DE2225612C2 - Cyclic methyl-fumaric dialdehyde monoacetals and process for their preparation - Google Patents

Description

in which R ¹ and R ^{2 are} different and denote either a hydrogen atom or a methyl group and R ³ and R ⁴ together denote a propylene radical which is optionally substituted by alkyl groups having 1 to 4 carbon atoms.

Z Process for the preparation of the cyclic methyl-fumaric dialdehyde monoacetals of the general Formula I.

R ³ -O

CH-C = C-C

/ 11V

R ⁴ -OR ² R ¹ O

(D

in which R ¹ and R ^{2 are} different and either represent a hydrogen atom or a methyl group and R ³ and R ⁴ together represent a propylene radical optionally substituted by alkyl groups having 1 to 4 carbon atoms, characterized in that a cyclic but-2- en-4-oI-l-al-acetal of the general formula II

R ³ -O

⁴ —θ '

R ² R ¹

(H)

in which R ¹ to R ^{4 have} the meanings given, oxidized with sulfuric acid chromic acid solution in acetone

The invention relates to cyclic methyl-fumaric dialdehyde monoacetals of the general formula I.

R ^} —O

CH-C = C-

R ⁴ -OR ² R ¹

in which R ¹ and R ^{2 are} different and denote either a hydrogen atom or a methyl group and R ³ and R ⁴ together denote a propylene radical optionally substituted by alkyl groups having 1 to 4 carbon atoms, and a process for their preparation.

These cyclic methyl-fumaric dialdehyde-monoaceta-Ie are used as intermediates in the synthesis of Carotenoids of extraordinary interest because they allow compounds such as retinal to be ^ -Apo-C25-Carotinal and 0-Carotene in a much simpler and more advantageous way to produce than it was possible according to the previously known syntheses.

For example, the review article »Syntheses in the Vitamin A series «by H. Pommer in Angew. Chem. 72, 1960, no. 22, pages 811 to 819, in particular page 815, the implementation of / J-Jonylidenäthyltriphenylphosphoniumbromid the formula

CH = CH-C = CH-CH-P- (C ₆ Hj) ₃ CH,

with numerous formyl compounds in a so-called Wittig reaction known According to this quote

results, for example, in the reaction of /? - Jonylidentriphenylphosphoniumbromid with

O = CH-C = CH-O-CO-CH ₃
CH ₃

vitamin A acetate, from which vitamin A can be produced by hydrolysis. The coveted Until now, retinal had to be produced by oxidizing vitamin A with manganese dioxide or nickel peroxide.

However, this oxidation only takes place with a yield of about 70% and involves considerable process engineering Difficulties and environmental problems with them.

Also not more advantageous for the production of

Retinal is that in HeIv. Chim. Acta Vol. XLV (1962), p

no 541-548 described process according to which one converts ■ / 7-Jonylidenäthyltripheriylphosphoniumbromid with formyl compounds to vitamin A acid esters, from which by reduction with the expensive LiAlH ₄ vitamin Α is produced, from which - as described above - retinal by oxidation could be produced.

It is known from Swiss patent specification 3 35 647. Wittig olefinations of ylides with polyene

to carry out methyl ketones to polyene aldehydes according to the following reaction equation:

P (C ₆ Hj) ₃

O - R>

O —R

O —R

O —R

Downside to this. Procedure is that the ylid must be produced here with the help of expensive organolithium compounds. In addition, can after this procedure neither retinal nor / J-apo-carotinal getting produced.

The in O. Isler "Carotenoids" (1971) Section VI, imposed modes of formation for retina! run in the Most of them come from Cai intermediates with a higher (e.g. vitamin A acid) or lower oxidation state which the retinal only needs in a laborious and lossy manner through reduction and / or oxidation must be made.

Only two processes (p. 377) according to scheme C13 + C7 lead directly to the oxidation stage of the retinais. It is a) a process that is based on Reel. Trav. Chim. Pays-Bas 84 (1965), page 1113 and b) to a Procedure based on NL-PS 64 04 175 as the original lit-

(C ₆ H ₅ J ₃ P

A very disadvantageous aspect of this process is that for Production of the ethylidene- (l) -triarylphosphonium compounds expensive and difficult to handle reagents how phenyllithium or butyllithium are necessary, and that the yields are also extraordinary are bad. An example of the production of retinal acetals is not included in this patent. The vitamin A alcohol methyl ether is only used in Yields of 10% of theory were obtained.

