JPS62294642A - Manufacture of substituted 2-oxocyclohexaneacetic ester - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a process for producing substituted 2-oxocyclohexane acetic acid esters and intermediates used in the production. The substituted 2-oxocyclohexane acetate obtained by the process of the invention is itself described by Mobilio et al.
o et al., U.S. Pat. No. 4,616,028, 1
It is an intermediate for the preparation of useful analgesic and anti-inflammatory drug compounds, described on October 7, 986.

More specifically, the present invention relates to the formula (■): [wherein R and R1 are lower alkyl; R1, R3 and R5 are hydrogen or lower alkyl having 1 to 6 carbon atoms; each R4 is independently hydrogen and A group selected from the group consisting of lower alkyl having 1 to 6 carbon atoms, or R3 together with R4 in the cis position relative to the carbon bonded to R3 -ec)
T, ÷m, or R5 together with R4 in cis position to R5 -CH=CH-CH=CH-
forming; m means 2 or 3].

Prior Art The closest prior art to this invention is: Mobilio et al., US Pat. No. 4,616,028. Mobilio et al. describe a method for producing analgesic and anti-inflammatory compounds from 1,4-disubstituted 2-oxone chlorohexane acetate of formula (V) and the 2-oxone cyclohexane acetate of formula (V). Disclosed. Mobilio et al.
In the method for producing 2-oxocyclohexane acetate of formula (V), expensive phenylselenenyl chloride is used. The present invention provides a novel method for producing the 2-oxocyclohexane acetate in high yields from inexpensive reagents, does not require purification of intermediate compounds by chromatography, and can be conveniently carried out on a large scale. . The process of the invention also provides high yields of the preferred isomer of the 2-year-old xonclohexane acetate of formula (V).

A, As5elin et a
! ) is the Journal of Medical Chemistry (J.

Med, Chem, H9, 787 (1976) discloses another method for the preparation of substituted 2-oxychlorohexane acetates of formula (V).

A. Aracelin et al., U.S. Pat. No. 4,057,559;
On November 8, 1977, yet another method for preparing substituted 2-oxychlorohexane acetates of formula (V) is disclosed.

SUMMARY OF THE INVENTION The novel intermediate compounds of the present invention have formulas (IV), (III)
and (II).

In formula E, R and R1 are lower alkyl, R1, R3 and R5 are hydrogen or lower alkyl having 1 to 6 carbon atoms;
Each R4 is independently selected from the group consisting of hydrogen and lower alkyl having 1 to 6 carbon atoms, or R3 is R
3 together with R' in cis position to the carbon bonded to form +CHJm, or R5 together with R4 in cis position to R5 to form -CH= CH-CH=
forming CH-: m is 2 or 3; and X means chlorine or bromine]; [wherein R and R1 are lower alkyl having 1 to 6 carbon atoms; ; and [wherein,
R and R1 are lower alkyl having 1 to 6 carbon atoms; and X means chlorine or bromine.

Also included in the invention are noastereomers of formula (IV) in which the 4-substituent is in either cis or trans position relative to the acetate chain in position 1. Racemic mixtures of such compounds are referred to herein as (IV-(±)cis) and (IV-(±)trans).

Optical isomers of the compounds of formula (IV) resulting from the asymmetric centers contained are also encompassed by the present invention. Such isomers can be obtained in substantially pure form by classical separation techniques and configurationally controlled synthetic methods.

Preferred intermediate compounds of the invention are of the formulas (IVa-(±)cis) and (lVi(±)cis): (IVa-(±)cis) (lVb-(±)cis) [wherein l-methyl acetate The ester group is 4-(2-
propenyl) group, or 4-(phenylmethyl) group] is an isomer of 2-oxocyclohexane acetate.

