DK144941B - PROCEDURE FOR PREPARING D-TRANS-PYRETRIC ACID - Google Patents

Description

(19) DENMARK (^) ijf

m) (12) PUBLICATION MANUAL mi 14494-1 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 5302/68 (51) IntCI.3 C 07 C 69/608 (22) Filing day 1 * Nov. 1968 C 07 C 67/30 (24) Race day 1 · Nov. 1968 (41) Aim. available 11 · May 19¾ (44) Presented 12 Jul. 19 ^ 2 (86) International application no.

(86) International filing day (85) Continuation day - (62) Master application no. -

(30) Priority 10 Nov. 1967 # 1277 ^ 5 * FR

(71) Applicant ROUSSEL-UCLAF S.A., Paris, FR.

(72) Inventor Jacques Mart el, ER.

(74) Associate Patent Agent by Magnus Jensen's Eftf.

(54) Process for the preparation of d-trans-pyrethric acid.

The invention relates to a particular process for the preparation of d-trans-pyrethric acid, also called 1- (R), 2- (R) -seq.-trans-ohryan-santhemum dicarboxylic acid monomethyl ester or 3,3-dimethyl-2- (R) - (2'-methoxycarbony1-trans-1'-propenyl) -1- (E) -cyclopropanoarboxylic acid, with the formula I set forth in the preamble of claim

The preparation by semi-synthesis of natural d-trans-pyrethrin-Q acid has great industrial interest, for this acid is a component of the natural pyrethrins and of insectioid highly active synthetic D-pyrethrin esters such as the ester of d-trans-pyrethric acid and (5- (Benzyl) -3-furylmethyl alcohol, which has a particularly strong knock-down effect.

t 3 144941 2

It is known to prepare d-trans-pyrethric acid by half-saponifying the known dimethyl ester of d-trans-chrysanemum-dicarboxylic acid, and the desired d-trans-pyrethric acid is obtained by purification of the crude product, cf. the description of TIS patent no. , 3,282,985. The known purification takes place by forming the quinine salt, fractional crystallization with organic solvent (acetone) and the release of the acid.

The process according to the invention is based on 1- (R), 2- (R) -hemicaronaldehyde or 3β-dimethyl-2- (R) -formyl-1- (R) -cyclopropane carboxylic acid with b.p. 115 ° C / 0.9 mm Hg and α2 = + 36 ° + 1 ° (c = 1 $, benzene), and of formula II

H

CH f = 0 H 3 v_r __ / '' aTT '

CH3 COOH

hvilken π which compound can be obtained by oxidation by ozone of d-trans-chrysanthemic acid following the procedure described for the racemate of Syo Yamamoto (Scient. Papera

Inst. Chem. Res. 3, 193-222 (1925)) and the process requires only one step to obtain d-trans-pyrethric acid from the aldehyde derivative.

The process according to the invention is peculiar to the characterizing part of claim 1.

The advantage of the process of the invention over the method of US Patent No. 3,282,985 is that the method of the present invention is a hemisynthesis starting from hemicaronaldehyde or 3,3-dimethyl-2- (R) -formyl 1- (R) -cyclopropane carboxylic acid, a compound readily available from chrysanthemic acid, while the process of the United States patent relates to a hemihydrolysis or semi-saponification of a dimethyl ester of dextro-trans-chrysanthemum dioarboxylic acid derived from a natural product.

The process of the present invention can be expressed by the following scheme: U4941 H C CH

X 1t X

/ \ CH_0 COCH / \

H \ / vH +> XH ~> \ / yH

V V-X cH.cr \ m y-X

X300H 2 COOH

'Λ H3cr N cooch3 followed by separation of pyrethric acid by the quinine salt.

The process of U.S. Patent No. 3,282,985 can be illustrated by the following scheme: H3Cv CH3 H3C CH3 Η3 ° \ ΡΗ3 / \ + NaOH - * / \ \

H / \ H H / \ "+ H / \ H

| f ^ COOCH3 ζ \ 0OH cf Y0CH3 τλ ^ / \: ooch3 (a) ^ c '^' Vooch ^ j (b) h3c / cooh (c) followed by separation of the pyrethrinic acid by means of the quinine salt.

The process of the invention in hemisynthesis allows the side chain of pyrethric acid (B) to be introduced into the cyolopropane carboxyl ring, while the process according to the US patent is only a separation of pyrethric acid by means of a quinine salt from the mixture obtained by hemihydrolysis or semi-saponification. of the dimethyl ester of dextro-trans-chrysanthemum-mum dicarboxylic acid (A) with the elimination of (2,2-dimethyl-3-methyl-oxy-arbonylcyclopropyl) -methacrylic acid (C).

Hemicaronaldehyde or 3,3-dimethyl-2- (R) -formyl-1- (R) -cyclopropanecarboxylic acid used as the starting compound of the process of the invention is obtained by gentle oxidation of chrysanthemic acid and is a more readily available compound than the dimetheblycer of dextrose. trans-chrysanthemum micdicarboxylic acid (A), which is difficult to isolate in the environment of numerous natural products obtained from pyrethrum.