In contrast, you can with the help of the new cyclic Methylfumaraldehyde monoacetals, which according to the method according to the invention on a relatively simple

O + (C ₆ Hj) ₃ P

that is to say, the Wittig reaction of a Ci ₅ - as with a C ₅ phosphonium salt to retinal, while the new cyclic Methylfumardialdehydmonoaceta-Ie a Wittig reaction of the known C | ₅ -phosphonium salt with the corresponding C ₅ -al to retinal becomes possible. A disadvantage of the DE = AS method

P (C ₆ H ₅ ) J + O

Decrease in temperature- In both cases it will be expensive and difficult to manage to implement organometallic reagents (such as butyllithium and lithium amide for a) and ethylmagnesium bromide for b)) required Retinal is only obtained after 3 reaction steps in both processes, in yields of only 55-66 or 13%. The hydrogenation necessary in the process of the NL-PS is with the expensive and dangerous L1AIH4 carried out

In DE-AS 10 17 163 a method for the production of, inter alia. Vitamin A aldehyde acetals or their hydrolysis product by reacting 8- [2 ', 6', 6'-trimethylcyclohexen-O'J-yrj-e-rnethyloctatrien-p.S,?) - on- (2), with an ethylidene- (l) -triarylphosphine, which is disubstituted in the 2-position by ether residues, claims:

O - R 1) Wittig reaction

O-R 2) hydrolysis

Retinal

In this way and with good yields, retinal acetals are obtainable in yields of about 90% of theory obtain.

Probably the most responsive to the method according to the invention comes the process of DE-AS 10 17 164. Herein, a process for the production of inter alia. Vitamin A aldehyde diethyl acetal or its hydrolysis product by reacting S - ^ '^' ^ '- Triinethylcyclohexen-l'-yl] -3-methylpentadiene- (2,4,) - al (l) (also 0-ionylidene acetaldehyde called) with 2-methyl-4,4-diethoxycrotylidene

(l) -triphenylphosphine claims:

O - R Wittig reaction

Retinal acetal

O —R

10 17 164 is that expensive and difficult to handle compounds such as butyllithium or phenyllithium have to be used _{to produce the C 5 phosphorylide required for this process, while the Wittig reaction made possible by the new methylfumaric dialdehyde mancetals}

Retinal acetal

cheap and technically problem-free bases, such as NaOCH _{3, can} be used. An example for them

Manufacturing of vitamin A aldehyde is included in this Patent not included. The production of vitamin A methyl ether described in the form of an example occurs only in yields of 10% of theory. An exemplary description of the in the mentioned DE-AS listed implementation of Qs-aJs / 3-JonyIidenacetaldehyd with the Cs-phosphonium bromide

CH ₃

CH ₂ -C = CH-CH (OC ₂ Hs) ₃
Br ⁰ P ⁹ CC ₆ Hj),

according to Wittig can be found in Makin in J. general Chem. (USSR) 32 (1962), pages 3105-3106. Makin also uses CH ₃ ONa in this reaction, but only receives the retinal in yields of about 10% of theory. Th, based on the Cs-phosphonium salt and in yields of about 18% of theory. Th based on Ij-ionylidene acetaldehyde.

In contrast, Retinal durr.h can implement the new and according to the method according to the invention 3-Methyl-fumaric dialdehyde mono-1-acetalated is surprisingly easy to prepare and in very good yields with the ylide, which is technically readily available as an intermediate product in an industrial vitamin A synthesis of / 3-JonylidenäthyltriphenylphosphoniumsaIzen and subsequent customary hydrolytic work-up in the presence of aqueous acids in a simple manner and with Yields of up to 90% of theory can be produced. The retina preserved! can now turn

_{| 0 can be} converted into / 3-carotene by a simple Wittig reaction with a retinyl triphenylphosphonium salt, which can be easily obtained from retinol or vitamin A acetate, and subsequent hydrolysis, which enables an overall more economical synthesis of J3-carotene