Formula (V) [wherein R and R1 are lower alkyl; R2, R3 and R8 are hydrogen or lower alkyl having 1 to 6 carbon atoms;
Each R4 is independently selected from the group consisting of hydrogen and lower alkyl having 1 to 6 carbon atoms, or R3 is R
3 and R4 in the cis position relative to the carbon bonded to form ÷CHtTh: m means 2 or 3] A novel method for producing a known compound represented by the formula (a)
(): [In the formula, R and R1 are the same as above] Compound (I) [A. Aracelin et al., Journal of Medical Chemistry, 19.787
(1976)] with a halogenating agent such as bromine, cupric bromide or sulfuryl chloride in a suitable solvent such as methylene chloride, chloroform, methanol, diethyl ether or acetic acid,
Formula (II): [wherein R, R' and X are the same as above]
A novel intermediate compound (II) was obtained; b) N, N
- lithium carbonate, calcium carbonate, in a suitable solvent such as dimethylformamide or dimethyl sulfoxide;
Compound (II) is dehydrohalogenated in the presence of a base such as diazabicycloundecane or collidine, with or without the addition of a salt such as lithium bromide or sodium chloride, to form a compound of formula (■): , R, R' and X are the same as above] was obtained; C) the compound (III
), with the formula: [wherein R2, R3 and R5 are hydrogen or lower alkyl having 1 to 6 carbon atoms; each R' is independently selected from the group consisting of hydrogen and lower alkyl having 1 to 6 carbon atoms; or R3 together with one of the R4 substituents to form 'c CHt+m; m is 2 or 3: and Y is SiR'R'R'', or SnR@R'R8 (R1
'', R7 and R6 are independently hydrogen, carbon atom number 1-
6 straight chain or branched lower alkyl, cycloalkyl,
means a group selected from the group consisting of aryl, arylalkyl, halogen and alkoxy] and the compound represented by Etch Sakurai (H.

Sakurai), Pure & Applied
Chemistry (Pureand Appl, Chem,
), 54, l (1982) and De Seifers et al.

5eyferth et at,) Journal of
Organic Chemistry, (J, Org, Ch
Em, ), 26.4797 (1961),
The reaction is carried out in the presence of a Lewis acid such as titanium tetrachloride, tin(IV) chloride, zinc chloride, zinc bromide, magnesium chloride, or magnesium bromide to form a compound of formula (IV): [wherein R and Tl' are lower Alkyl, R2, R3
and R5 is hydrogen or lower alkyl having 1 to 6 carbon atoms; &R' is a group independently selected from hydrogen and lower alkyl having 1 to 6 carbon atoms, or R3
is in the cis position relative to the carbon bonded to R3 and together with R4 forms +CII μm; m is 2 to 3;
X tints chlorine or bromine. L, but the weir at position 4 is that the isomer located in the cis position relative to the 1st and 5.) acetate groups is more dominant than the trans isomer.] A novel intermediate compound (IV) represented by d) dehalogenating said compound (IV) with a reducing agent such as zinc in a weak acid or with sodium dithionite to obtain the desired compound (V).

Formula (V): [wherein R and R1 are lower alkyl; R2 and R3
is hydrogen or lower alkyl having 1 to 6 carbon atoms: R4 in the trans position relative to R5 is a group R5 selected from the group consisting of hydrogen and lower alkyl having 1 to 6 carbon atoms;
together with R' in the cis position relative to R5 =C
A novel method for producing a compound represented by j that forms l-1-CI (-CH=Cl-) comprises: a) the compound (
III), the formula (■): g ■ [wherein R1 and R3 are hydrogen or carbon atoms 1 to
lower alkyl, R4 in the trans position with respect to R5 is a group selected from the group consisting of hydrogen and lower alkyl having 1 to 6 carbon atoms, R5 together with R4 in the cis position with respect to R5 -CH= CH-C[(= CH
- is formed: Z means chlorine, bromine or iodine] and copper bromide (1) - dimethyl sulfide complex, cuprous iodide, cuprous bromide, copper acetate, chloride Copper 1,
In the presence of a copper salt such as tributylphosphine cuprous iodide complex, or cuprous cyanide, and at the same time titanium tetrachloride, zinc bromide, zinc iodide, zinc triflate,
The reaction is carried out in the presence of a Lewis acid such as lithium bromide, lithium iodide, magnesium bromide, magnesium chloride, magnesium triflate, or stannic chloride.