For this reason, the process of the invention is much more interesting from an industrial point of view than the method of the prior art.

In particular, the process can be carried out as follows: - The anhydrous organic solvent in which the condensation of the phosphonopropionic acid ester with the hemicaronal aldehyde is carried out is e.g. an ether such as tetrahydrofuran, diethyl ether, dioxane or dimethoxyethane, an aliphatic alcohol such as methanol or tert-butanol, dimethyl sulfoxide or also a disubstituted amide such as dimethylformamide.

The highly basic agent in which the condensation of the hemicaronaldehyde and the phosphonopropionic acid ester is carried out is e.g. an alkali metal amide such as sodium amide, an alkali metal hydride, an alkali metal alcoholate or an alkali metal.

- The condensation of the hemicaronaldehyde and the phosphonopropionic acid ester is carried out under inert atmosphere to avoid possible oxidation of the aldehyde as far as possible.

In a suitable hereditary manner, the purification of the crude condensation product is effected by forming an alkali metal salt, such as the sodium or potassium salt, of the (+) - or D (-) - threo-1β-ni-trophenyl-2-H, ir-dimethylaminopropane. 1,3-diol salt or also of the 1-quinine salt, which allows the elimination of unwanted isomers.

The 0,0-dialkyl-1-methoxycarbonylethylphosphonate used is preferably 0,0-dimethyl or 0,0-diethyl-1-methoxycarbonylethyl phosphonate.

0,0-dimethyl-1-methoxycarbonylethyl phosphonate is not believed to be described in the literature. By analogy with the preparation of alkyl phosphonoacetates (cf. Arbusov, J. of General Chem. Of USSR, 66., 297 and 61, 620), 0.0-dimethyl-1-methoxycarbonylethyl phosphonate is prepared by the condensation of trimethylphosphite (CH O) P with a methyl oc halogen propionate, by condensation 5 5 1 * 4941 Ο 'Τ of the trimethyl phosphonoacetate (CH 2 O) 2 P-CH 2 on a methyl α-halogen propionate.

An example of the preparation of 0,0-dimethyl-1-methoxycarbonyl-ethyl phosphonate is given below.

O, O-diethyl-1-methoxycarbonylethyl phosphonate is prepared according to H. W. Coover et al. (Am. Eoc. 22 »si <3rd 1963 (1957)).

The following example illustrates the method of the invention.

6 144941

Preparation.

O-dimethyl-1-methoxycarbonylethyl phosphonate.

Tinder nitrogen atmosphere heats a mixture of 124 »1 g trimethyl phosphite and 183.7 g methyl a-bromopropionate to 115 ° 0. The reaction mixture is kept at this temperature for 48 hours. After cooling, the reaction mixture is rectified under reduced pressure to give 76.9 g of O-dimethyl-1-methoxycarbonylethyl phosphonate with b.p. 140 ° C / 18 mm Hg, which is used immediately for condensation with hemicaronaldehyde.

The saponification number of this product is 285 mg of potassium hydroxide for 1 g.

This connection is not believed to be described in the literature.

Example.

d-trans-pyrethric acid or 5,3-dimethyl-2- (R) - (21-methoxycarbonyl-trans-1T-propenyl) -1- (R) -cyclopropane carboxylic acid. content: $ 92) and the mixture is cooled to -5 ° C and dropwise introduced with a solution of 17.7 g of 0.0-dimethyl-1-methoxycarbonyl-ethyl phosphonate dissolved in 40 ml of tetrahydrofuran. The reaction mixture is brought to 20 ° C, and stir for 3 hours at this temperature and introduce 1.92 g of sodium amide (content: $ 92), cool the reaction mixture to -5 ° C and dropwise a solution of 6.4g. 1- (R) -hemi-caronaldehyde (or 3,3-dimethyl-2- (R) -formyl-1- (R) -cyclopropanecarboxylic acid) in 40 ml of tetrahydrofuran. Bring the reaction mixture to 20 ° C and keep this temperature for 3 1/2 hours, then evaporate to dryness under reduced pressure. Water is added to the evaporation residue and the aqueous phase is washed with ether, the combined ether extracts are washed with water, the aqueous phases are mixed and acidified to a pH of 1 by the addition of concentrated hydrochloric acid. The aqueous acidic phases are extracted with methylene chloride and the combined methylene chloride extracts are washed with water, dried and evaporated to dryness under reduced pressure.

a) Purification by formation of the l-quinine salt.

The evaporation residue (9.48 g) is dissolved in 100 ml of acetone containing 16 $ water and the solution is added 12 g of left-turn quinine base, then the reaction mixture is heated on a steam bath until complete dissolution and slowly cooled. The crystals formed are isolated by suction and 9 »19 g of crude 1-quinine salt are obtained.

A further yield of the same quality of 2.14 g is obtained from the mother liquors.

