopherols, and particularly tocopherols and their alcohols S, at a high selectivity and high yield. [Embodiment] According to the present invention, this object is achieved by using a Lewis acid as a catalyst or a mixture of a Lewis acid and a Bruce's acid under a force of I, preferably; an absolute pressure of V 1.1 bar, more preferably From about i" to about 20 baht: absolute pressure 'even better than from about 1.1 bar to about 6.0 bar. It has been surprisingly found that pressures are produced in condensation reactions such as TMHQ or TMHQA benzene age with compounds such as IP, PH or derivatives thereof and 98122.doc 1378924 PTMHQ or PTMHQA and/or its isomers to produce tocopherols The ring closure reaction has a positive effect in the tocopherol and tocopherol deuteration reaction. Thus, in one aspect, the invention relates to a process for the preparation of the following compounds: 2-alkenyl-3,5,6-tridecylhydroquinone (formula j, n = 〇i3; Rl = hydrogen) and 3 olefin Benzyl-2,5,6-trimethylhydroquinone]-alkanoate (Formula, 11=〇 to 3; Rl=ethylidene, propyl sulfonyl, trimethylethenyl, h〇2C_CH2_Ch2_c〇 , nicotine sulfhydryl or arachidyl), the best is 2-phytyl, 3,5,6-trimethylhydroquinone (formula I, ruler-hydrogen and 11=3) and 3-phytyl-2 ,5,6-tridecylhydrogenated _1_chain-burning acid ester (Formula 1, R1=ethylidene, propylidene, trimethylethenyl, h〇2C-CH2-CH2-C0, final test a method for preparing a mercapto or benzhydryl group and n=3),

The preparation method is carried out by using 2,3,5-trimethylhydrazine (formula π, rL hydrogen) and 2,3,6-trimethylhydroindole-1-alkanoate (Formula 11, 1^). = ethyl hydrazino, propyl sulfonyl, trimethyl ethane hydrazino, H 〇 2C-CH 2 -CH 2 -CO, nicotine decyl or benzhydryl), respectively,

(II) Reaction with a compound of formula III and / or formula IV in an organic solvent 98122.doc 1378924

Wherein R1 is hydrogen, ethylidene, propyl sulfonyl, trimethylethenyl, Η〇β ch2-ch2_co, nicotine sulfhydryl or benzhydryl, R2 hydroxy, ethoxylated, benzoyloxy a base or a halogen, and η is an integer from 0 to 3, and wherein the reaction is carried out under pressure in the presence of a Lewis acid as a catalyst or a mixture of a Lewis acid and a Brillis acid, preferably at least 巴Absolute pressure, better than the absolute pressure from about 1 bar to about 2 bar 'even better than the absolute pressure from about 1 bar to about 6. bar. This method is hereinafter referred to as method 1. With respect to the substituent R1: preferably hydrogen or an ethylidene group, more preferably hydrogen. With respect to the substituent R2: preferably R2 is a hydroxyl group, an ethoxylated group, a benzamidineoxy group, a chlorine or a desert. Preferably, R2 is a hydroxyl group, an ethyloxy group or a gas, and most preferably R2 is a hydroxyl group. Regarding the integer η: preferably η is 3. It is preferred to produce (cyclos)-2-alkenyl-3,5,6-dimethylhydroquinone, such as (all-racemic)-PTMHQ, or (full racemization) in Process 1 of the present invention. )-3_ dilute 2,5,6-dimercaptohydroquinone-indole alkanoate, for example (full racemization) · PTMHQA 'especially (full racem) _3_ phytyl · 2,5,6 Trimethylhydrogen is a small ethylene I (PTMHQAc), but the invention is not limited to the production of the specific isomer form and can be used by using the appropriate isomer form as the starting material 98122.doc 1378924 ( For example) phytol (Formula IV 'R2=〇h and n=3), isophytol (Formula III, R2=〇H and n=3) or derivatives thereof to obtain other isomeric forms. Thus, for example, when using (branches-phytol, (full and) _isophytol, isophytol, or (and anthraquinone/?)-isophytol or a suitable (iso) phytol derivative, (i?,i?)-PTMHQ or (i?,/?)-PTMHQA is available. Method 1 is also applicable to containing from one to four methyl groups, a total of 1 to 3 radicals and at least one unsubstituted Alkenylation of a phenol at a position wherein the unsubstituted position is ortho to the hydroxy group. Thus, another object of the invention is to use a compound of the formula ΙΠ and / or IV in an organic solvent to contain from one to four a method of alkenylation of a total of 1 to 3 hydroxyl groups and at least one unsubstituted position, wherein the unsubstituted position is at the hydroxyl ortho position

Η (Ε/Ζ) (丨V) 2 R and η have the same meanings and preferred choices as above, and wherein the reaction exists under pressure in a Lewis acid as a catalyst or a mixture of a Lewis acid and a Brucenic acid. Preferably, an absolute pressure of at least 1.1 bar is preferred, and an absolute pressure of from about 1.1 bar to about 20.0 bar is preferred, even more preferably from about 1.1 bar to about 6.0 bar absolute. This method is hereinafter referred to as method 1Α. Regarding the phenol used as the starting material in the method 1A: a particularly suitable phenol having the following formula Ila 98122.doc

X

X

Stuffed base, propyl sulfonyl, trimethyl ethyl ketone, -r is ... which; the broth or benzoyl group and χ, χ 2 and χ 3 are each independently nitrogen or Yin, the limit condition ν2η ν3 right Both hydrazine and hydrazine are methyl, then r-based, (tetra)-based, tris-ethylidene-based, H02C-CH2_CH2_C 〇, in the test of the base or laughter. A base of brewing, namely 虱醌, 2- Methylhydroquinone, 2,3-dimethylhydrogen S-Kun, 2,5-di-f-hydrogen H6·di-f-hydrogen, 2'3,5•trimethylhydrogen and 2'3,6- Trimethyl hydrogen brewing" chain burnt vinegar. The preferred ones from this group are 2,3,5·trimethylhydrogen and 2,3,6-trimethylhydrogen small chain sulphuric acid vinegar, more preferably 2,3,5-trimethyl hydrogen. Stuffed with 2,3,6•trimethylhydrogen]·acetic acid vinegar, the best system is 2,3,5·tridecylhydroquinone. In another aspect, the present invention relates to a process for the preparation of a compound of formula VII, preferably ~ fertility (formula V „, Rl=hydrogen and n=3) and its key-burning vinegar (formula VII R acetamidine, Propyl base, trimethyl ethane group, H〇2c_CH2_

a) (Step a) optionally, 2,3,5-trimethylhydroquinone (formula n, Rl = hydrogen) and 2,3,6-dimethylhydroindole-1-alkanoate (Formula II, rL ethyl thiol, propyl sulfhydryl, trimethyl ethane fluorenyl, HChC-CHrCHrCO, nicotine sulfhydryl or benzamidine. The preparation method is carried out by the following steps 98122.doc 12 base)' respectively, with the formula ΠΙ and / Or

reaction

Iv compound in organic solvent

And η have the same meaning and preferred choice as above, and b) (step b) (4) 2 alkenyl·3, Μ·trimethylhydrogen (step 1 R ― gas obtained by step a) ''preferably 2_phytyl_3,5,6-trimethylhydroquinone (Formula I, R hydrogen 1 and n-3), 3-alkenyl-2,5,6-trimethylhydroquinone· 1 • alkanoic acid esters (formula I, R-ethylidene, propylidene, trimethylethenyl, h〇2C_Ch2_CHrCO, nicotine sulfhydryl or benzhydryl), preferably 3-phytyl 2,5,6_5 methylhydroquinone-1-alkanoate (formula Rl=acetamidinyl, propyl fluorenyl, triterpene ethyl aryl H〇2C-CH2_CH2-CO, thiol or benzene Stirring and n=3) and optionally one or more double bond isomers are placed in an organic solvent, 闭环1 (π) ° is subjected to a ring closure reaction to form a chroman derivative VII, preferably alpha tocopherol VII, Rk hydrogen, η = 3) or its alkanoate (formula νπ, rU 乙, propyl sulfonyl, trimethyl ethinyl, H 〇 2C_CH2_CH2_co 1 test II or 98122.doc 13 1378924 benzene a mercapto group and n=3), wherein at least one of steps a) and b) is in the presence of a Lewis acid as a preparation agent or a mixture of a Lewis acid and a Bronsted acid OK, compared with

It is better than the absolute pressure of at least 1.1 bar, more preferably from about 丨丨bar to about 2 20.0 bar absolute pressure, even better than the absolute pressure from about 丨 bar to about 6 〇 bar. This method is hereinafter referred to as method 2. Depending on the activity of the catalyst and the reaction conditions, the compound of the formula is reacted with a compound of the formula and/or the compound of the formula IV to give the final product of the formula VII, preferably a tocopherol and an alkanoate thereof, whereby the compound of the oxime is not isolated. Such as pTMHQ (Formula I 'R丨=hydrogen and n=3) and PTMHQA (Formula I, Ethyl, Acrylidene, Trimethylsulfonyl, HOzC-CHs-CH^CO, Nicotine Sulfhydryl or Benzene Mercapto group and n=3) ° Therefore, another aspect of the present invention is to prepare a chroman derivative such as α_the reproductive age (formula VII 'Rk hydrogen and η=3) and its alkanoate (formula νπ, Rl = ethyl hydrazino, propyl fluorenyl, trimethyl ethane fluorenyl, H 〇 2C-CH2-CH2-CO, nicotine sulfhydryl or abbreviated and n = 3)

The preparation method is carried out by using 2,3,5·trimethylhydroquinone (formula n, Rl=hydrogen) and 2,3,6-trimethylhydroquinone-hydrazine alkanoate (formula n, RU) Ethyl, propyl, trimethylsulfonyl, H〇2C_CH2-CH2-CO, nicotine sulfhydryl or benzhydryl), respectively, 98122.doc 1378924

Reacting with a compound of formula III and / or formula IV in an organic solvent

(IV), R1, R2 and η have the same meanings and preferred choices as above, wherein the reaction is carried out under pressure in the presence of a Lewis acid as a catalyst or a mixture of a Lewis acid and a Brunsto acid, preferably at least The absolute pressure of 1 · 1 bar is more preferably from about 1.1 bar to about 20.0 bar absolute pressure, even better than the absolute pressure from about 1.1 bar to about 6.0 bar. This method is hereinafter referred to as method 3. In the method 3, the starting material may also be a compound of the formula IX instead of the compound of the formula III and/or IV.