, ₅ will. Furthermore, a retinyl triphenylphosphonium salt can be elegantly converted into the / J-Apo ^ -carotinal (/? - Apo-12'-carotinal) by Wittig olefination with 2-methyl-fumaric dialdehyde-1-acetals and subsequent hydrolysis. In contrast, the

, ₀ Production of ^ -Apo-Cas-Carotinal from roughly comparable building blocks according to known processes is much more expensive. For example, it can be prepared by linking a cig aldehyde with a Ce acetal according to the following scheme:

HC

CH (OR) ₂

Cond. With LiNH ₂
or Grignard reaction

CH (OR) ₂

OH acid treatment

(? jr dehydration and

Hydrolysis of the acetal function)

Partial hydrogenation
isomerization

^ -ApO-C ₂₅ -Ca rotinal (cf. Helvetica Chim. Acta 42 (1959), page 849, last paragraph including formula scheme, page 848, center).

As can be seen from the reaction scheme, this synthesis is used in addition to that in our process necessary C-C linkage and the hydrolysis of the acetal groups, there are further synthetic steps, such as partial hydration and isomerization necessary.

Knowing the above "state of the art" inevitably results in the enormous importance of the easily accessible new methylfumaric dialdehyde monoacetals as building blocks for the synthesis of compounds of the vitamin A series and of carotenoids, since it is possible to use them for successive Wittig syn theses to perform countless compounds of biological and pharmacological importance.

The cyclic methyl-fumaric dialdehyde monoacetals of the general formula I.

R-O

R 'O

R 'R'

ti

in which R and R ^{: are} different and denote either a hydrogen atom or a methyl group and R 'and R' together denote a propylene radical optionally substituted by alkyl groups having 1 to 4 carbon atoms, are prepared according to the invention in a simple manner with very good yields by that a cyclic but-2-en-4-ol-l-alacetal of the general formula II

R - O

R ¹ O

CII -C = C-CH-OH (III

R 'R ¹

in which R to R- have the meaning given above, oxidized with sulfuric acid chromic acid solution in acetone.

It is known that alcohols can be oxidized to the corresponding ketone with a sulfuric acid chromium solution, the so-called Jones reagent, in acetone (cf., for example, L F. Fieser, Reagents for Organic Synthesis (1967), pp. 142 to 143). However, it was extremely surprising that the oxidation succeeds with good success in the present case, since x + J-unsaturated acetals generally hydrolyze very quickly in acidic solution. Correspondingly, an analogous oxidation with chromic acid in a sulfuric acid solution z. B. when using dimethyl or ethylene glycol acetals of the corresponding but-2-en-4-oi-l-ale as starting materials.

The cyclic methyl derivatives of but-2-en-4-ol-1-al-acetals of the formula II required as starting materials can, for example, in a simple manner by conventional methods by acetalizing ^ -formylcrotyl acetate or 3-methyl-4-acetoxycrotonaldehyde and then Reacting the acetals obtained can be prepared with a methanolic solution of sodium methylate.

The oxidation is generally carried out as follows:

The alcohol to be oxidized is dissolved in acetone and to this solution at temperatures from - to "20 ° C added the sulfuric acid solution of chromic acid 5 to 1 -r 3O ^C C ₁ preference""else -5

The acetone is generally used in such amounts that the alcohol to be oxidized is in about 0.1 to 0.8, preferably 0.2 to 0.4 molar solution is present.

A reagent according to Jones, for example, is used as the sulfuric acid chromic acid solution, which is about 8 normal in chromic acid and sulfuric acid and used in equivalent amounts. But you can also with an excess, for example up to 50% Chromic and sulfuric acids work. It is advantageous to use an excess of 10 to 20% of a 4 to 8 normal solution of chromic acid and sulfuric acid.

The reaction mixture is worked up in the customary manner by pouring the reaction mixture into it approximately the same amount of water, extraction with a solvent that is practically immiscible with water and distillation.