The first and second yields are combined and crystallized by acetone containing 16 # of water, yielding 7 »5 g of 1-quinine salt of 1 ~ (R), 2- (R) -seq.-trans-ohrysanthemum diearboxylic acid monomethyl ester with m.p. 169 ° and α2 = -101.5 ° (c * 1 #, methanol).

An additional yield of the same quality is obtained from the mother liquors from the purification.

In a mixture of 60 ml of ether and 60 ml of 2N hydrochloric acid, introduce the 7 »5 g of the quinine salt obtained above and stir, separate the ether phase by decantation, wash it with water, extract the washing liquid with ether, combine the ether phases, dry them and evaporates them to dryness under reduced pressure. The residue is rectified in vacuo to give 2.61 g of d-trans-pyrethric acid or 3,3-dimethyl-2- (a) - (2, -methoxycarbonyl-trans-1 * -propenyl) -1 ~ (R) -cyclo-propane carboxylic acid with b.p. 130 ° 0 / 0.2 mm Hg and? 2 = + 81.5 ° (c = 1.2 #, carbon tetrachloride).

Analysis: Ο ^ Ξ ^ Ο ^ - 212.24 calculated: C # 62.25 H # 7.60 found: 62.5 7.8 TJ «V. spectrum (ethanol):

Wax at 238-239 Βΐμ ε = 15,100 I.R. spectrum (chloroform): The I.E. spectrum is identical to that of Matsui et al. published (Agr. Biol. Ohem. Japan, £ 2, page 374 (1963)).

HoM.R. spectrum (deuterochloroform) (reference: 60 MHz):

The HoM.Respect is consistent with the trans configuration of the ring and the trans configuration of the olefin chain. It is resolved as follows: - 76 and 83 MHz corresponding to the hydrogen atoms of the methyl groups in the 3-position, - 101.5-107 MHz corresponding to the hydrogen at the 1-position (doubled), - 117.5-119 MHz corresponding to the hydrogen atoms of the methyl group of side chain, - 128-138-143 MHz corresponding to hydrogen at the 2-position (triplet), - 227.5 MHz corresponding to the hydrogen atoms in the methyl group in the ester group, - 387-397 MHz corresponding to the hydrogen atoms in the double bond in the side chain ( doubled), and - 664 MHz corresponding to the Hydrogen in 0-0H at the 1 position.

IN! 0

Circular dichroism (dioxane): \ ax 232 “μ Δε = + 7.98 b) Purification by formation of the sodium salt.

The residue (9.48 g) is dissolved in 60 ml of acetone. Clay is added 4.5 ml of 10 R sodium hydroxide solution.

The hatrium salt crystallizes out. Lightly suction at a temperature between 0 and 5 ° 0 and washed with acetone. The sodium salt of d-trans-pyrethric acid is obtained with a2 + - + 56 ° + 2 ° (c = 1 #, water). The product is soluble in water and insoluble in acetone and ether.

Proceeding as indicated in (a), one obtains d-trans - pyrethric acid, which is identical to that described above.

c) Purification by formation of the L (+) - threo-1-p-nitrophenyl-2-H, H-dime-thylaminopropane-1,5-diol total.

The residue (9.48 g) is dissolved in 30 ml of ethyl acetate.

Clay is added 11.1 g of 1 (+) - thre o-1-p-nitro phenyl-2-N, N-dimethylamino-propane-1,3-diol, and the mixture is refluxed until complete dissolution. The clay is cooled at a temperature between 0 and 5 ° C and the salt crystallizes out. Lightly suction and wash with ethyl acetate. Clay is obtained 11.4 g of 1 (+) - threo-1-p-nitrophenyl-2-, H-dimethylaminopropane-1,3-diol salt of d-trans-pyrethric acid.

The product is pale yellow. Mp. 125 ° 0, α2 = + 52 ° + 2 ° (c = 1 $, ethanol). Easily soluble in methanol and acetone, slightly soluble in water, ether and ethyl acetate.

This connection does not mean to be described in the literature.

Proceeding as indicated in (a), one obtains d-trans - pyrethric acid, which is identical to that described above.

Claims (2)

9 U4941 Patent Claims. A process for the preparation of d-trans-pyrethric acid, also called 1- (r), 2- (R) -seq.-trans-chrysanthemum dicarboxylic acid monomethyl ester or 3,5-dimethyl-2- (R) - (2, -methoxycarbonyl-trans-1'-propenyl) -1- (R) -cyclopropane carboxylic acid, of formula I CH. C & OCH, 3'c ^ II OL f "H CH3> XxK" OH & I characterized in that 1- (R), 2- (R) -hemicaronaldehyde of formula II H CH iC = ° H -VS CH3 \ r The presence of a strong basic agent and in an anhydrous organic solvent is reacted with O, O-dialkyl-1-methoxycarbonylethyl phosphonate of the formula IIIO Kt>? ^ CO-CH 2 PCH K-0 ^ CH, 3 m where R represents an alkyl group of 1-6 carbon atoms on which it