如此 So in order to obtain the compound of formula X '0

R

(X) R1, R2 and η have the same meanings and preferred choices as above. This method is referred to hereinafter as Method 4 in 98122.doc 15 1378924. Although it is preferred to produce (all-racemic)-chroman derivatives in methods 2 and 3 of the present invention, such as (full-race)-TCP (formula VII, R!=hydrogen and n=3) and Cyclo)-TCPA (formula VII, RL ethyl hydrazide, propyl sulfhydryl, trimethyl ethane fluorenyl, HO 2 C-CH 2 -CH 2 -CO, in the saponin or benzoquinone and n = 3), especially ( Full racem) - TCPAc (formula VII, R) = ethylidene and n = 3), but the invention is not limited to the production of the particular isomeric form and may be suitably used as a starting material. Isomer forms such as phytol, isophytol or derivatives thereof are used to obtain other isomeric forms. Therefore, when using (see) _ PTMHQ, (foot i?)-PTMHQA, (foot)-phytol, (full;;)-isophytol, (& i?)-isophytol, Or isophytol or a suitable (iso) phytol derivative, 'for example (and angxiong i?)-TCP/(i^, 足i?)-TCPA can be obtained. In a particularly preferred embodiment of the invention, TMHQ reacts with PH (Formula IV, R2 = OH and n = 3) and / or IP (in the formula, R2 = 〇HXn = 3), preferably in reaction with hydrazine, To obtain cx-tocopherol (formula νπ, Ri = hydrogen and n=3), wherein intermediate compounds of formula V (see below) and VI (see below) are formed, such as 2-_  _ 3, 5, 6 Hydroquinone (Formula I' R] = hydrogen and n = 3, as a major component), 2_(3,7,u,i5_tetramethyl-hexadec-3-enyl)-3,5,6 -trimethylhydroquinone (Formula Va, Rl = hydrogen) and 2-[3-(4,8,12-trimethyl-tridecyl)-but-3-enyl]_3,5,6 Methylhydroquinone (formula Via, R = hydrogen).

98122.doc -16- 1378924

Processes 2 and 3 can also be carried out using phenol of the formula Ila, whereby, in addition to alpha-tocopherol and its alkanoates, for example, other tocols (formula, n=3) and tocopherols can be obtained. (Formula Vila, n=3). X1

(Vila) Accordingly, another aspect of the present invention is a process for the preparation of a compound of the formula Vila, which is obtained by the following steps a) (step a), optionally taking a compound of the formula Ila

X1 R

0H reacts with a compound of formula III and / or IV in an organic solvent

R2, R3, η, X1, X2 and X3 have the same meanings and preferred choices as above, and b) (step b) such that all of the compounds of formula la obtainable by step a) are treated as appropriate with 98122.doc 1378924 Or a plurality of double bond isomers thereof are placed in an organic solvent to carry out a ring closure reaction to form a compound of the formula Vila.

Wherein at least one of steps a) and b) is carried out under pressure in the presence of a Lewis acid as a catalyst or a mixture of a Lewis acid and a Brunsto acid, preferably at least 1 kPa absolute pressure, more preferably The absolute pressure from about 1.1 bar to about 20.0 bar is even better than the absolute pressure from about 1 bar to about 6.0 bar. This method is hereinafter referred to as Method 2A. Depending on the activity of the catalyst and the reaction conditions, the final product, the compound of the formula Vila, can also be obtained in step a of method 2A, so as not to separate the compound of the formula la. Therefore, another aspect of the present invention is to prepare a compound of the formula Vila 1

(Vila) The preparation method is carried out by making a compound of the formula Ila

(lla) reacting with a compound of formula III and / or IV in an organic solvent 98l22.doc -18- 1378924

R2, R3, η, X1, X2 and X3 have the same meanings and preferred choices as above, wherein the reaction is carried out under pressure in the presence of a Lewis acid as a catalyst or a mixture of a Lewis acid and Bruce's acid. Preferably, the absolute pressure is at least 1 bar, more preferably from about 1.1 bar to about 20.0 bar absolute pressure, and even better from about 1.1 bar to about 6.0 bar absolute pressure. This method is hereinafter referred to as method 3Α. In another aspect, the invention relates to a compound of the formula Vllld (if η = 3: a butyol alkanoate and a tocopherol alkanoate), in particular a tocopherol alkanoate (formula Vllld ' η =3 ' 乂丨 = again 2 = 乂 3 = 曱 base) preparation method, Λ

The oxime preparation method is a compound of the formula VHd obtained by the method according to the invention (if n=3: then tocol or tocopherol), in particular α-tocopherol (formula Vlld 'η=3 'methyl) Reacts with a sputum, Λ

Preferably, the reaction is carried out in the presence of a Lewis acid as a catalyst 98122.doc -19 1378924. In another preferred embodiment, the reaction is carried out under reduced pressure, preferably at an absolute pressure of less than 0.9 bar, or at a pressure of preferably at least 1.1 bar absolute (hereinafter referred to as a method). 5). Regarding the symbol η: it is an integer from 〇 to 3. Regarding the symbols X1, X2, and X3: they have the same meanings as given above. With respect to the substituent R: it is selected from the group consisting of an ethyl sulfonyl group, a propyl fluorenyl group, a trimethyl ethane fluorenyl group, a H 〇 2CNCH 2 -CH 2 _CO group, a nicotine sulfhydryl group or a benzamidine group; preferably a R system HOf-CHrCHrCO or More preferably, R is an ethyl group. In a preferred embodiment, the present invention relates to a compound of the formula VIIIaK, preferably a compound of the formula VIIIa (n = 3) (motherol alkanoate and tocopherol alkanoate), more preferably a method for preparing a chain-saturated acid ester (formula VIII, n=3) compound,

1 X1

_) (Va) The preparation method is carried out by making a compound of the formula V„c, preferably vnc(n=3) (tocol or fertility), and better tocopherol (formula VIIb, n=3) The compound reacts with the oxime,

(viib), (Vile) The reaction is specifically carried out in the presence of a Lewis acid as a catalyst at a reduced I, preferably at an absolute pressure of less than 0.9 bar, or under pressure, preferably at least hl Absolute pressure of Ba (hereinafter referred to as Method 5A) 〇98l22.doc •20- 1378924 About the symbols η, X1, X2 and X3: Meaning. It has the same meaning as described above with respect to the substituent R: it is selected from the group consisting of ethyl sulfonyl, acetonide, = earth, dimethyl acetamyl, H 〇 2 C-CH 2 -CH 2 _CO, in the brewing base or benzoquinone Preferably, the composition of the V is H〇2C-CH2-CH2-CO or the ethylene-based base, and the p-type D method is used for the calculation. The same method as the compound of the formula vm and VIIIa can be prepared. (IV) The compound of the formula X wherein R1 is an ethyl group, a propyl group _

Base, ho2c-ch2-ch2-co, nicotine thiol or benzoate A

- methyl ethyl τ 丞 丞, and η is an integer from 0 to 3, the preparation method of the ruthenium compound is made by the compound of the formula X (R1 is hydrogen and η has the same meaning as the above, „σ) The appropriate oxime is reacted at the Lewis & L ^ as a catalyst at y under reduced pressure, preferably at an absolute pressure of less than 0.9 bar or at a pressure τ ' preferably at least at an absolute pressure of at least 1 · 1 bar. The present invention: - the method of the present invention, hereinafter referred to as the method 5 Ββ 4 s in a preferred embodiment of the method 5 of the present invention, the production of the formula, the color of the vinegar, such as (all-rotation)-TCPA VIII, n=3 ; see) ^ 疋 全 (all please spin) - TcpAc (formula VIII, n = 3 and R = ethyl thiol), the month is not limited to the production of the specific isomer form and can be borrowed Temporarily dip by use as a starting material ^ ^