A preferred method involves adding compound (VIXZ-bromine) to compound (III) in the presence of about 0.1 molar equivalents of copper (1)-dimethyl sulfide summer coalescence and about 1 molar equivalent of zinc bromide. Formula (IV): [wherein R and R1 are lower alkyl, R2 and R3 are hydrogen or lower alkyl having 1 to 6 carbon atoms; It4 in the trans position with respect to R5 is hydrogen and The group R5 selected from lower alkyl having 1 to 6 carbon atoms together with R4 in the cis position relative to R5 represents -CII=CI-
forming 1-CII=CII-; and X tints chlorine or bromine. However, for the group at position 4, the isomer at the cis position with respect to the acetate group at position 1 is more dominant than the trans isomer. ;b) dehalogenating said compound (IV) with a reducing agent such as zinc in a weak acid or with sodium dithionite to obtain the desired known compound ().

Next, the present invention will be explained in more detail with reference to Examples.

Examples Example 1 3-bromo-1-ethyl-2-oxocyclohexa-3
-enoacetic acid methyl ester ((III)R--CI-1
3: Preparation of R'=-C,I (5:X-Br) 136 m4 (127
mmol, 2.5 equivalents), A. Aracelin et al., Journal of Medical Chemistry, 19.78
7 (1976), l-ethyl-2-
Oxocyclohexane acetic acid methyl ester l O, Og
(50.5 mmol) dropwise into a stirred solution. The mixture was stirred for an additional 30 minutes and treated with isobutylene to consume excess bromine. The reaction mixture was concentrated and 20.2 g of 3,3-dibromo-1-ethyl-2-oxocyclohexane acetic acid methyl ester (>100%
) was obtained (a portion of the oil was recrystallized from hexane to obtain a solid, melting point 61-62°C). Dissolve the oil in 62ml of N,N-dimethylformamide and add 6.4g of lithium bromide.
(74 mmol) and 3.9 g (54 mmol) of lithium carbonate. The reaction mixture was heated and stirred at 100° C. for 1 hour. The reaction mixture was poured into 100 ml of water and extracted with toluene (4xloOml). The toluene extract was washed with water (4 x 50 mC), dried (MgS
O,)L and concentrated to give 13.8 g (99% yield) of 3-bromo-1-ethyl-2-oxocyclohex-3-ene acetic acid methyl ester as a pale orange oil. This product was used in Example 2 without further purification.

NMR (CDC123,200MH2) δ0.87 (3
H.

t), 1.65 (2H, dq), 2.3-2.6 (5H
, m), 2°9 (I H, d), 3.65 (3H, s)
, 7.3 (IH, m).

Example 2 3-bromo-■-ethyl-2-oxo-4-(2-propenyl)cyclohexane acetic acid methyl ester ((R'
) : R= CH3; R'= Ct Hs
; Production of 3-bromo-1-ethyl-2-oxocyclohexa-
13.8 g (50.2 mmol) of 3-ene acetic acid methyl ester was dissolved in CH* C12t (distilled from CaH) 50 mQ
and cooled to -20°C. The mixture was diluted with TiCl
2.14.28 g (75.3 mmol) and then after 1 hour 6.9 g (9.6 mQ,
60.2 mmol) was added dropwise. Heat the mixture to -20℃
The mixture was stirred for 1 hour and then quenched with 42 ml of methanol followed by 56 ml of water. The mixture was then extracted with toluene (4x 150ml). The combined toluene extracts were washed with 100 ml of saturated sodium chloride solution, dried (MgSO, ), concentrated and 3-bromo-
Isomer mixture of 1-ethyl-2-oxo-4-(2-propenyl)cyclohexane acetic acid methyl ester 15.9
g (yield 99%) was obtained.

This product was used in Example 3 without further purification.

NMR (CD C13, 200MHz) δ0, 8 (
3H, t).

1.5-2.8 (11H, m), 3.6 (3H, s),
5.0-5.2 (3H, m), 5.5-5.8 (I H
, m).

This compound crystallized upon standing for a long period of time.

Example 3 Preparation of cis-1-ethyl-2-oxo-4-(2-propenyl)cyclohexane acetic acid methyl ester (Va-(±)cis).