By means of the process according to the invention, it was possible for the first time to use the intermediate products for the

Methyl-fumaric dialdehyde monoacetals of the general Formula I to manufacture.

example

To a solution of 37.2 g (0.2 mol) of 2-methyl-but-2 · s-4-ol-l-al (2 ', 2'-dimethylpropylene) acetal in 1 liter of acetone at +5 ⁰ C at once a Mixture of 15.2 g of chromium trioxide and 23 g of concentrated sulfuric acid, which was made up to 100 ml with water, was added. The reaction mixture is then poured into 1 liter of cold water and extracted three times with 150 ml of benzene and the combined benzene phases are wiped with 5% sodium bicarbonate solution. When the combined benzene extracts are worked up by distillation, 31.8 g of 2-methyl-fumaric dialdehyde-1 - (2 ', 2'-dimethylpropylene) acetal are obtained. The yield is accordingly 85% of theory.
Bp ₀ 1 = 82 to 85 ° C;
NMR (o [ppm). CDCI ,. TMS):

10.10 (d, IH): 6.10 (m, IH): 4.80 (S. IH);

3.58 (m. 4H):

2.1 8 (p. 3H): 1.21 (p. 3H): 0.75 (p. 3H).

In the same way as described above, the following methyl-fumaric dialdehyde monoacetals are obtained by reacting 0.2 mol of the corresponding methyl-but-2-en-4-ol-1-al-acetals:

2-methyl-fumaric dialdehyde-1- (r.3'-propylene) acetal K po ι = 80 ^c C: Yield 78% of theory.
NMR (<5 [ppmJ. CDCl _3. TMS):

10.08 (d. 1H); 6.12 (i.e. 1H ). 4.93 (p. 1 H):

4.00 (m, 4H);

2.18 (p. 3H): 2.0-1.2 (m. 2H).

2-methyl-fumardiaidehyd-1- (2 ', 4'-penty! En) -acetal:
Kpo.2 = 70 to 72 ° C; Yield 75% of theory. NMR (of ppm). CDCl ₃ , TMS):

10.08 (d, 1H); 6.17 (m.1H). 4.95 (p. 1H);

4.1 -3.6 (m, 2H);

2.18 (m, 3H), 1.6-U (m, 2H); U4 (d.6H).

3-MethyI-fumaric dialdehyde-l- {2'.2'-dimethylpropylene) acetal:

Kp <u = 85 to 87 = C; 78% of theory. NMR (oppmj. CDCl ₃ : TMS):

9.47 (S, 1H). 635 (m. 1H); 530 (d. 1H);

3.60 (m, 4H):

132 (d, 3H): 1.24 (S, 3H); 0.77 (p. 3H).

The 2-methyl-but-2-en-4-ol-1 used as starting material above -al- (2 ', 2'-dimethylpropylene) -acetal has been prepared as follows:

a) Acetalization of / 7-formylcrotyl acetate

A mixture of 142 g / J-formylcrotyl acetate, 107 g of neopentyl glycol, 0.2 g of p-toluenesulfonic acid and 500 ml of benzene is allowed to boil for 3 hours under reflux and with water removed. The cooled reaction mixture is washed with NaHCC> 3 solution and dried _{over Na2SO 4.} 216 p 2-methyl-4-acetoxy-biit-2-en-1-al-1 - (2 ', 2'-dimethylpropylene) acetal of Kpo.i = 95 ° C. are obtained.

b) reaction with methanolic sodium methylate

A mixture of 228 g of the above 2-MethyI-4-acetoxy-but-2-en-1 -al-1 - (2 ', 2'-dimethylpropylene) -acetal;
5 ml of a 30 percent strength by weight methanolic sodium methylate solution and 250 ml of methanol are heated at 450 torr and a bath temperature of 60 ° C., the methanol being distilled off. 150 ml of methanol are then added again and this is distilled off. The residue is taken up in methylene chloride, washed with water and concentrated. This gives 172 g of 2-methyl-but-2-en-4-ol l-al (2 ', 2'-dimethylpropylene) acetal from Κρη, ι = 106 to 110 ⁰ C.

Claims (1)

Claims: 1. Cyclic methyl-fumaric dialdehyde monoacetals of the general formula I. R ³ -O / CH-C = C-C / I I V R ⁴ -OR ² R ¹