Vllb buys a suitable isomeric form such as TCP (Equation 13) to obtain other isomeric forms. Therefore, when 98l22.doc 21 1378924 (R, R, R)-TCP is used as a starting material, for example, (7) oxime and) TCPA/TCPAc can be obtained, which is due to the fact that the epimerization does not react. Occurs when the temperature is below 12 °C. The same applies to other compounds of the formula Vile used as starting materials, such as, for example, tocols and tocopherols, if n = 3 〇 in a preferred embodiment, if process 2 or 3 is used as a catalyst In the presence of a Lewis acid, the (all-racemic) _α·tocopherol (formula Vllb, η=3) obtained by the method 2 or 3 is subjected to acetalization using acetic anhydride after the solvent is removed and is completely converted without Further purification. If the catalyst (Louis acid) of the reaction as described above is still present, no additional catalyst is required. Further, a particular advantage is that the preparation of the reaction mixture such as (all-rotation)·tocopherol can be acetylated at the reaction temperature of the reaction mixture. When an indium (ruthenium) salt is used as a catalyst, the acetylation can be carried out even at room temperature for a short reaction time (up to 10 minutes). Separation (full racemization) of _α•tocopherol acetate after acetamization yields excellent yield [by (full racem) _α•tocopherol, >99 5%]. Lewis acid and a mixture of Lewis acid and Bruce's acid. A mixture of Lewis acid and/or Lewis acid and Bruce's acid used as a catalyst under pressure in all methods 1 to 5: Proficiency in the art. All Lewis acids and mixtures of Lewis acids and Brunsert acids can be used as catalysts for the condensation of TMhq or TMHQA with IP, PH or its derivatives. Suitable catalysts such as boron trifluoride (BF3) A mixture of boric acid (especially orthoboric acid) and oxalic acid, trifluorosulfonate and isotonic acid. Preferred is a Lewis acid having a metal cation radius varying from about 73 pm to about 90 pm, preferably from about 73 98122.doc • 22·1378924 pm to about 82 pm, such as Fe2+ (0.74 A), Zn2+ (0.74 A). The radius of In3 + (0.81 A) and Sc3+ (0.73 A) is particularly suitable. The Lewis acid is an indium (III) salt such as indium (III) halide, indium (III) triflate [In (S03CF3) 3; In(OTf)3] and bis(trifluoromethanesulfonamide) indium (III) [In((NS02CF3)2)3; In(NTf2)3]; such as those described in EP 0 658 552 A1 Pages, lines 14 to 21 and page 6 to line 23 to page 7 and line 33 of the cerium (III) salt, such as cerium (III) fluorosulfonate [Sc(S03F)3], bismuth triflate (111)[54〇丁〇3] and fluorobenzenesulfonate sharp (111)[3(;(303(:6114?)3]; bis(trifluoromethanesulfonamide)铳(III)[Sc(NTf2) 3], cerium (III) nitrate [Sc(N03)3], cerium (III) sulfate [Sc2 (S04) 3] and bis(trifluoromethanesulfonamide) zinc (II) [Zn(NTf2) 2] More preferred are InCl3, In(OTf)3 and Sc(OTf)3, of which InCl3 is the best. Indium and strontium salts InCl3, In(OTf)3 and Sc(OTf)3 are known to be commercially available. a compound, for example, InCl 3 from Fluka (No. 57 100), In (OTf) 3 and Sc (OTf) 3 from Aldrich (Nos. 442 151 and 418 218). They can all be in solid form, anhydrous or aqueous (wherein InCl3'4 H20 is a Examples) and use as a solution or suspension. The catalyst is preferably dissolved or suspended in water for processes 1 and 2. The concentration of the aqueous solution is not critical. In addition, all of the Lewis acids described above are resistant to acetic anhydride and other oximation agents. And a protic solvent such as decyl alcohol, ethanol, and water. The Lewis acid used as a catalyst after the reaction is terminated can be recycled. Particularly suitable Lewis acid and Bronsted acid mixture is the following system: · Zinc (II) compound / hydrochloric acid, Zinc (II) compounds (preferably ZnCl2) / gaseous HC1 and iron (II) chloride / gaseous HC1. Ferric chloride (II) can be obtained by reacting iron with HC1 98122.doc • 23-1378924, It therefore produces a system equivalent to the iron(II) chloride/gaseous HC1 system. Suitable zinc(II) compounds are the (II) salts, such as ZnCl2, ZnBr2, and all zinc that forms ZnCl2 under the reaction conditions ( π) compounds such as ZnOIf a ZnCl2/hydrochloric acid or ZnCl2/gaseous HC1 system is used, it is preferred that the reaction be disclosed in the last paragraph of page 4 and the first paragraph of page 5, such as EP 0 100 471 A1, which is incorporated herein by reference. It is carried out in the presence of an amine or in the presence of an ammonium salt. Alternatively, the reaction is preferably carried out by using an amine or NH3 pretreated oxime or IV compound such as IP or PH as described in DE-OS 26 06 830. Preparation of starting materials The starting material TMHQAc can be obtained, for example, by selective hydrolysis of 2,3,5-dimercaptohydrogenated diacetate as described in ΕΡ·Α 1 239 045. 2,3,5-trimethylhydroquinone diacetate can be, for example, by acetic anhydride or such as EP_a 〇 850 910, EP-A 0 916 642, EP-A 0 952 137 or EP-A 1 028 Prepared by catalytic rearrangement of ketoisophorone acid in the presence of another oxime agent as described in 103. The (iso) phytyl compound can be produced by conventional methods known to those skilled in the art. The phytol and its derivatives represented by the formula IV of n=3 can be used in the E/z_mixture as well as in the pure E- or pure Z- form. Preferably, phytol and its derivatives represented by the formula are used as the E/Z mixture. The best starting material selected from (4) phytochemicals is IP. Tian Ran also uses the isomer form of any other suitable (iso) phytol derivative to the right TMHQ/TMHQA as the other component, then (foot) phytol, (full / phytol, (four)" ) _ phytol or (10), acetoin or isophytol or an appropriate (iso) phytol derivative of 98122.doc • 24-1378924 'for example, can be used to obtain (and )) _PTMHQ / other (b) (methyl Hydrogen compounds and compounds of the formulae III and IV and wherein η is 〇, 1 or 2 can be prepared by methods known to those skilled in the art. Method 1, step a of method 2, step a of method 2a, it is obvious that the compound of formula II and RkHpTMHQ; = formula na and X1, χ2 and Χ3 = fluorenyl and R3 = hydrogen) is used as a reactant in the present invention. The method will result in the production of a compound of formula I (Ri = H) such as PTMHQ (n = 3), and when using formula II and R1 =: ethyl, glyceryl, trimethylethyl, H〇2c_ Ch2-ch2_co, compound (=Tmhqa), especially TMHQAc, can obtain formula I and Ri=acetamid, propyl fluorenyl, trimethyl ethyl hydrazide, H 相应A compound of 2C-CH2_CH2-CO, nicotinyl or phenylhydrazine, such as PTMHQA/PTMHQAc (n=3). If TMHQ/TMHQA is reacted with a compound of formula III and/or IV and both of which have a η of 3', then a small amount of the following PTMHQ/PTMHQA isomer may be formed as a by-product in step 1 of method 1 and methods 2 and 2; :(ζ)- or (Ε)-2-(3,7,11,15-tetramethyl-hexadecene-3-ylidene)-3,5,6-trimethylhydroacid (formula va and R-gas 'see above) / (Z)- or (E)-3-(3,7, ll,15-tetramethyl-hexadecyl_3_alkenyl)-2,5,6-trimethyl Phenylhydrazine-1_alkanoate (Formula Va and Rl=ethylidene, propylidene, trimethylethenyl, H〇2C_CH2_CH2_c〇'nicotinyl or arachidyl; see above) and / Or 2-[3-(4,8,12-trimethyl-tridecyl)-but-3-enyl]-2,5,6-tridecylhydroquinone-i-alkanoate ( Via and ethyl acetyl, propyl, trimethyl ethane, H 〇 2 C _ CH 2 _ CH 2 _ 〇 烟, nicotine thiol or benzoyl; see above). If other compounds of the formula and/or ... 98122.doc • 25- 1378924 (n=0, 1 or 2) are used, a small amount of the compound of the formula V&VI may also form a by-product.

PTMHQ/PTMHQA and its isomers represented by the formulae Va and Via (see above) produce an intermediate of α-tocopherol or an alkanoate thereof (final product). Depending on the activity of the catalyst and the reaction conditions, the reaction proceeds to give the final product (steps a & b of Process 2) or slow enough to allow the intermediates to be separated (step a) of Method 2 only. The same applies to steps a and b of the method. In a preferred embodiment of Process 1 and Method 2, TMHQ reacts better with pH and/or 1? The reaction is conveniently carried out under an inert atmosphere, preferably a gas of nitrogen or argon. Preferably, the S-reaction is carried out at an absolute pressure of at least 1 bar, more preferably from about Μbar to about 20.0 bar absolute, even more preferably from about 1.1 bar to about 6.00 bar absolute. More advanced, preferably from about 1.7 to about 5.1 bar absolute, preferably from about 2 Torr to about 3.6 bar absolute. Since the reaction is carried out under reflux, the reaction temperature depends on the pressure used, 98l22.doc -26. 1378924 and / or η. Accordingly, the reaction temperature is suitably from about 1 to about 'preferably from about 9 (rc to about 160 t, more preferably from about (1) to about 16 ° C and most preferably from about 125 to about 15 (TC.) The organic solvent is a non-f-sub-polar organic solvent such as an aliphatic tobacco, a toothed aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, and a mixture. A preferred example of the aliphatic hydrocarbon is straight Chain, branch or ring, hydrazine, a) soil. 15_Zorane. Particularly preferably linear, branched or cyclic C6• to Ci〇 bond, especially preferably hexane, heptane, octane and Cyclohexane or a mixture thereof. Preferred examples of the toothed aliphatic hydrocarbon are mono- or polydentate linear, branched or cyclic c, · to C15-alkane', and particularly preferred examples are single or polychlorinated Or desertified straight chain, branched chain or ring CV to c15. Chain burning. More preferably single or polychlorinated direct bond, branch or ring C, to Cl5. Chain m is • three gas, burning, α two Chlorobutyl, methylene chloride and dibromomethane. #优选的优选的优选的苯苯,苯苯、o,······························· Trimethylbenzene (P CUmene) 'Nye and its mixture, particularly preferably toluene. Preferred examples of the functional aromatic hydrocarbons are mono- or poly-benzene. Especially preferred, chlorobenzene, 1,2·dichlorobenzene, ^3. Dichlorobenzene, bisphenol benzene. The preferred non-polar solvent varies with different catalysts: right InCl3 is used as a catalyst, (iv) toluene and money are preferred solvents; :: preferably heptane. If Sc ( When 〇Tf)3 is used as a catalyst, it is the best 'grain toluene. If Fe(FeC12VHCl(g)("g"= gas) catalyst system is used, the best solvent is also toluene. 98J22.doc -27 1378924 Right using a system of ZnCh/hydrochloric acid or ZnCl2/HCl(g) ("g"= gas), preferably step 1 of method 1 or method 2/2a) such as Ep 〇ι〇〇471 A1 In the presence of an amine as disclosed in the last paragraph of page 4 and the fifth paragraph, which is incorporated herein by reference. This method can also be described as a formula III or formula with amine or NH3 as described in DE_〇s % 06 830 The iv compound is subjected to a pretreatment such as IP or PH. If the amine is from about 0.05 to about 5.0% by weight, preferably about the weight of the compound m or IV used, 〇" to about 2 〇% by weight, the optimum solvent for the reaction with Zn(II) catalyst system is benzene. If no amine is present, then the best reaction is carried out with Zn(H) catalyst system. The solvent is heptane. The compound of formula II or II a (best: 1^11 (^ or 1^11 (^^(^)) and the molar ratio of the compound of formula III or IV used in any reaction The mixture suitably varies from about 0.95:1 to about 1:1", preferably from about 1:1 〇1 to about 1:1.05. The amount of the aprotic non-polar organic solvent to be used is preferably from about 0.1 ml to about 6.0 ml, preferably from about 5 ml to about 3, based on 1 mm of the compound of formula 111 or 1 V used. 〇ml. The relevant amount of catalyst, based on the compound of any of the nia IV used, will depend on the catalyst system and reactants employed. Conveniently, the catalyst phase is opposed to at least 0.01 mol% based on any compound III or IV used. Generally, the relative amount of catalyst varies from about 〇1 to about 3 〇 mol%. The optimum relative amount of catalyst will vary from catalyst to catalyst and will depend on the reactants: If InCl3 is used as the catalyst, it is preferably used in any of the compounds 98122.doc -28- 1378924 111 or 1V used. For example, from a relative amount of from about 0.1 mol% to about 2.5 mol%, particularly preferably from about 0.1 mol% to about 2.0 mol%, more preferably from about 〇1 to 1〇m〇 A relative amount of 1%, even more preferably from about 〇1 to about 0 5 m〇l%. If Sc(OTf)3 is used as the catalyst, it is preferably present in a relative amount from about 〇〇5 mol% to about 2. 〇mol% of any compound III or IV used. From about 0.075 to about 1.5 mol% relative! 'More preferably from about 〇. 1 to about 丨〇mol% relative amount. _ If Fe and/or FeCh is used in combination with HC1 as a catalyst, it can be, for example, in DE-OS 21 60 1〇3 (page 5, end of paragraph 2 and patent application scope 9) and in US 3,789,086 (third The amount described in Block, lines 27-60) exists. ψ If Zn(II) and/or znCh is used as the catalyst, it can be, for example, in Examples 1 to 12 of US 2,411,967, in US 3,708,505 (page 1, right shed '26-44 line), DE-0S ι96 54 〇38 (page 2, line 55_63; page 3 'line 4-6; page 3' line 60 to page 4, line 19; line 4, line 29-38) appealing to the EP -A 0 1〇〇471 (page 7, lines 19-24), in DE-OS 26 06 830 (page 4 'last two lines to five top two paragraphs), in us 4,191,692 ( The second column, lines 49-62) exists in the amount described. The phrase "amount of catalyst" in this context is understood to mean the weight of pure Lewis acid or pure Brillis acid, although the catalyst may be impure, ie in the form of an adduct combined with a gluten agent and/or It should also be understood as being present in the form of a solution/suspension. The relative amount of Brunswick acid is also dependent on the acid used and can be selected accordingly. 98l22.doc -29- 1378924 The reaction can be carried out batchwise or continuously, and is generally operated in a very simple manner, for example (1) by adding such a state in portions or continuously in a solvent (preferably in such a state) of formula III Or a mixture of a compound of IV to a Lewis acid, a compound of formula Ila/II (preferably: TMHQ or TMHQA; optimal: TMHQ or TMHQ Ac) and a solvent. If a catalyst system consisting of a Lewis acid and a Brilliant acid is used, the compound of Bronsted acid to Lewis acid, Formula IlaAI is added continuously or in batches (preferably continuously) (best: TMHQ or TMHQA(c)) And a mixture of solvents. Alternatively, (ii) a Lewis acid in such a state or in an aqueous solution and a compound of the formula III and/or IV in such a state or dissolved in a non-polar solvent (preferably in such a state) to a compound of the formula Ila/II may be continuously added (best: TMHQ or TMHQA(c)) and solvent. The Brunsert acid is then added to the mixture continuously or batchwise (preferably continuously). Conveniently, the compound of formula III or IV is added continuously to the compound of formula Ila/II (best: TMHQ or TMHQ(c)), preferably from about 30 to about 150 minutes, in about 15 to about 180 minutes. Preferably, it is within about 45 to about 13 minutes. The Lewis acid is preferably added in one portion, i.e., in its entirety, to a mixture of the compound of formula Ila/II (best: TMHQ or TMHQA (c)) and a solvent. After the completion of the addition of the compound of the formula III or IV (in a non-polar solvent), the reaction mixture is further heated at the reaction temperature for about 10 minutes to about 360 minutes, preferably about 30 minutes to about 240 minutes. This treatment can be achieved by a procedure known in organic chemistry. Step b of Method 2, Step b of Method 2a 98122.doc • 30-1378924, it is easy to see that in the method of the present invention, a compound of Formula II or Ila and R1 and R3 is used (such as pTMHQ or Its isomers) as a reactant to produce maternal phenol or tocopherol such as alpha-tocopherol, and when using formula II and indole, propyl sulfonyl, trimethylethenyl, h〇2C_CH2_Ch2_CO A compound of nicotine sulfhydryl or benzhydryl group and n = 3 will give the corresponding parental saponin or tocopherol alkanoate such as tocopherol alkanoate. For the preparation of alpha-tocopherol or tocopherol alkanoate, pTMHQ or PTMHQA prepared by any of the methods known to those skilled in the art, and optionally one or more isomers thereof, may be used. A variety of isomeric systems are obtained as starting materials in the preparation of PTMHQ or PTMHQA as a minor by-product. This ring closure reaction can use a compound of the formula π described above (for example, TMHQ: Formula II and R = hydrogen; 4TMHqa: Formula π and B-Mercapto, Propionyl, Dimercapto, and H〇2C-CH2_CH2 The catalyst having the same reaction as -CO, nicotinyl or phenylhydrazine or Ila with a compound of the formula III and/or a compound of the formula IV is carried out under substantially the same reaction conditions. Thus, in the case of, for example, PTMHq or PTMHQA and optionally one or more of the isomers, the reaction time of step a can be simply extended according to the step & production, that is, step b is sufficient, that is, the reaction time is extended from about 3 minutes to about 24 minutes, increasing the amount of catalyst and / or increasing the reaction temperature. Processes 3 and 3a This reaction can be carried out under substantially the same reaction conditions using the same catalyst as in step a) of the methods 2 and 2a described above. "The type of catalyst, 98122.doc • 31 · 1378924 catalyst amount and reaction Depending on the temperature, the reaction is terminated in the intermediate product of formula Ia/I or is carried out to the final product of formula VII/VIIa. Method 4 This reaction can be carried out under substantially the same reaction conditions using the same catalyst as in the steps a) of the methods 2 and 2a described above. Regardless of the nature of the catalyst, the amount of catalyst, and the reaction temperature, the reaction proceeds to the final product of Formula X.