3-Bromo-1-ethyl 2-oxo-4-(2-propenyl)cyclohexane acetic acid methyl ester 15.9g
(50.3 mmol) was dissolved in 107 m12 of acetic acid,
It was treated with 19.4 g (302 mmol) of zinc dust. The stirred mixture was heated to 100° C. for 5 hours, then cooled to room temperature. Excess zinc was removed by filtration, and the filtrate was added 10 ml of water.
0- was added and extracted with toluene (3x 150ml). The combined toluene extracts were then washed with saturated sodium bicarbonate solution, dried (MgSO, ), and concentrated to give cis-1-ethyl-2-oxo-4 as a yellow oil.
-(2-propenyl)cyclohexane acetic acid methyl ester ti,t4g (yield 93%) was obtained. The oil is distilled (
108 DEG -113 DEG C. at 0.3 mm Hg) to give 10.06 g (84% yield) of the product as a clear oil.

Gas chromatography analysis showed a ratio of cis:trans isomers of 7.5:1.

NMR (CD C (!3.200 MH2) δ0.8 (
3H, t).

1.5-2.6 (13H, m), 3.6 (3H, s),
5.0-5.1 (2H, m), 5.6-5.8 (IH,
m).

The isomer ratio (cis:trans) after bromine removal in Example 3 was 7.5:l. In subsequent experiments, in Example 2 a high selectivity ratio of 15:1) was obtained by adding allyltrimethylsilane as a 20% methylene chloride solution dropwise over 1 hour in Example 3.
It turns out that 71 will be awarded.

Example 4 Preparation of cis-1-ethyl-2-oxo-4-(2-propenyl)cyclohexane acetic acid methyl ester (Va-(±)cis) 3-bromo-1-ethyl-2-oxo-4-(2 -propenyl)cyclohexane acetic acid methyl ester 20041
19 (0,631 mmol) and sodium dithionite 1. Ig (6.31 mmol) was added to N.

N-Dimethylformamide: Dissolved in water (5 mc each) and stirred for 2 days under nitrogen atmosphere. The solvent was then removed under vacuum (0, l mmHg) at room temperature. The residue was partitioned between 1oono2 of ether and 50+n+2 of water.

The ether layer was dried (MgS 04) and concentrated to give a pale yellow oil. The product is then converted to bulb-to-bulb (bu
lb to bulb) distillation (85° C. at 0.1 mmHg) to obtain cis-1-ethyl-2-oxo-4-(2-propenyl)cyclohexane acetic acid methyl ester 128*9 (85% yield). Ta. It was identified as the product of Example 3 by NMR.

Example 5 Cis-1-ethyl-2-oxo-4-(phenylmethyl)cyclohexane acetic acid methyl ester (Vt+-(±)
Production of 3-bromo-1 in 107 mQ of dry tetravitrofuran
-ethyl-2-oxocyclohex-3-ene acetic acid methyl ester 10 g (36.3 mmol, prepared in Example 1) and copper bromide (D-dimethyl sulfide complex 746
zl? A solution of (3.63 mmol) was prepared under a nitrogen atmosphere.
It was stirred at 0° C. and treated with 8.17 g (36.3 mmol) of anhydrous zinc bromide. After 5 minutes, the mixture was dissolved in 36.3 mmol of pennormagneum chloride (2M solution in THF,
The length was 18.2 m, so the dropwise treatment was carried out. After 45 minutes, an additional 8 mmol of benzylmagnesium chloride was added followed by copper bromide (1
) 30 ytg of fib dimedimethyl complex was added followed by an additional 16 mmol of pendylmagneneum chloride. The reactants were added to 1-1 cf! of 1M! Quenched with 150m and extracted with 4 x 50m+2 ether. The extracts were combined, dried over magnesium sulfate, and concentrated to give 3-bromo1-ethyl-2-oxo-4-(phenylmethyl).
Cyclohexane acetic acid methyl ester was obtained.

This compound was then treated with N,N-dimethylformamide 7
Stirred in 4 mQ and 350+ nQ of water and treated with 109 mmol (18,96 g) of sodium dithionite. The mixture was heated at 55° C. for 20 minutes under a nitrogen atmosphere, poured into 200 mC of water and extracted with 4 x 100 m[rho] of ether-petroleum ether (1:1). The extracts were combined, washed with 100 m of water (! and 100 mQ of saturated sodium bicarbonate (aqueous solution), dried over magnesium sulfate,
Concentrate to give 10.48 g of product as a pale yellow oil (36,3
mmol, 100% crude yield). Analysis using capillary 〇〇 showed that the cis isomer was the main component, with a diastereomer ratio j of 41:1. The intermediate 3-
Reduction of bromo-1-ethyl-2-oxo-4-(phenylmethyl)cyclohexane acetic acid methyl ester to the title compound can also be carried out as described in Example 3.

