FR2706452A1 - Process for the preparation of intermediates of vitamins A and E and carotenoids - Google Patents

Abstract

The present invention relates to a process for the preparation of intermediates of vitamins A and E or carotenoids which consists in condensing a tertiary alcohol and a vinyl halide in the presence of a palladium-based catalyst.

Description

PROCESS FOR PREPARING INTERMEDIARIES OF

VITAMINS A, E AND CAROTENOIDS

  The present invention relates to a new process for preparing intermediates of vitamins A, E and carotenoids. This process involves reacting an allyl derivative with a halide

  vinyl in the presence of a palladium catalyst.

  The present invention consists in reacting an allyl derivative of formula (I) below: B

RA [I)

AT

  in which: - A represents a hydroxyl group, oxygen or a bond with B - B represents a methyl or methylene group or a bond with A, - R represents an alkyl group or one of the following units:

CH3 -

  in which n is an integer greater than or equal to 0 and less than or equal to 4, the broken line possibly representing a double bond with a vinyl halide of the following formula (II): x1, z (II) Xa: <n in which X represents Cl, Br, I or SO 3 CF 3 or a leaving group -n is equal to 0 or 1; Y and Z each represent an alkoxy group preferably having 1 to 4 carbon atoms or together form an oxyalkylidenoxy group or Y represents hydrogen and Z represents a group:

= CH-CH2-C = CH X

CH3

  in the presence of a palladium catalyst.

  Compounds having the following general formula HI are obtained: B

R Z (111)

  A n 'which, after contact with a protic acid allow access to the aldehyde intermediates of vitamins A, E or carotenolides of formula: B

R / E.CHO

  The aprotic acids are chosen especially from hydrochloric acid,

  hydrobromic, nitric, sulfuric, perchoric or para-toluenesulfonic.

  Among the compounds of formula (I), non-limiting mention may be made of vinyl ionol-nerolidol, methyl-2-butene-3-ol-2-myrcene-linalool-methylvinyl ketone. Among the compounds of formula ( II) mention may be made without limitation: 1-iodo-1-diethoxy-4,4-methyl-2-butene-1-bromo-1-diethoxy-4,4-methyl-2-butene-1-chloro-1-diethoxy 4,4-methyl-2-butene-1,8-diiodo-1,8-dimethyl-1,4-1,4-1,4atratrate The reaction is preferably carried out in the presence of a base. This base is chosen in particular from the silver or thallium carbonates or the silver or thallium salts of an organic acid, when in the formula (1I) X represents iodine. This base is chosen in particular from alkali carbonates or acetates

  or alkaline earth when in formula (11) X represents bromine.

  The catalyst based on palladium may be chosen from

  palladium such as chloride, acetate or a palladium zerovalent complex.

  In the case where in the compound of formula (II) X represents bromine, it is preferred to use a catalyst based on a phosphine monodentate or bidentate such as triphenylphosphine, tritolylphosphine, tris-p-methoxyphenylphosphine, dimethylaminophenylphosphine, bidiphenylphosphinyl-1,2 cyclobutane and 1,4 butane. The reaction solvent is chosen from, in particular, protic or aprotic polar solvents such as water, dimethylformamide, N-methylpyrrolidone,

  dimethylsulfoxide, dimethylacetamide, benzonitrile, acetonitrile, an alcohol.

  The intermediates of formula (II) are new intermediates when X represents iodine, they are claimed as such for the preparation of vitamins A and E. The intermediates of formula (II) are new intermediates when X represents the iodine, they are claimed as such for the preparation of vitamins A and E. The intermediate of formula:

  is also claimed as an intermediate for the preparation of carotenoids.

  The iodinated intermediates are prepared in particular by the action of potassium iodide in the presence of a catalytic amount of nickel bromide and zinc on the corresponding brominated derivative in accordance with the publication of TOKAGI,

  NAYAMA and INOKAWA published in Chemistry Letters, 1978, pages 1435-1436.