Method 5A According to another aspect of the invention, a compound of formula VIIc, such as, for example, α-sodium® tocopherol or γ-tocopherol or any other as described in DE-OS 21 60 103, page 5, paragraphs 2 and 4 The tocol described in the above can be converted into its alkanoate (compound of formula Villa), such as its acetate, which is treated by deuteration in the presence of a Lewis acid as a catalyst. Preferably, it is at an absolute pressure of less than 0,9 bar, or under pressure, preferably at an absolute pressure of at least bar. More preferably, the absolute reaction pressure is from about 2 bar to about 9 bar (even more preferably from about 0.1 bar to about 0.9 bar, most preferably from about 2 bar to about 9 bar) and from about 1.1 bar to about 1〇.〇巴 (even better from about hlba to 6 〇巴, even better from about 1 · 1 bar to about 5 〇, preferably from about 丨丨巴. to 3.0 bar) change. · Therefore, the present invention is also directed to a method for preparing a simmered acid vinegar in the presence of a Lewis acid as a catalyst under reduced pressure, preferably at less than 巴9 bar. Absolute pressure, or in dust. Lower, preferably at least M bar absolute pressure - down. 98122.doc 32. 1378924 According to the invention, the deuteration can be carried out using conventional deuteration agents such as acid anhydrides or toothings. These examples are anhydrides or halides of alkanoic acids such as acetic acid, propionic acid, tridecyl acetic acid, succinic acid, nicotinic acid and benzoic acid. Acetic anhydride or acid hydrides, especially acetic anhydride, are preferred. The molar ratio of the compound of formula vile to the oximation agent in the reaction mixture is suitably from about 1:1 to about 1:5, preferably from about 1:1 to about 1:3, more preferably from about 1:1.1. Approximately 1:2 » Appropriate Lewis acids are indicated above. The amount of Lewis acid used as a catalyst is based on less moles of reactants (i.e., compound of formula Vile or oximation agent) and can range from about 0.006 mol% to about 2.0 m〇1%, Preferably, from about mol75 mol% to about 丨5 mol%, more preferably from about 〇1 m〇1% to about mol%, the Lewis acid is operated in a batch mode. For continuous operation, the amount of catalyst will be adjusted according to the size of the reactor and the flow rate of the reactants. It should be understood that the determination of the appropriate values for the numerical values used for batch operations is within the ordinary skill range. As in other methods of the invention, the Lewis acid is added in one portion, i.e., in its full amount. Preferably, the catalyst is added as a water soluble or suspension. The temperature of the deuteration depends on the temperature of the catalyst system used and the reactants (produced from the previous method steps). The deuteration reaction can generally range from about 20 to about 200. (: carried out at a temperature, preferably about 6 Torr to about, more preferably about 80 to about 16 (rc. When the indium (ruthenium) salt is used as a catalyst, the oximation reaction is preferably less than 12 〇. It is preferably carried out at a temperature of 98122.doc -33 - 1378924 from about 15 to about 120 C, preferably at room temperature, and also 郎A "曰A from about 15 to about 40 ° C. Preferably, the reaction is Substantially no additional organic solvent is present. In the context of the present invention "substantially free of additional organic solvents" means that substantially no organic solvent is present during the reaction and the organic solvent is not added arbitrarily. However, there may be trace amounts of The organic solvent is present as an impurity in the starting material: or the catalyst. In other words, the reaction is carried out substantially, that is, except for the compound of the formula Vile, the oximeing agent and the catalyst, 'no other compound is intended to be the reaction, so that the reaction Initially, the amount of any terpene substance other than the starting material, the formula, the compound and the brewing agent, and other than the catalyst in the reaction mixture is < 5% by weight, preferably % by weight, more preferably external weight.%, and no additional compound is added during the reaction. Alternatively, the reaction may also be carried out in the presence of an additional organic solvent, for example, a mouth-to-bit ratio. The reaction is conveniently carried out in the presence of an inert atmosphere, preferably a gas or chlorine gas. According to the present invention, the special feature of the deuteration is when the use of palmitic tocol and fertility, for example (enantiomerically pure form and the growth of the hatch, the indium as a catalyst) In the presence of a salt and at a π degree below (10), for example, from about 2 (TC to about 12 〇t, substantially no difference:: is used. Therefore, if used, for example, Fertility as the starting point of the 夤 'is obtained (full 杓-tocopherol alkanoate. In the method 5 特别 particularly better implementation of the financial, ~ fertility ^ ^ type touch, 98122.doc -34 · 1378924 n= 3; see above), /5-tocopherol (formula Vile, XkxLCHs, X2=H and n=3), γ-tocopherol (formula Vile, X2=X3=CH3 'X^H and n=3) and δ - Tocopherol (formula Vile, 丨=乂2=11, X3=CH3 and η=3), preferably α-tocopherol and/or 3-tocopherol, more preferably α-tocopherol Fertility a phenol alkanoate (formula V111/VIIIa, η=3 and R, X1, X2, X3 have the same meanings as above and a preferred choice of the compound). More preferably, especially in the indium (ΙΠ) salt as a catalyst The preferred acetate is prepared in the presence and at a temperature below 120 ° C, preferably at room temperature, i.e. at a temperature between 15 and 40 ° C.