NMR (CDCj!3/TMS, 200M) (z) δ0
18 (t, 3H, J = 7.5Hz), 1.4-2.9 (
m, I 3H), 3.6 and 3.7 (2s, 3H, 0CH3 of the main and minor isomers), 7.1-7.5 (m
, 5I-().

The ketone of Example 3.4 or 5 can be subjected to Fischer indole synthesis conditions as described in Mobilio et al. U.S. Pat. No. 4,616,028, in methanol.
The corresponding hydrazone is formed by flowing with 2-ethylphenylhydrazine or phenylhydrazine for an appropriate period of time.

The hydrazone solution was then cooled to O'C, treated with acetyl chloride to generate hydrogen chloride, and refluxed for an additional 45 minutes to effect the indole cyclization of Fischer. The resulting ester can be hydrolyzed with potassium carbonate in aqueous methanol to yield the well-known substituted tetrahydro-IH-carbazole-1-acetic acid, which exhibits analgesic and anti-inflammatory activity.

Methods for determining analgesic and anti-inflammatory activity and treating inflammatory or pain conditions are disclosed in U.S. Patent No. 2, Mobilio et al.
It is described in No. 4616028.

Claims (10)

[Claims] (1) Formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) [In the formula, R and R^1 are lower alkyl; R^2, R^
3 and R^5 are hydrogen or lower alkyl having 1 to 6 carbon atoms; each R^4 is independently hydrogen and 1 to 6 carbon atoms;
a group selected from the group consisting of lower alkyl of 6 or R^3 together with R^4 in the cis position to the carbon bonded to R^3 to form -(CH_2)-m; , or R^5 together with R^4 in cis position to R^5 forms -CH=CH-CH=CH-; m
is 2 or 3; and X means chlorine or bromine]. (2) Formula (III): ▲Mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, R and R^1 are lower alkyl having 1 to 6 carbon atoms; and X means bromine or chlorine. ] A compound represented by. (3) Formula (II): ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R and R^1 are lower alkyl having 1 to 6 carbon atoms; and X means chlorine or bromine. ] A compound represented by. (4) Formula (IVa-(±)cis): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IVa-(±)cis) The compound of item (1) above, represented by the formula (IVa-(±)cis). (5) Formula IVb-(±)cis): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IVb-(±)cis) The compound of item (1) above, which is represented by the formula: (IVb-(±)cis). (6)a) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R and R^1 are the same as below] A compound represented by the following is added to a halogenating agent in a suitable solvent. A compound represented by the formula (II): ▲Mathematical formula, chemical formula, table, etc.▼(II) [In the formula, R and R^1 are the same as below; and X means chlorine or bromine] (II); b) Dehydrohalogenation of compound (II) in the presence of a base and optionally an additional salt in a suitable solvent to obtain formula (III)
: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, R and R^1 are the same as below, and X is the same as above] Obtain the compound (III) represented by; c) The compound (III) ), the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^2, R^3 and R^5 are hydrogen or lower alkyl having 1 to 6 carbon atoms; each R^4 is independently a group selected from the group consisting of hydrogen and lower alkyl having 1 to 6 carbon atoms, or R^3 together with one of the R^4 substituents forms -(CH_2)-m; is 2 or 3; Y is SiR^6R^7R^8 and SnR^6
R^7R^8; R^6, R^7 and R^8 are independently hydrogen, straight chain or branched lower alkyl having 1 to 6 carbon atoms, cycloalkyl, aryl, arylalkyl,
means a group selected from the group consisting of groups selected from the group consisting of halogen and alkoxy] with a compound represented by the following in the presence of a Lewis acid,
Formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) [In the formula, R, R^1, R^2, R^3, R^4 and R
^5 is the same as below, X is the same as above] Obtain the compound (IV) represented by: d) Dehalogenate the compound (IV) using a reducing agent to obtain the desired compound (V). Formula (V) characterized by obtaining: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) [In the formula, R and R^1 are lower alkyl; R^2, R^
3 and R^5 are hydrogen or lower alkyl having 1 to 6 carbon atoms; each R^4 is independently hydrogen and 1 to 6 carbon atoms;
a group selected from the group consisting of lower alkyl of 6 or R^3 together with R^4 in the cis position to the carbon bonded to R^3 to form -(CH_2)-m ;