  The initial brominated intermediates when n 'is equal to 1 are prepared for example by bromination of the methyl-3-butene-3, al-1 diethylic acid in a halogenated solvent at a temperature below 0 C followed by deshydrobromation

  of the derivative obtained in the presence of potassium tert-butoxide.

  The invention will be more fully described with the aid of the following examples which

  should not be considered as limiting the invention.

  PREPARATION OF BROMO-1 DIETHOXY-4.4 METHYL-2 BUTENE-1

OEt Na2CO3 OEt OEt + Br2 OEt (I)

(0) CC01 - O4 B

   C Br OEt OEt XE + 0t0 + QEt ++ OH + KBr Br EOt + K OE And ± OK 0 C y -l'E, Br Br (II) * Preparation of (I): Bromination In 75 ml of carbon tetrachloride, 7.1 g of enacetal (O) (44.9 mmol) and 8 g of sodium carbonate (1.7 eq, 76.3 mmol) are introduced successively. The mixture is brought to -20 ° C. and a solution of 7.2 g of dibrome in 10 ml of carbon tetrachloride is added dropwise over 15 minutes. The discoloration is immediate. We

  leave stirring at -20 ° C. for 15 minutes then filter and concentrate cold.

  * Preparation of (II): Deshvdrobromation In a 250 ml tricol equipped with a thermometer, a magnetic stirrer and swept with argon, the crude dibromo compound (I) obtained from 37 mmol of enacetal is charged. (O) and 80 ml of anhydrous ether. It is cooled in a water / ice mixture. We

  introduced in 3 fractions potassium tertbutylate (56.2 mmol).

  Stirring is allowed between 0 and 10 C for 4 hours. It is hydrolyzed with 50 ml of H 2 O. Extracted with isopropyl ether and washed 4 times with water. The organic phase is dried over MgSO4 and concentrated. The red liquid obtained (7.047 g) is purified on an amicon silica column: 2045 mm neutralized with 1% triethylamine.

  Eluent: isopropyl ether 1 pentane 40.

  4.246 g of pale yellow liquid are obtained: (II) 89% o (Z: 57% E: 43%) and RR: 43% calculated relative to the enacetal (0) v OEt NMR1H (AM 360 Bruker CDCl3 - HMDS - t: 27 C): 5. cis: 1.14 ppm (t-6H); 1.79 (s - 3H); 2.47 (d - 2H); 3.40 to 3.55 (m - 4H); 4.58 (t-1H); 5.89 (s - 1H) trans: 1.12 (t 6H); 1.78 (s - 3H); 2.35 (d - 2H); 3.40 to 3.65 (m - 4H) 4.50 (t-1H)

  PREPARATION OF DIETHOXY-4.4 IODO-1 METHYL-2 BUTENE-1

  EtO and Q: k OEt + Ki 2 B rO And + KBr Zn Br (II) DMF: 60/800 C (111) In a reactor, Schott 15 ml, 90.7 mg zinc (1.39 mmol) was charged. ), 3.020 g of KI (18.2 mmol), 3.980 ml of a 0.17 M NiBr 2 solution in DMF (0.67 mmol), 1.589 g of the 89% bromine compound (II) (5.96 g). mmol) and 7.5 ml of DMF

  Anhydrous. A magnetic stirrer and an argon sweep are installed.

  We spend 2 hours 30 with ultrasound (60 <T <95 C - F: 20000 Hz -

  Sonoréacteur). After returning to ambient temperature, the reaction mass is filtered through

  Florisil is extracted with ether and washed with water.

  It is dried over MgSO 4, concentrated under reduced pressure and gives a bright yellow liquid which is purified on a silica column neutralized with 1% triethylamine.

Eluent: ether-1 pentane-40.

  1.035 g of a colorless liquid is recovered: (III) 96% o (E: 40% o Z: 60%)

RR: 59%.