Process 5B is carried out using the same catalyst as described above for Process 5 A under the same reaction conditions. Method for preparing α-tocopherol or its alkanoate formulation

The alpha-tocopherol or its alkanoate obtained by any of the methods of the present invention can be further formulated by any method known to those skilled in the art, for example, as described in US 6,162,474, US 2001/0009679. US 6,180,130 ' US 6,426,078 ' US 6,030,645 ' US 6,150,086 ' US 6,146,825, US 6,001,554 ' US 5,938,990 ' US 6,530,684 > US 6,536,940, US 2004/0053372, US 5,668,183 ' US 5,891,907 ' US 5,350,773 ' US 6,020,003 ' US 6,329,423 'WO 96/32949, US 5,234,695, WO 00/27362, ΕΡ 0 664 1 16 , US 2002/0127303, US 5,478, 569 > US 5,925,381 ' US 6,651,898 ' US 6,358,301 ' 1^ 6,444,227, \¥〇96/01 103 and 胥〇 The method disclosed in 98/15195 is 98122.doc -35· 1378924. The following examples further illustrate the invention. EXAMPLES A small amount of the following by-products were obtained in the following examples: PTMQ: Phytyl-trimethyl hydrazine:

PTD: phytoene = dehydration by-product of IP (which can be easily separated); BZF: benzofuran:

Phyto-phenylene compounds and their double bond isomers (which can be easily separated):

The products were analyzed by gas chromatography using internal standards. Jeffsol EC50® is available from Huntsman Corp., PO Box 15730 Austin, Texas, USA/Antwerp 2030, a solvent blend of Belgium consisting of ethylene carbonate and propylene carbonate in a volume ratio of 1:1. If the example is carried out under "atmospheric pressure" (comparative example), it is indicated that the reaction is carried out at a pressure of from about 0.96 bar to about 1.03 bar. 98122.doc -36- 1378924 Examples 1-32: InCl3 or In ( OTf)3 as a catalyst method Example 1-14: Preparation of PTMHQ Example 1-3: InCl3 as a catalyst in the presence of a catalyst as InCl3 (the amount of which is given in Table 1) at atmospheric pressure, 12.88 mmol TMHQ and 8.58 Methyl IP was reacted in the solvent or solvent system given in Table 1. The reaction time was 2 hours. Further details and results are shown in Table 1. Examples 4 and 5: In(OTf)3 was used as a catalyst in the incremental increment of In as a catalyst ( OTf)3 (see Table 1) was reacted in a mixture of 12.88 mmol TMHQ and 8_58 mmol IP in 20 ml heptane and 20 ml Jeffsol EC50® in the presence of atmospheric pressure. Further details on the reaction conditions and results are shown in Table 1. 1 : The amount of THMQ is 12.88 mmol in all conditions, and the amount of IP is 8.58 mmol in all cases. Example catalyst catalyst amount [mol%] Solvent reaction temperature reaction time [hour] PTMHQ yield [%] IP meter) 1 InCl3 0.1 20 Ml Jeffsol EC50®+20ml Heptane 94〇C 2 47.2 2 InCl3 2.0 20 g butyl acetate reflux 2 60.2 3 InCl3 2.0 20 g diethyl ketone reflux 2 80.3 4 In (〇Tf)3 0.01 20 ml Jeffsol EC50®+ 20 ml heptane 94 〇 C 12 58.7 5 In (〇Tf) 3 1.0 20 ml Jeffsol EC50® + 20 ml heptane 22 〇 C 100.5 90.5 Examples 6 and 7 : InCl 3 as a catalyst

The amount of TMHQ was reacted with 17.17 mmol of IP in 45 ml of toluene at 110 ° C 98122.doc -37 - 1378924 at atmospheric pressure in the presence of 1.0 mol% InCl3- as catalyst. Further details and results are presented in Table 2. Example 8: In(OTf)3 was used as a catalyst to give TMHQ (38.63 mmol) and IP (25.75) at atmospheric pressure and 22 °C in the presence of 1.0 mol ° / 〇 In (OTf) 3 as a catalyst (in terms of IP). M, 97%, added over 1 hour) reacted at a molar ratio of 1.5:1. Further details and results are shown in Table 2. After separating the hept phase and washing the heptane phase with Jeffsol EC50® (60 ml), the resulting mixture (suspension in heptane) was filtered under vacuum. The paste-like almost colorless solid was analyzed by GC. Example 9: In(OTf)3 was used as a catalyst in the presence of 1.0 mol% In(OTf)3 as a catalyst (in terms of IP) at 22 ° C and atmospheric pressure to give TMHQ (24_691 g, 161.1 mmol) and IP ( 3 8.83 3 m Bu 107.4 mmo BU 97%, added during 1 hour) Reaction with a molar ratio of 1.5:1. Further details and results are shown in Table 2. After separating the heptane phase and washing the heptane phase with Jeffsol EC50® (250 ml), the resulting suspension in heptane was filtered under vacuum. The paste-like almost colorless solid was analyzed by quantitative GC. Table 2: The amount of catalyst in all conditions is 1 · 0 mol% (in terms of IP). Example 6 7 8 9 Amount of TMHQ [mmol] 17.17 25.76 38.63 161 Amount of IP [mmol] 17.17 17.17 25.75 107 Catalyst InCl3 InCl3 In(OTf)3 In(OTf)3 Solvent Alum Benzene 60 ml Jeffsol EC50® + 60ml Heptane 250 ml Jeffsol EC50® + 250 ml Glowing reaction temperature 110 ° C litre 22〇C 22〇C Reaction time [hours] 10 2 92 192 PTMHQ yield (by IP) 63.9 73.6 88.7 59.7 98122.doc - 38- 1378924 Examples 10-14 200 mmol TMHQ with 200 mmol IP (Example and 13) and 203 mmol IP, respectively, in the presence of increasing amounts of In(OTf) 3 (Example 10) or InCl 3 (Example i 14) as catalyst (Examples 11, 12 and 14) were reacted in 100 ml of an organic solvent. Examples 10 and 14 were carried out under pressure, whereby Examples 11-13 were carried out under atmospheric pressure. The reaction temperature, pressure, reaction time and solvent type are shown in Table 3. Table 3: In all cases, the amount of solvent is 1 〇〇 ml. The amount of TMHQ was 200 mmol in all conditions. In Examples 11, 12 and 14, an IP excess of 1.5 mol% in moles based on the amount of TMHQ was used. The PTMHQ yield is based on IP. Example IP amount [mmol] Catalyst and its amount [mol% l Solvent reaction temperature pressure [bar] Reaction time PTMHQ Yield [%] 10 200 0.001 In (〇Tf)3 Benzene 137 〇C 2 3 hours 35.0 11 203 0.25 InCl3 Geng Burn 98〇C 1 4 hours 61.2 12 203 0.5 InCl3 Geng Burn 98〇C 1 3 hours^8.8 13 200 1.0InCl3 Heptane 98〇C 1 2 hours 43.4 14 203 2.0 InCl3 CH2C12 40〇C + 86〇C 4 23 hours + 22 hours 52.9

Examples 15-29: Preparation (full racemization) _TCP Example 15-16: Preparation at atmospheric pressure (full racemization) - TCP in a 250 ml Biichi reactor or equipped with a stirrer, thermometer, pressure indicator, Dean-Stark separator And an autoclave with a reflux condenser, at a temperature of 114 ° C under a continuous stream of nitrogen and at an absolute pressure of 1.0 bar, 30.447 g (200 mmol) of TMHQ (99.97%), a defined amount of InCl3 (see Table 4; IP meter) and 100 ml of stupid. Add 74.035 98122.doc •39- 1378924 at a feed rate of 1.234 ml per minute

1111 (20〇111111〇1)1? (94.6%). Approximately 3.61111 water was collected until the end of the reaction. After completion of the addition, the reaction mixture was allowed to pass at 114 C for 1 hour and η cooled to room temperature. The reaction mixture was concentrated under reduced pressure (45 ° C at 95 to 15 mbar). Obtain (full racemization)-TCP as a viscous oil. The results are shown in Table 4. Examples 17-18: Preparation under pressure (full racemization) - TCP Examples 15 and 16 were repeated, but the reaction was carried out at 137 ° C under an absolute pressure of 2 bar. After 1 hour, the reaction mixture was cooled to room temperature at 13 7 ° C and the pressure was released at room temperature. The results are shown in Tables 4 '5 (Example 18 only) and 12 (Example 18 only).

Example 19: Preparation under pressure (full racemization) - TCP In a 250 ml Biichi reactor or autoclave equipped with a stirrer, thermometer, pressure indicator, Dean-Stark separator and reflux condenser, at i47 ° C, Under continuous nitrogen flow and at an absolute pressure of 3.4 bar, 30.447 g (200 mmol) of TMHQ (99.97%), 5 ml of InCl3 (0.2 Μ aqueous solution, 0.5 mol%, 1 mmol) and 100 ml of toluene were heated. 75.304 ml (203 mmol) of IP (94.6%) was added at a feed rate of 0.605 ml per minute. Approximately 3.6 ml of water was collected until the end of the reaction. After the addition is completed, at 147. (: The reaction mixture was stirred for 1 hour and cooled to room temperature. The pressure was then released. The reaction mixture was concentrated under reduced pressure (45 at 110 to 15 mbar). The yield was 92.0% - by IP. The results are shown in Tables 4 and 6. 7, 8, and 12. Table 4: Comparison between atmospheric pressure and pressure test using I11CI3 as a catalyst in toluene. In all cases, IP conversion is 100 〇/〇. 98122.doc •40 · Example catalyst catalyst amount [mol%] Solvent reaction temperature 纟 it] Pressure [bar] TCP yield [%] = TCP selectivity [%] 12 InCl3 0.5 Geng gauge 98 1.0 18.5 15 InCl3 0.5 Toluene 114 1.0 59.8 16 InCl3 2.0 Toluene 114 1.0 90.1 17 InCl3 0.5 toluene 137 2.0 81.2 18 InCl3 2.0 toluene 137 2.0 95.7 19 InCl3 0.5 heptane 147 3.4 92.0 Examples 20 and 22 (*): Prepared with InCl3 as a catalyst in different solvents at a pressure of 1378924 (full racemization) - TCP φ at 137 ° C in 100 ml of toluene or at 147 ° C in 100 ml of heptane, 200 mmol TMHQ with 203 mmol IP (corresponding to molar excess 1.38 mol% - by TMHQ Measure) Add IP during 120 minutes. Then the mixture is further reacted 60 minutes. All yields and selectivity (given in Table 5) are based on IP. See also Table 6.