m means 2 or 3] A method for producing a compound shown in the following. (7)a) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The compound shown by is dibrominated with bromine in a methylene chloride solvent, and the compound shown by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ b) treating the dibromo compound with lithium bromide and lithium carbonate in N,N-dimethylformamide solvent;
Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Obtain a monobromo compound shown by c) Add titanium tetrachloride dropwise to a methylene chloride solution of the monobromo compound to react, and then add a methylene chloride solution of allyltrimethylsilane. d) Add the allyl bromo compound to zinc in acetic acid. (Va-(±)cis) characterized by debromination with sodium dithionite in aqueous or aqueous N,N-dimethylformamide to obtain a compound of the desired formula (Va-(±)cis).
: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Va-(±)cis) The method of item (6) above for producing a compound represented by. (8)a) Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R and R^1 are the same as below] A compound represented by the following is halogenated in an appropriate solvent. dihalogenated with an agent, and is represented by the formula (II): ▲Mathematical formula, chemical formula, table, etc.▼(II) [In the formula, R and R^1 are the same as below; and X means chlorine or bromine] obtain compound (II); b) dehydrohalogenate compound (II) in a suitable solvent in the presence of a base and optionally added salt to obtain compound (II) of formula (I);
II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) [In the formula, R and R^1 are the same as below, and X is the same as above] Obtain the compound (III) represented by: c) The compound (III), formula: (VI): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VI) [In the formula, R^2, R^3, R^4 and R^5 are the same as below, and Z means chlorine, bromine or iodine]
A compound represented by: and a copper (I) bromide-dimethyl sulfide complex, cuprous iodide, cuprous bromide, copper acetate, cuprous chloride, tributylphosphine-cuprous iodide complex, or In the presence of a copper salt such as cuprous cyanide, titanium tetrachloride, zinc bromide, zinc iodide, zinc triflate, lithium bromide, lithium iodide, magnesium bromide, magnesium chloride, magnesium triflate, Alternatively, by reacting in the presence of a Lewis acid such as stannic chloride, the formula (
IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) [In the formula, R, R^1, R^2, R^3, R^4, and R^5 are the same as below, and X is the same as above. d) Dehalogenating the compound (IV) with a reducing agent to obtain the desired compound (V): Formula (V): ▲ Formula, There are chemical formulas, tables, etc.▼(V) [In the formula, R and R^1 are lower alkyl; R^1 and R^3 are hydrogen or lower alkyl having 1 to 6 carbon atoms;
R^4 in the trans position with respect to R^5 is a group selected from the group consisting of hydrogen and lower alkyl having 1 to 6 carbon atoms, R^4 in the cis position with respect to R^5, R^5
and form -CH═CH-CH═CH-]. (9)a) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The compound shown by is dibrominated with bromine in a methylene chloride solvent, and the dibromo compound shown by the formula; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ b) treating the dibromo compound with lithium bromide and lithium carbonate in N,N-dimethylformamide solvent;
Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Obtain a monobromo compound of the formula, and c) about 0.1 molar equivalent of copper (I)-dimethyl sulfide complex and about 1 molar equivalent of zinc bromide. A solution of benzylmagnesium chloride in tetrahydrofuran is added dropwise to a solution of the monobromo compound and dimethyl sulfide in tetrahydrofuran to react in the presence of , to obtain a benzylbromo compound represented by the formula (IVa-(±)cis): d ) The benzyl bromo compound is debrominated with zinc dust in acetic acid or sodium dithionite in aqueous N,N-dimethylformamide to give the desired formula (Vb-(±)cis)
(Vb-(±)cis): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(Vb-(±)cis)) the method of. (10) a) The compound represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is dibrominated with bromine in a methylene chloride solvent, and the dibromo compound represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ b) treating the dibromo compound with lithium bromide and lithium carbonate in N,N-dimethylformamide solvent;
Formulas characterized by obtaining the desired compound: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Items (6) to (9) above for producing the compound shown in
One method for each item.