  IR: 1064-1125 - 1616 - 3060 cm-1 Mass spectrum: m / e 239 (exact mass measurement: C7H12OI) m / e 103 (100%) 1H NMR (AM 360 Briiker - CDCl3 HMDS - t: 27 C) cis: 1.14 ppm (t - 6H); 1.89 (s - 3H); 2.47 (d - 2H); 3.35 to 3.45 (m - 4H); 4.57 (t-1H); 5.89 (s-1H)

  trans: 1.12 ppm (t-6H); 1.81 (s - 3H); 2.44 (d - 2H); 3.35 to 3.45 (m -

4H), 4.50 (t-1H), 5.94 (t-1H);

  COUPLING DIETHOXY-4.4 IODO-1 METHYL-2 BUTENE-1 SUR

  DIFFERENT OLEFINS (Table A) B OE Pd (OAc) 2 OEt -50 and Base 1 + J 0 RQEt R 5 + vOtDMF: 65C R AEt A

A A

  In a 5 ml flask swept with argon, equipped with a condenser and magnetic stirring, charge: - Pd (OAc) 2: 10.7 mg (0.048 mmol - 0.05 eq) - the base : TIOAc (283 mg - 1.1 eq) or Ag2CO3 (144 mg - 0.55 eq) olefin (about 3 eq) QEt OEt - IZ / E: 61/39 (270 mg - 0.95 mmol - 1) eq) - anhydrous DMF: 2 ml The flask is immersed in a preheated oil bath at 65 ° C. and allowed to stir for the time indicated in Table A. After cooling to room temperature, the reaction mass is diluted

  ether and filter on Florisil (magnesium silicate).

  The organic phase is washed twice with water and twice with saturated NaCl solution, filtered on paper, dried over magnesium sulphate and concentrated at 25 ° C.

under 80 mb.

  The orange liquid obtained is then purified on an amicon silica column.

  - 45 tm neutralized with 1% triethylamine.

  Eluent: CH2C1250 - acetone-1 or CH2Cl2 / Acetone 50/1 The isolated structures are characterized by 360 MHz NMR / spectrometry of

  massse / infrared and elemental analyzes C-H-O-

  The yields are calculated relative to the iodinated compound.

  The coupling is selective on the carbon [and the bond formed is always

TRANS.

  SYNTHESIS OF ALDEHYDES (Table A) B and HBr Cat R "A Ett + H2 O + 2 EtOH A. o C In a 10 ml flask equipped with a condenser and a magnetic stirrer, 0, 5 mmol of acetal, 12 ml of a solution [acetone 192 ml + H 2 O 1 ml] is refluxed (60 ° C.) for 5 minutes before introducing 0.1 ml of an acid solution

[HBr 0.1 ml + acetone 5 ml].

  After returning to ambient temperature, the reaction mass is extracted with

  ether (100 ml) and wash 3 times with water.

  The organic phase is dried over MgSO4 before concentrating with Rotavap.

  The red oil obtained is purified on an amicon silica column: 0.020 0.045 mm Eluent: 1-ether pentane-5 The aldehydes obtained are characterized by 1 H NMR, they are identical to

those described in the literature.

EXAMPLE 8

    EO Pd (OAc) 2 5 EO J] ". + LvOEt D FK2C53 O DMF: 65C 8 (a) 2

1

  In a 5 ml flask swept with argon, equipped with a condenser and with magnetic stirring, charge: Pd (OAc) 2: 6.5 mg (0.029 mmol: 0.05 eq) - K 2 CO 3: 187 mg (1.36 mmol: 2.4 eq) -olefin: 191 mg (2.73 mmol: 4.9 eq) OEt OE-I: 159 mg (0.56 mmol: 1 eq) -DMF anhydrous -Bu4N + Cl-: 75 mg (0.71 mmol: 1.3 eq) The reaction is carried out as in Example 1 but at a temperature of 22 ° C. for 4 hours 30 minutes. The extraction and purification are carried out carried out as