Examples 21, 23 and 24: using different amounts of indium salt as a catalyst and preparing under pressure (full racemization) - TCP in 1371 in 100 ml of toluene or at 147 ° C in 100 ml of heptane, making 200 mmol TMHQ reacted with 200 mmol IP. Add IP during 60 minutes. The mixture was then further reacted for 60 minutes. All yields and selectivity (given in Table 5) are based on IP. : Table 5: Effect of indium salt counterion. In all cases, the amount of catalyst was 2.0 mol%, based on IP. In all cases, the IP conversion rate is 100. /. . * IP molar excess 1.38% 98122.doc 41 1378924 Example catalyst solvent IP addition time [hours] Pressure [bar] TCP yield [%] = TCP selectivity [%] 18 InCl3 Toluene 1 2.0 95.7 20* InCl3 Toluene 2 2.0 95.5 21 InCl3 heptane 1 3.4 89.5 22* InCl3 heptane 2 3.4 93.9 23 In(OTf)3 toluene 1 2.0 72.3 24 In(OTf)3 heptane 1 3.4 65.6 in two solvents (heptane and stupid) In the case of using InCl3, an excellent yield was obtained. Since a 28 to 30% difference in selectivity is observed, the selectivity of the catalyst for forming the desired 6-membered ring product (full-race)-TCP is extremely high compared to the result of using In(OTf)3. . It has also been found that a slight excess of IP (+1.38 mol%) in toluene results in a better yield of reaction with IP and TMHQ relative to the molar amount (see Table 5, Example 22). In fact, (full racemization)-TCP can be isolated after treatment to give a 93.9% yield. It is emphasized that a 1.5/1 TMHQ/IP ratio is required at atmospheric pressure, whereas under pressure, the molar ratio is sufficient to produce a desired color full ring compound (full racemization)-TCP in a significant yield. Notably, the ratio of TMHQ used for these reactions under pressure is 20 times higher than atmospheric pressure (4 mol/L instead of 0.2 mol/L) and does not affect the yield of the reaction.

Example 25: InCI3 was prepared as a catalyst under pressure (full racemization) - TCP 200 mmol TMHQ was reacted with 203 mmol IP at 137 ° C in 1 〇〇 ml 曱. Add IP during 120 minutes. The reaction mixture was then further reacted for an additional 60 minutes. Yield - in terms of IP - is given in Table 6. See also Table 7.

Example 26: InCl3 as a catalyst and prepared under pressure (full racemization) - TCP 98122.doc • 42- 1378924 200 mmol TMHQ was reacted with 203 mmol IP at 137 ° C in 100 ml of toluene. Add lp during 120 minutes. The reaction mixture was then further reacted for an additional 566 minutes. Yield - in terms of - is given in Table 6. Example 27: InC丨3 as catalyst and prepared under pressure (full racemization) - TCp 200 mmol TMHQ and 203 mmol IP at 147 ° C in 100 ml toluene The reaction was carried out. IP oxime was added during 120 minutes and the reaction mixture was further reacted for an additional 120 minutes. Yield _ in 1 Å - given in Table 6. Table 6: Effect of InC 3 amount. Conversion rate of ip under all conditions 1 〇〇0/〇. Example InCl3 amount [mol%] Solvent pressure [bar] TCP yield [%] = D-CP selectivity [%] 12 0.5 heptane 1.0 18.5 19 0.5 Geng 3.4 92.0 20 2.0 A stupid 2.0 95.5 22 2.0 Geng 3.4 3.9 93.9 25 0.5 Toluene 2.0 90.2 26 0.25 Toluene 2.0 85.1 27 0.25 Heptane 3.4 81.5 When the amount of I11CI3 is reduced to 〇·25 mol %, good yield (full racemization)-TCP can be obtained (see Table 6 'Examples 26 and 27). However, a longer reaction time (e.g., up to 566 minutes in Example A, Example 26) is required to obtain an almost complete ring closure. Obviously, especially in heptane, 〇·5 is used. The best result for (full racem) _TCp can be obtained with mol% to 2% of catalyst I11CI3 (selectivity (yield)) In toluene and heptane, the desired color-filled product (all-racemic)-TCP was isolated to give a yield of 90.2 up to 96.0%. Example 28: in a ring at an absolute pressure of 4.0 bar Prepared in hexane (full racemization) _ 98122.doc -43· 1378924

TCP

200 mmol TMHQ was reacted with 203 mmol IP at an absolute pressure of 4.0 bar at 135 ° C in 100 ml of cyclohexane in the presence of 0.5 mol % InCl 3 (by IP). Add IP at 120 minutes. The mixture was then further reacted for 380 minutes. The (all-raceset)-TCP yields given in Table 7 are based on IP.

Example 29: Preparation in hexane under pressure (full racemization) - TCP In 100 ml of hexane, 200 mmol of TMHQ was reacted with 203 mmol of IP in the presence of 0.5 mol% of InCl3 (in terms of IP). IP was added at 120 ° C and at an absolute pressure of 4.0 bar at 120 minutes. The mixture was then further reacted at 125 ° C and an absolute pressure of 4.0 bar for 180 minutes and further reacted at 135 ° C for 206 minutes at an absolute pressure of 5.1 bar. The (all-raceset)-TCP yields given in Table 7 are based on IP. Table 7: Effect of solvent. The conversion rate of IP is 100% in all conditions. Example solvent reaction mixture temperature pressure [bar] TCP yield [%] = TCP selectivity [%1 19 Geng 145 〇 C 3.4 92.0 25 Toluene 137 〇 C 2.0 90.2 28 Cyclohexane 135 〇 C 4.0 86.6 29 Pit 125 /135〇C 4.0/5.1 75.1 One of the advantages of heptane over toluene is that there are no by-products attributed to the solvent such as phyto-toluene compounds. Example 19 (-a)-19-e: Reproducibility All reactions were carried out in 100 ml of heptane at an absolute pressure of 3.4 bar and 147. The underarm was carried out with 200 mmol TMHQ, 203 mmol IP, 0.5 mol% InCl3. 98122.doc -44* 1378924 Add ip during 120 minutes. The reaction time is 6 minutes. All yields are based on IP. The results are summarized in Table 8. Table 8: Test Reproducibility, Total Conversion of IP: Example 丁0卩 Yield [%]=TCP Selectivity [%] 19(-a) 92.0 19-b 91.8 19-c 90.6 19-d 92.3 19- e 91.2 Since only the maximum difference of 1〇4% was observed in the five trials with an average yield of 91.6%, a good reproducibility was found.

Example 30-37: Method for Sc(OTf)3 as Catalyst Example 30-31: Azeotropic Removal of Water Preparation (Full Race)_TCP In a Biichi Reactor with Dean-Stark Separator, 200 mmol TMHQ and 200 mmol IP was reacted in 100 ml of toluene in the presence of 0.1 mol% Sc(OTf)3 (in ip). Ip was added during the 60 minutes at the temperature and pressure listed in Table 9. The mixture was then further reacted at the same temperature and pressure for 60 minutes. The yield and selectivity of (all-racemic)-TCP listed in Table 9 are in terms of IP.

Example 32: Preparation without azeotropic removal of water (full racemization) _tcP In a high pressure dad reactor, 200 mmol TMHQ and 200 mmol IP in the presence of IP·0·1 mol% Sc(OTf)3 in 100 ml A Stupid reaction. IP is added during 60 minutes and at an absolute pressure of 3.6 bar and at a temperature of 140 °C. The mixture was then further reacted at the same temperature and pressure for 60 minutes. The yield and selectivity of (all-race)_TCP listed in Table 9 are in terms of IP. 98122.doc 45 · 1378924 Example 33: Non-azeotropic removal of water (full racemization) - Preparation of TCP In a 250 ml high pressure helium reactor equipped with a mechanical stirrer, thermometer and pressure indicator, 34.396 g (221 mmol) ) TMHQ (98%), 1 mmol LV (: (0 £ £') 3 (0.5 111 〇 1% - in 1 Å) and 5 〇 1111 曱 benzene at a pressure of 5.6 bar absolute in a nitrogen atmosphere 140 ° Heating at C. 72.350 ml (200 mmol) IP (97%) was added at a feed rate of 2.412 ml per minute. After complete addition the reaction mixture was stirred at 140 ° C for one hour, cooled to room temperature and reached room temperature. The pressure is released. The reaction mixture is concentrated under reduced pressure (45 ° C, 95 to 15 mbar) to obtain a viscous oil (94.76 g) and analyzed by quantitative GC. (IP) The yield of -TCP was 81.4%.

Examples 34 to 35: Azeotropic removal of water preparation (full racemization) - TCP Examples 30 and 31 were repeated except that 1.0 mol% Sc(OTf)3 was used instead of 0.1 mol% Sc(OTf)3. See Table 9 for the yield and selectivity of IP (full racem)-TCP. Example 36 Example 35 was repeated but the reaction was carried out at a higher temperature and higher pressure. Details and results are shown in Tables 9 and 12. Example 37: Water was not azeotropically removed (preparation of the complete racemic was repeated Example 32, but using 1.0 m〇i〇/0 Sc(OTf)3 instead of using 〇] mol% Sc(OTf)3. The yield and selectivity of (full racemization) _TCp are shown in Table 9 〇 Table 9: Comparison of the use of Sc(〇Tf)3 as a catalyst in toluene at atmospheric pressure and low pressure test. 98122.doc •46- 1378924 Example Sc(OTf)3 Amount fmol%] Azeotropic removal water pressure [bar] Reaction mixture temperature TCP yield [%] = TCP selectivity p/〇i 30 0.1 is 1.0 110 ° C 78.2 31 0.1 is 2.0 137 〇C 74.5 32 0.1 No 3.6 140°C 72.6 33 0.5 No 5.6 140°C 81.4 34 1.0 Yes 1.0 110-117°C 80.7 35 1.0 Yes 2.0 137〇C 81.6 36 1.0 Yes 2.2 150°C 84.0 37 1.0 No 3.6 140 °C 78.8 Example 38-47: Method using Fe/HCl as catalyst Example 38: Preparation in a Btichi reactor (full racemization) - TCP φ equipped with a stirrer, thermometer, pressure indicator, Dean-Stark separator In a 500 ml Biichi reactor with reflux condenser, 91.3 g (595 mmol) TMHQ (99.5 ° / 〇), 0.16 g (2.86 mmol) iron powder and 137 g benzene at 1.9 bar absolute pressure The argon gas stream was heated to 14 〇〇c. When the temperature of the reaction mixture was 14 〇t, the hydrogenation gas was fed at a rate of 0.333 g per minute for 5 hours (saturated for 30 minutes, IP was added for 4 hours) Then further reaction was carried out for 30 minutes; a total of 1 〇〇g of HC1 gas was added to the reaction mixture over a period of 5 hours. After 30 minutes at 136. (: under a stream of vaporized hydrogen, and at an absolute pressure of 2.05 bar, 187 9 was added at 616111111 〇 1) 1 (97.5%) at a feed rate of 0.78 g per minute. The temperature of the reaction mixture was increased from 136 during the addition of mIP (4 hours) (: to 146 ° C until the end of the reaction, Only about 14 ml of the aqueous phase was collected. After the completion of the IP addition, the reaction mixture was at 146. (: further stirred for 30 minutes, then the hydrogen chloride stream was stopped, replaced with a stream of argon and the solution was cooled to room temperature. The pressure was released. The reaction was combined and concentrated under reduced pressure (45 C '95 to 15 mbar) to obtain a viscous oil 98122.doc • 47· 1378924 (270.2 g) and analyzed by quantitative gc. The total yield (full racemization)-TCP yield was 91.5%.

Examples 39-42: Preparation under pressure (full racemization) - TCP Repeat Example 38 using the same TMHQ, ip, and Fe amounts. However, the amount of HC1 and the time of addition of 1P are different. The pressure at which the reaction proceeded was also slightly different in Examples 39-41. Further details and results are shown in Tables 1 and 13 (Examples 41 and 42 only).

Examples 43-46: Preparation at atmospheric pressure (full racemization) - TCP In a Biichi reactor with a Dean-Stark separator, 600 mmol TMHQ and varying IP (see Table 1 〇) at 137 g toluene (Example 48 only) And Example 49: 171.1 g toluene) was reacted in the presence of varying amounts of iron powder and the fed HC1 gas (see Table 10). HC1 gas was added to TMHQ in toluene at a feed rate of 0 333 g per minute. The mixture of TMHQ and toluene is saturated with HC1 for 30 minutes. After that, in the time listed in Table 1 ,, ip is added under the HC1 flow under the absolute dust of 1. The total mixture is added after the IP is added. The reaction was further carried out for 30 minutes under temperature and pressure and continued flow of HC1. The HC1 stream is then stopped and the reaction mixture is processed. The yield and selectivity of the (full-race)_TCP listed in the table are in ip. Example 47: Prepared under pressure (completely repeating Example 46 but the reaction was carried out at an absolute pressure of 2 to 1 bar instead of 1. 〇巴. Further details and results are shown in Table 表. Table 10: in toluene (under reflux) A comparison between the test at atmospheric pressure (Examples 43-46) and the test under pressure (Examples 38-42 and 47) with Fe/HCl as the catalyst; the conversion of IP is 1% in all cases. Rate and selection 98J22.doc -48· 1378924 The selectivity is in ip. Example TMHQ/IP [mmol/mmol] Fe amount [mol%] HC1 [ΙΟ'3 kg] IP addition time [hour/s] Pressure [bar TCP yield [%]=TCP selectivity r%i 38 595/617 0.5 100.1 4 2 1 91.5 39 595/617 0.5 139.3 6 2 0 91.6 40 595/617 0.5 41.0 1 2 0 93.2 41 595/617 0.5 39.9 1 2 0 92.0 42 595/617 0.5 60.2 2 2 1 93.2 43 600/616 0.5 60.0 2 1 0 26.0 44 600/617 0.5 99.9 4 1 0 89.4 45 600/617 0.5 138.9 6 1 0 89.6 46 600/570 13.7 59.9 2 1 0 7.2 47 600/570 13.7 59.9 2 2 1 92.7 Example 48_53: Method using ZnCl2/HCl as catalyst

Example 48: Preparation in heptane in the absence of an amine at atmospheric pressure (full racemization) _TCP 322 mmol TMHQ and 320 mmol IP The reaction was carried out under reflux of 163.3 g of heptane in the presence of ZnCl 2 and HC 1 gas (see Table 11 for the amount of catalyst) as a catalyst. . The reaction was carried out at 1.0 bar. Further details and results are given in Table 11. Example 49: Preparation in heptane in the absence of an amine under pressure (full racemization) - TCP Example 48 was repeated, but the reaction was carried out at an absolute pressure of 2.1 bar instead of 1.0 bar. Further details and conclusions are given in Table 11 Example 50: Preparation in hexane in the presence of an amine under pressure (full racemization) _TCp equipped with a stirrer, thermometer, pressure indicator, Dean-Stark separator in 500 ml and In a Bachi reactor of reflux condenser, 60 g (394 mmol) of TMHQ (99.5%), 12·5 g (91.7 mmol) of ZnCl2, 1.2 g of tridecylamine and 177.7 g of hexane were placed in a continuous stream of argon and Heating to 92 ° C at an absolute pressure of 2.2 bar » When the temperature of the reaction mixture reaches 92 ° C, chlorination 98122.doc • 49 · 1378924 hydrogen gas is added to the reaction mixture at a feed rate of 0.035 g per minute To saturate the reaction mixture with HC1. (The hydrogen chloride stream is continuously fed during the addition of (7) and during the further reaction time, i.e., the HC1 gas is added within 25 hours). After 30 minutes, 122.6 g (403 mmol) of IP (97,5%) was added at a feed rate of 2.05 g per minute at a flow of hydrogen chloride at 94 ° C and an absolute pressure of 2.2 bar. The temperature of the reaction mixture during the IP addition increased from 94 to i 〇〇 ° C ° until about 7.4 ml of the aqueous phase was collected. After all IP was added, the reaction mixture was at 1 Torr. (: further stirring for 60 minutes, then stopping the flow of argon chloride (using a total of 5.3 g of hydrogenated gas in 2.5 hours), replacing it with a stream of argon and cooling the solution to room temperature. The reaction mixture was concentrated under reduced pressure (110 to 15 mbar at 45 ° C) to obtain a viscous oil (176.88 g) and analyzed by quantitative GC. (full racem) _ TCP yield to ip Calculated as 94.9%.

Example 51: Preparation in hexanes in the presence of an amine under pressure (full racemization) - TCP Example 50 was repeated except that 404 mmol was added instead of 403 mmol IP, and 49.9 g of HCl gas instead of 5.3 g of HCl gas was used. Further details and results are shown in Table 11.

Example 52: Preparation in Hexane in the presence of an amine at atmospheric pressure (full racemization) - TCP Example 51 was repeated using the amounts of TMHQ, IP, ZnCl2, tridecylamine and HCl gas listed in Table 11 Yin. However, the reaction was not carried out at 1.2 bar and at 1.0 bar. The results are shown in Table 11.

Example 53: Preparation in heptane in the presence of an amine at atmospheric pressure (full racemization) - TCP Example 51 was repeated using the amounts of TMHQ, IP, ZnCl2, tridecylamine and HCl gas listed in Table 11. However, the reaction was not carried out in hexanes at 98122.doc • 50-1378924, but in heptane. The results are shown in Tables 11 and 13 °. Table 11: Heptane under reflux (Examples 48, 49 and 53) using ZnCl2/HCIg as catalyst or hexane (Example 50_52) under reflux at atmospheric pressure (1.0 bar) Comparison of tests with tests under pressure (2.1-2.2 bar). 1P is added within one hour under all conditions. All yields and selection rates are based on IP. The conversion rate of IP is 1〇0% in all cases. Example TMHQ/IP [mmol/mmol] Z11CI2 Amount [mol%] (by IP) Thirteen leuco [10-33 kg] HC1 [10-3 kg ] Pressure [bar] TCP yield [%] = TCP selectivity [%] 48 322/320 18.3 0 39.9 1.0 75.9 49 322/320 18.3 0 40.0 2.1 86.6 50 394/403 22.7 5.3 2.2 94.9 51 394/404 22.7 1.2 49.9 2.2 94.1 52 394/402 22.8 '1.2 50.0 1.0 77.8 53 394/400 22.8 1.2 49.9 2.2 91.0 Example 18, 19-d, 23: Amount of by-products For the five tests, the exact analysis of by-products is given in the table. 12. Table 12: Comparison of the detailed results of Lewis acid as a catalyst and the selectivity. Example 18 19-d 23 34 36 TMHQ to IP amount rmmol/mmol] 200/200 200/203 200/200 200/200 200/200 Catalyst InCl3 InCl3 In(OTf)3 Sc(OTf)3 Sc(OTf)3 Amount of catalyst [mol%] 2.0 0.5 2.0 1.0 1.0 Solvent 曱 庚 庚 曱 曱 曱 曱 曱 曱 反应 反应 reaction temperature [°c] 137 147 137 110-117 150 Pressure [bar] 2.0 3.4 2.0 1.0 2.2 IP addition time [ Minutes] 60 126 60 60 60 Crude product [l〇Jkg] 94.42 92.96 101.4 90.22 94.69 DHTC according to GC verification [%1__ 0.00 0.15 0.00 0.00 0.00 According to GC verification BZF [%] 0.33 0.31 7.43 3.83 2.70 TCP based on GC verification [%] 87.28 86.84 61.45 76.72 76.40 TCP yield [%1 95.7 93.7 72.3 80.7 84.0 98122.doc 51 1378924 As stated, InCl3 has a higher selectivity for forming TCP than In(OTf)3 and Sc(OTf)3. Table 13: Comparison of detailed results and selectivity of a mixture of Brunswick acid and Lewis acid as a catalyst. Example 41 42 53 TMHQ to IP amount [mmol/mmoll 595/617 595/617 394/400 catalyst Fe+HCl Fe+HCl ZnCl2+HCl+ thirteenth amine catalyst amount [mol%] 0.5 Fe 0.5 Fe 23.0 ZnCl2 HC1 Gas amount [g] 39.9 60.2 49.9 Solvent toluene toluene toluene reaction mixture temperature 135-146 〇C 137-147 ° C 106-109. . Pressure [bar] 2.0 2.1 2.2 IP addition time 60 minutes 120 minutes 60 minutes crude product [10-3kg] 271.2 270.9 176.69 DHTC according to GC assay [%] 0.54 0.39 0.05 According to GC verification BZF [%] 0.24 0.38 1.23 TCP based on GC [%] 90.0 91.3 88.9 TCP Yield [°/〇] 92.0 93.2 91.0 Example 54: Preparation (all-raceo)-3,4-dehydro-α-tocopherol 15.22 g (99.2 mmol) TMHQ (99.2%), 29 mg (0.5 mmol) of iron powder and 70 ml of benzene were added to a 200 ml flask equipped with a Biichi reactor, and the resulting beige suspension was stirred at 750 rpm. The reaction mixture was heated to 1 Torr at a constant heating rate of 2 K per minute. HC1 was added at a flow rate of 33.8 ml per minute and argon was added at a flow rate of 3.5 mi per minute. After 45 minutes the reaction temperature reached 111 ° C and 31 〇 ig (102.4 mmol) of 1,2-deazaisophytol (97.3%; from Teranol in Lalden, Switzerland) at a feed rate of 0.138 g per minute at 225 minutes Added inside. During the addition of 1,2-dehydroisophytol, the solution was slowly distilled to maintain a constant solution volume throughout the period of 98122.doc -52 - 1378924. The reaction temperature also rose from 111 ° C to 157 ° C. After the 1,2·dehydro-isophytol was completely added, the reaction mixture was stirred at this temperature for 45 minutes and cooled to room temperature. When the heating is over, the HC1 flow is stopped and replaced with a stronger argon flow. The temperature of the reaction mixture after 1 hour was 60 °C. The reaction mixture was then concentrated under reduced pressure (601,300 to 18 mbar). The resulting oil was further concentrated under reduced pressure (60: (:, 0.3 to 0.1 mbar) for more than 2 hrs to afford crude product (45.6 g). Quantitative GC analysis of crude product indicated that it mainly contained TMHQ (25.6 %) and (all-raceo)-3,4-dehydro-indole:·tocopherol (21.1%). The crude product can be purified by two successive column chromatographys (first with ethyl acetate/hexane = l/9 (v/v; silicone 60 (Merck), particle size 0.063-0.2 mm) and finally with ethyl acetate / hexane = 1 / 丨 9 (v / v) to obtain (full race dehydrogenation - --tocopherol (5.23 g, GC 81.7%, 1 〇.0% isolated yield, 44.1% yield based on conversion).