Example 1

  A calculated yield is obtained with respect to the iodinated derivative of 80% of derivative of formula 8 (a) above, the EZ / EE distribution of the two cis / trans isomers on the link 3 is 62/38. 53/53 Methylation of Derivative 8 (a) O QOEt 1) THF-78 C Et - / '- QOEt + MeLi OEt 8 (a) 2) H20 O In a 10 ml flask swept with argon, load ketone (a) (0.549 mmol) and 4 ml of THF. The flask is immersed in a bath at -78 ° C. 0.875 ml of a 1.6 M methyllithium solution in ether is slowly run in. After 1 hour 20, it was hydrolyzed with a mixture of water (0.5 ml) / THF (4 ml). It is allowed to rise to room temperature. Extracted with ether. Wash with water. We dry

  organic phase on MgSO4 before concentrating it.

  The yellow liquid obtained (0.132 g) is purified on an amicon silica column.

  : 0.020 - 0.045 mm neutralized with 1% triethylamine.

  Eluent: CH2Cl2-50 acetone-1 0.97 mg of hydroxyacetal 1-a (Z / E: 58-42%) is obtained

RR: 73.5% - T: 84% - RT: 87.5%.

TABLE A

  COUPLING REACTIONS OF DIETHOXY-474 IODO-1 METHYL-2 BUTENE-1 ON DIFFERENT OLEFINS

B B OEt

EXAMPLE RBASE EZ / EE RT R DISTRIBUTION

  OLEFIN EXAMPLE BASED ON TC t (h) A 4 3 2 53 53 6 4 2 ISOMERIC 1B = R = CH3 TI OAc 65 31 33% 54/46 65% A = OH 3 eq 1, 1 eq. 2 isomers 2 B = R = CH3 Ag2CO3 67 8 82% 60/40 82% 85% 2 isomers A = OH 2.8 eq 0.52 eq. 2 isomers 2Z: 26%

2E: 74%

  B = CH3 TI OAc 65 4 75% 65/35 75% 72% 4 isomers 1,02 eq. 2 isomers 45% (all trans) 18% A = OH 2, 8eq 27%% 4 B = CH3 T1 OAc 65 24 38% 52/48 75% 2 major isomers 1.05 eq. 2 isomers 13 trans 72% 13cis28% R = C A = OH 2,8g q B = CH3 Ag2CO3 65 3 82% 60/40 82%

0.54 eq.

  R = A A OH 3 eq 6 B = CH3 Tl OAc 58 5 77% 63/37 81-85% 87.5% 4 isomers 1.02 eq. 2 isomers 48% (all trans) 28%

R = 12

  14% A = OH 2.8 6q 1%% 7 B = CH2 Ag2CO3 67 4.15 65% 73% 5-6 isomers 0.55 eq. 2 isomers R = a A = bond with B

  COUPLING OF BROMO-1 DIETHOXY-4,4 METHYL-2 ON DIFFERENTES

OLEFINS

(TABLE B)

  And Pd (OAc) 2 Q and R S + -R and OHc + BrtK2CO3 OH O 1 -F13r phosphine

DMF-90 C

  In a 5 ml flask equipped with a condenser, magnetic stirring and swept with argon, charge: - Pd (OAc) 2: 10.6 mg (0.047 mmol, 0.05 eq.) - K2CO3 milled: 448 mg (3.24 mmol)

phosphine: 0.11 eq.

olefin: 3 eq.

  ! W / O Et - Br Z / E: 57/43: 257.4 mg (0.95 mmol - 1 eq.) Purity: 87% DMF anhydrous: 2 ml Dipped in a preheated oil bath at 90 ° C and allowed to shake during the

duration indicated in the table.

  The treatment and purification are identical to those of Examples 1 to 7.

  COUPLING REACTIONS OF BROMO-I DIETHOXY-4,4-METHYL-2-BUTENE-1 ON DIFFERENT OLEFINS

TABLE B

  EXAMPLE OLEFIN PHOSPHINE TC t (hl) RR GLOBAL SELECTIVITY DISTRIBUTION OF COUPLING a / p ISOMERIC <O 4HOEt 9 P 90 28 77% 85/15 OH OEt 67% (Z / E 55/45) OH Mo - .. OEt OH 10 % (2iso: 60/40) ^ And

OH 9%

  N (<oEt H <and 15% (2iso: 55/45) OE!