98122.doc 53-

Claims (1)

1378924 X. Patent application scope: 101. 9. 0 3 Patent application No. 093137721 Chinese patent application scope replacement (September 101) 1. A method for preparing a color-filled derivative la, By reacting a compound containing 0 to 4 methyl groups, a total of 1 to 3 hydroxyl groups, and at least one unsubstituted position with a compound of the formula and/or hydrazine, wherein the unsubstituted position is in a hydroxyl group Neighborhood, R2 is a hydroxyl group, an ethoxylated group, a benzoquinoneoxy group or a halogen, η is an integer from 0 to 3, and R3 is hydrogen, ethyl hydrazino, propyl fluorenyl 'trimethyl ethinyl, h 〇 2C_CH 2 _ ch 2 _co Final inspection of thiol or benzoic acid, and X, X and X3 are each independently hydrogen or a sulfhydryl group, and the restriction condition is that if XI, X2 and X3 are both fluorenyl groups, then R3 is only ethyl fluorenyl group, propyl fluorenyl group, tridecyl acetyl group, H 〇 2C. -CH2-CH2-CO, terminally ground or alum, wherein the reaction is in the presence of a Lewis acid as a catalyst or a mixture of a Lewis acid and a Bronsted acid. · Perform in an organic solvent at an absolute pressure of from 1 bar to 6 bar. 2. The method of claim 1, wherein the reaction is carried out at an absolute pressure of from 2 to 6 bar. 98122-10I0903.doc 1378924 3. The method of claim 1 wherein the phenol has the formula iIa V1 Χ2^γ^0Η X3 (Ha) x1, X2 and X3 are each independently hydrogen or methyl, and R3 is hydrogen, acetyl group 'propionyl' trimethylethenyl, H〇2C_CH2_CH^CO, smoke Alkali sulfhydryl or alum-based, the limitation is that if χ1, & and X3 are both methyl, R3 is only ethyl acetyl, propyl sulfonyl, trimethyl ethinyl, H 〇 2C-CH 2 - CH2_CO, 醯 醯 or awkward. 4. The method of claim 1, wherein the phenol has the formula π R1 is hydrogen, ethyl fluorenyl, propyl sulfonyl, trimethyl ethane-based CH2-CO, a tasting base or a stupid base. H〇2C-CH2- 5_ A method for preparing a formula ‘by following the steps a) Compounds of formula IIa as appropriate 98122-10l0903.doc -2. i^/^924 x1 Reaction with a compound of the formula 111 and/or 1V in an organic solvent (III) b) subjecting the compound of the formula Ia, which can be obtained from step a), and optionally one or more of its double bond isomers, to an organic solvent for ring closure to form a chromatin derivative, Vila, V1 R2 is hydroxy, ethoxylated, benzamidine or halogen, and R3 is hydrogen, ethyl hydrazino, propyl fluorenyl, trimethyl ethinyl, h 〇 2c_ch 2 _ ch 2-co, nicotine sulfhydryl or benzoquinone The sulfhydryl group, X:, X: and X3 are independently hydrogen or methyl, and the limitation is that if χ1, X2 and X3 are both methyl groups, then R3 is only ethyl acetyl, propyl sulfonyl, trimethyl ethane Base, H〇2C-CH2-CH2-CO, nicotine sulfhydryl or benzamidine, and η is an integer from 0 to 3, wherein at least one of the steps a) and b) is to 6 Under the absolute pressure of Ba, it is carried out in the presence of a mixture of Lewis acid or Lewis acid as a catalyst and Bruce 98l22-l0l0903.doc. 6. The method of claim 5, wherein the reaction is carried out at an absolute pressure of from 2 bar to 6 bar. 7. A method for preparing a chroman derivative, Vila, X1 By reacting a phenol comprising 0 to 4 methyl groups, a total of 1 to 3 hydroxyl groups, and at least one unsubstituted position with a compound of formula III and / or IV, wherein the unsubstituted position is in the vicinity of a hydroxyl group Position, R is hydroxy, ethoxylated, benzamidine or worm, R is hydrogen, ethyl hydrazino, propyl fluorenyl, trimethyl ethinyl, ho2c-ch2-CHrCO, nicotine sulfhydryl or Stupid thiol, XX and x are each independently hydrogen or methyl, and the restriction is that if χι, X2 and X3 are both methyl', then r3 is only ethyl, propyl, trimethylethenyl H 〇2C-CH2-CH2-CO, nicotine decyl or phenyl fluorenyl, η is an integer from 0 to 3 where the reaction is in the presence of a Lewis k as a catalyst or a mixture of a Lewis acid and a Brillis acid ^"Under the absolute pressure of 6 bar, it is carried out in an organic solvent. 8_ The method of claim 7, wherein the reaction is carried out at an absolute pressure of from 2 bar to 6 bar 98122-1010903.doc IHW2A. A method such as Kiss 2, 3, 4, 7 or 8, wherein η in the formulas (1) and ... is 3. 10. A method of preparing an alkanoate of formula VIIIa, It is by reacting a compound with a suitable brewing agent. a group consisting of propyl sulfhydryl, trimethyl ethane fluorenyl, H 〇 2C — CH 2 — CH 2 — c 〇, nicotine fluorenyl and benzhydryl groups, and characterized by the reaction being as a catalyst at an absolute pressure of from 1. It is carried out in the presence of a Lewis acid. U. The method of claim 10, wherein the reaction is carried out at an absolute pressure of from 2 to 6 bar. 12. The method of claim 8, wherein the method is any one of the methods of the Lewis acid-based trichlorinated steel, the three indigo indium, the indium molybdenum, and the second. Indium acetate, ginseng [bis(trifluoromethanesulfonamide)] indium, indium triflate or vanadium triflate. 13. The method of any of the preceding claims, wherein the mixture of Lewis acid and Bruce's acid as catalyst 98122-10l0903.doc 1378924 is Znci2 and HCl or Fe and/or FeCl2 and HCl. a mixture. 14. The method of claim 1 wherein the &tocopherol used (Χ1=Χ2=Χ3=methyl and η=3 of formula VIIc) is obtained according to step b) of the method of claim 5 Reaction mixture. 15. The method of claim 5, characterized in that all steps are carried out at an absolute pressure of from 1 bar to 6 bar. 16. The method of claim 15, wherein the reaction is carried out at an absolute pressure of from 2 to 6 bar. η. The method according to any one of claims 1 to 8, 14 and 15, wherein the solvent is a non-polar aprotic organic solvent, and the method of claim 17, wherein the non-pure non-purity free % hexane, Alkane, heptane, octane q "burning, dichloroethylidene, two gas hospitals, two gas ethane _ dimethyl benzene, m- fluorene benzene, the group of the present dichloro stupid and m benzene. - gas 19. - Preparation of tocopherols, tocopherols, gamma-co-alkanoates, the method of phenol and δ-sodium phenol, by means of a method as claimed in丨# ^ 6 ' 7 and 8 in the middle of the knife, the α-tocopherol, and δ-tocopherol reacted with the sputum. θ phenol"·Tocopherol 20. The method of claim 19, which is for use in the method of claim 2G, which is used for the production of bismuth sulphate. 22· - Preparation. _ Fertility, β Fertility _ ^ fertility vinegar vinegar. The method of burning vinegar, which is caused by the two fertility and 5-fertility chain, β-tocopherol γ sheng 98122-I010903.doc 1378924 fertility and δ - Fermentation is respectively reacted with a deuteration agent selected from the group consisting of acid anhydrides and functional groups of acetic acid, propionic acid, tridecyl acetic acid, succinic acid, nicotinic acid, and benzoic acid, which is characterized by the reaction as a catalyst. 23. The method of claim 22, wherein the reaction is carried out at a temperature of less than 12 Torr (5:: 24. The preparation of tocopherol, beta-tocopherol, A method of gamma-tocopherol, δ-tocopherol or an alkanoate thereof, wherein tocopherol, ρ-, respectively, obtained by the method of any one of claims 1, 2 to 8, 1 and U Tocopherol, gamma-tocopherol, δ-tocopherol or an alkanoate thereof. Fertility or its alkanoic acid 25. The method of claim 24, For the preparation of esters 26. - Seed compound of formula X, By making a compound CO and the compound of formula IX are reacted in an organic solvent 98122-1010903.doc 1378924 丨丨(IX) R1 is hydrogen 'ethyl hydrazide, propyl fluorenyl, trimethyl ethinyl, h〇2C_ch2 CH2-CO, Or benzoyl, R2 is hydroxy, ethoxylated, benzylideneoxy or halogen' and η is an integer from 〇 to 3, the reaction is at an absolute pressure of Μ巴至6巴, in Catalyst It is carried out in the presence of a mixture of Lewis acid or Lewis acid and Brunsten acid. 27. The method of claim 26, wherein the reaction is carried out at an absolute pressure of from 2 bar to 6 bar. 28. A process for the preparation of alpha-tocopheryl stearate or gamma-tocopheryl sulphonate by reacting a compound of formula with a suitable oxime, X1 Wherein 'X1, X2 and χ3 are methyl groups and n = 3, characterized in that the reaction is carried out in the presence of a Lewis acid as a catalyst at an absolute pressure of less than 0 9 bar. 29. The method of claim 28, wherein the reaction is carried out at an absolute pressure of from 0.02 bar to 0.9 bar. 98l22-10J0903.doc