"A" H "'E' 73% (Z / E: 50/50)

p i-oMe 90 21 70% 95/5 OH OEEt

OH 3 OH

H EEt 5%

__ _ _ ___ 10%

  i H And he P90 23 62% 89/11 = Xi l | N // [MaO 89% (Z / E '50/50) I% OH / Me 11% t Y1i% (2iso: 70/30) wt% (2iso: 70/30) EXAMPLE OLEFINE PHOSPHINE TC t (hl) RR GLOBAL SELECTIVITY DISTRIBUTION OF ISOMERIC COUPLING lz..X '= 83% (Z / E: 50/50) 12 POHp 90 6 45% 92/8 Y' = 7% D) 3 Product (s) no identified 10%

X '= 96.5% (Z / E: 50/50)

  13 OH9.yO90 6 54% 96.5 / 3.5Y '= 3.5%

X '= 81% / (Z / E 50/50)

  14 N <2P "" pf 2 90 6.5 53% 84/16 Y16% unidentified 3%

X '= 91% (Z / E: 50/50)

  This OH'y 90 22 64% 92/8 Y '8% unidentified 1%% (

Claims (10)

  1 - Process for preparing intermediates for vitamins A, E and carotenoids, characterized in that: in a first step, an allyl derivative of formula (I) below is reacted: B R'A / (I)   Wherein: A represents a hydroxyl group, oxygen or a bond with B - B represents a methyl group or a bond with A - R represents an alkyl group or one of the following units: CH 3 - I ' in which n is an integer greater than or equal to 0 and less than or equal to 4, the broken line may represent a double bond with a vinyl halide of the following formula (II): xz (II) in which X represents Cl, Br , I or SO3CF3 - Y and Z each represents an alkoxy group having 1 to 4 carbon atoms or together form an oxyalkylidenoxy group where Y is hydrogen and Z a group having the following formula: CH-CH2-C = CH X CH3 -n 'is equal to 0 or 1   in the presence of a palladium catalyst.   In a second step, the product resulting from the first step with a protic acid.   2 - Process according to claim 1 characterized in that the compound of formula (I) is an allyl alcohol selected from vinyl 3 ionol, methylbutenol,   linalool, nerolidol, methyl vinyl ketone.   3 - Process according to claim 1 characterized in that in the compound   of formula (II) X represents bromine.   4 - Process according to claim 1 characterized in that in the compound   of formula (II) X represents iodine.   - Process according to claims 1 and 3 characterized in that it operates in   present of a base selected from alkali carbonates or acetates.   6 - Process according to claims 1 and 4 characterized in that it operates in   presence of a metal salt selected from silver or thallium salts.   7 - Process according to claims 1 and 3 characterized in that it operates in   presence of a monodentate or bidentate aromatic phosphine selected from   triphenylphosphine, tri-O-tolylphosphine, tris-p-methoxyphenylphosphine, dppb (bis) diphenylphosphine butane).   8 - Process according to claim 1 characterized in that the catalyst based   palladium is selected from palladium acetate, palladium chloride.   9 - Process according to claim 1 characterized in that one operates in a   aprotic polar solvent or in a protic polar solvent.   - Process according to claim 9 characterized in that the solvent is selected from dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, dimethylacetamide, acetonitrile, benzonitrile, an alcohol and water. 11 - Process according to claim 1 characterized in that in the second step, the protic acid is selected from hydrochloric acid, hydrobromic acid,   nitric, sulfuric, perchloric, paratoluenesulfonic acid.   12 - Intermediate for the preparation of vitamins A and E of formula Y in which Y and Z each represents an alkoxy group having from 1 to 4 carbon atoms   carbon or together form an oxyalkylidieneoxy unit.   13 - Intermediate for the preparation of carotenoids of formula: