JPS637538B2 - - Google Patents

Description

[Detailed description of the invention]

TECHNICAL FIELD This invention relates to a process for making new and useful compounds. More specifically, the present invention relates to a method for producing α-methyl-3,4-dihydroxyphenylalanine derivatives. It is known in the art that various alanine compounds are used in the treatment of hypertension (see US Pat. No. 2,868,818). Furthermore, because the D-form of the compound is therapeutically inactive and only the L-form of the compound is therapeutically active, hypertension is preferably treated with L-α-methyl-3,4-dihydroxyphenyl. Treatment with enylalanine is also known in the art. Removal of the D-form reduces toxicity and increases efficacy (U.S. Pat.
3344023 and UK Patent No. 936074). The L-isomer of α-methyl-3,4-dihydroxyphenylalanine is commonly referred to as L-α-methyldopa or methyldopa. Furthermore,
It is also known in the art that alkyl esters of L- or DL-α-methyl-3,4-dihydroxyphenylalanine are useful in the acute treatment of hypertension by parenteral administration (U.S. Pat. 3230143). Other esters and derivatives of DL- or L-α-methyl-3,4-dihydroxyphenylalanine with special structures are also active in the treatment of hypertension and have been shown to be compounds for such treatment. I understand. It has also been found that certain new compounds have much higher activity than known compounds and, as a result, require lower dosages than known compounds. It is therefore an object of the present invention to provide a method for producing new and useful compounds that are active in the treatment of hypertension. The purpose of the above is the formula: or an acid addition salt thereof (wherein, Y is -COOH or a carboxylic acid salt,
A ₁ and A ₂ are each H) with the formula: [In the formula, m and n are each 0, 1 or 2; R ₁ and R ₂ are each H or lower alkyl; R ₃ is a group X-R ₄ (wherein X is -O-, -S- or -NH -; R ₄ is an alkyl containing up to 5 carbon atoms or an unsubstituted or halogen-substituted acyl group of an organic acyclic carboxylic acid; X ₁ is hydroxyl or halogen. A formula characterized by esterification with a compound of: [In the formula, m, n, R ₁ , R ₂ , R ₃ , A ₁ , and A ₂
is achieved by the present invention, which provides a method for producing the compound or its acid addition salt as described above. The present invention also relates to the formula: An acid derivative or an acid addition salt thereof (wherein Y is -COOH, R ₅ and R ₆ are each hydrogen or together are diphenyl ketal, and R ₇ is carbobenzyloxy) of the formula: [In the formula, m and n are each 0 or 1; R ₁ and R ₂ are each H; R ₃ is a group X-R ₄ (wherein, X is -O- or -NH-; R ₄ is 5 is an unsubstituted or halogen-substituted acyl group of an organic acyclic carboxylic acid containing up to ₁ carbon atoms; [In the formula, m, n, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ and
A formula characterized in that R ₇ is as described above] or an acid addition salt thereof is obtained and reduced: [In the formula, A ₁ and A ₂ are respectively H; m, n,
R ₁ , R ₂ and R ₃ are as described above] or an acid addition salt thereof. The present invention further provides the formula: or an acid addition salt thereof (wherein Y is -COOH, _R5 , _R6 are each hydrogen or taken together diphenyl ketal, and _R7 is carbobenzyloxy) of the formula: [In the formula, m and n are each 0 or 1; R ₁ and R ₂ are each H: R ₃ is a group X-R ₄ (wherein, X is -O- or -NH-; R ₄ is 5 is an unsubstituted or halogen-substituted acyl group of an organic acyclic carboxylic acid containing up to ₁ carbon atoms; [In the formula, m, n, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ and
R ₇ is as described above] or an acid addition salt thereof is obtained, and this is hydrolyzed: [In the formula, A ₁ and A ₂ are respectively H; m, n,
R ₁ , R ₂ and R ₃ are as described above] or an acid addition salt thereof. Regarding the L-isomer of the resulting compound, it must be noted that the asymmetric carbon atom is the carbon containing the amino and methyl groups in the acid part of the molecule. It is this part of the molecule that is referred to as the L-configuration. In this case, although the L configuration is an optical isomer of the l or levorotatory form, the L configuration refers to the configuration and not to the optical rotation. However, in some cases, when R ₁ and R ₂ are different groups,
It must be noted that the carbon atoms to which they are attached are also asymmetric carbon atoms and can therefore exist as L or D configurations. As discussed below, all isomers of this portion of the compound are active. As discussed further below, these stereoisomers were separated, but their configuration was not determined. As a result, they were designated simply as α and β-isomers. In either case, both the α and β-isomers are active regardless of configuration. In the treatment of hypertension, the compounds of the invention are generally administered in an amount of about 0.005 to 300 mg/Kg of animal body weight, preferably about 0.05 to 100 mg/Kg. In a more preferred implementation, the compound is administered in an amount of about 0.1 to 25 mg/kg of animal body weight. In this regard, it must be noted that the amount used must be adjusted according to the activity of the compound, the desired blood pressure lowering response and the weight of the animal.
In the dosage ranges mentioned above, highly active compounds are given in lower dosages and less active compounds are given in higher dosages. When the L isomer of a compound of the invention is provided in the substantial absence of the D isomer, the required amount of L isomer to be used is approximately racemic, since the D-isomer is therapeutically inactive. This is half of the amount used by the body. However, the compounds of the invention differ to some extent in activity, and as a result racemic forms of the less active compounds of the invention may require dosages several times that of the highly active compounds. do. Generally, the compounds will be administered in the amounts used above. In a single use form of a pharmaceutical composition consisting of an inert pharmaceutically acceptable diluent and a compound of the invention or a pharmaceutically acceptable acid addition salt thereof, the active compound will generally be about 1 mg to 2000 mg, preferably is present in the composition in an amount of about 5 mg to 1000 mg. In a preferred implementation, the active compound is about 10 mg to
Present in an amount of 500mg. A single usage form of a compound is
It may be administered in a single slowly acting dose or in several smaller doses throughout the day, generally from 2 to 8 doses. In therapeutic methods, the L isomer, which contains substantially no D isomer compared to the racemate, is used in reduced amounts. However, differences in the activity of various compounds necessitate the use of different dosages. In some cases, compounds may be several times more active than other compounds, and as a result the racemic form of one compound may require less usage than the L isomer of the second compound. The method of the invention is practiced with the amino acid portion of the molecule in the L configuration. The expressions “(−CH ₂ ) _o ” and “(−CH ₂ ) _n ” also mean

【formula】

[expression] and

Including branched alkylene groups such as [Formula] do. Preferably n and m are 0 or 1.
Ru. The expression “pharmaceutically usable acid addition salts” is
An expression well known in the art,
and by reaction of the free base with an inorganic or organic acid.
It includes compounds produced by it is hydrochloric acid
Includes salts, hydrobromides, salts with sulfuric acid, etc. “Amino acids that do not substantially contain the D isomer
The term "L isomer" refers to the term "L isomer of
It means that it exists in an impossible amount. But long
, the D isomer is substantially absent from the composition.
is desirable. In the following examples, referred to as L isomer
, the compound is substantially in the L configuration.
100% (i.e. 99% or more). The compounds of the invention are preferably prepared in tablets, pills, caps.
Cells, powders, granules, sterile parenteral solutions or suspensions
Unit uses such as liquids, oral solutions or suspensions, etc.
They may be used in the form of compositions that are administered in dosage forms.
When manufacturing solid compositions such as tablets, the active
Corn lees as a pharmaceutical diluent or carrier as an ingredient
powder, lactose, sucrose, sorbitol,
Talc, stearic acid, magnesium stearate
of gum, dicalcium phosphate, rubber and similar substances.
Mix with ordinary tablet ingredients such as. Compounds of the invention
Tablets or pills of composition consisting of
is the delayed action or expected continued action of the encapsulated drug.
Laminated to provide a usage form that gives the advantages of
Or it can be blended. For example, tablets or
The pill consists of an internally used ingredient and an externally used ingredient that envelops it.
It can be made up of ingredients for two
The ingredients resist disintegration in the stomach and preserve internal components.
Allows to pass intact into the duodenum
or to help delay release.
It can be separated by a terrestrial layer. like this
Various types of services for the entertainment layer or coaching
Substances can be used. substances like this
is a large number of polymeric acids or polymeric acids and
Eratsuk and cetyl alcohol, cellulose acetate
It includes mixtures with substances such as Special
Enteric coaching is advantageous for Cochin
Together with known substances that contribute to the enteric nature of
It consists of a styrene-maleic acid copolymer. combination
The product can also be used when administered in the form of suppositories or diluted
Administered with osmotic agents such as methyl sulfoxide
It is also useful when For administration of a composition comprising a compound of the invention
Liquid forms that can be mixed include cottonseed oil, sesame oil, and coconut oil.
Use edible oils such as oil or peanut oil.
Appropriately flavored emulsions and elixirs
sir and similar pharmaceutical vehicles. aqueous suspension
Suitable dispersing or suspending agents for liquids are synthetic or
and natural rubbers such as gum tragacanth and arabiyago
Mu, alginate, dextran, sodium carbonate
ruboxymethylcellulose, methylcellulose,
Including polyvinylpyrrolidone, gelatin, etc.
Ru. Sterile suspensions or solutions are not suitable for parenteral use.
It is necessary. Isotonic formulations containing suitable preservatives
are also highly desirable for injectable use. As used herein, a single usage form is
The word is appropriate as a unit usage form for warm-blooded animals.
means a physically discrete unit of
The unit is compatible with any necessary pharmaceutical diluents, carriers or vehicles.
Calculated to give the desired therapeutic effect together
containing the predetermined amount of active substance. single
The specification of the form of use shall include (a) the specific properties and characteristics of the active substance;
and the specific therapeutic effect to be achieved; (b) as detailed herein;
Therapeutic use of active substances such as those described in
Due to limitations inherent in formulation techniques for therapeutic use,
It's coming and coming. In a suitable oral single use form
Examples are tablets, capsules, pills, powder sachets, granules,
wafer, cassie, teaspoon amount, dropper
quantities, ampoules, vials, and as described herein
and other forms such as The following examples are given to illustrate the invention.
and is not intended to limit the invention.
stomach. Unless otherwise stated, all parts are parts by weight.
Ru. “Decompression” used in the following examples is different from
15-25 mmHg at 25-35°C unless otherwise specified.
If you use vacuum to remove the solvent, the resulting raw material
products are often solvates, and as a result
All solvents except those bound to the product
Although the agent is removed, the example is
means the formation of a product. Reference example 1 A L-3-(3,4-diphenylmethylenedio)
xyphenyl)-2-methylalanine hydrochloride
manufacturing L-3-(3,4-dihydroxyphenyl)-2
-Methylalanine hydrochloride [L-α-methyldopa
Hydrochloride] 19.3g (0.0777mol) and dichlorodi
A mixture of 37 g (0.156 mol) phenylmethane is slowly
Oil bath preheated to 190°C under slow stirring
Soak in. Reactions marked by intense gas evolution
After the start of the reaction, the reaction mixture was stirred rapidly for 6 min at 190°C.
Stir, remove from hot oil bath and then cool to 25-30 °C
do. Combine the crude products from the 12 times diethyl
Slurry with ether 3, filter, diethyl
Wash with ether 2, then at 30°C below 50mm pressure.
dry. Dissolve the product in ethanol, then vinegar
by adding ethyl acid to precipitate the product.
to achieve recrystallization. Melting point 267-268℃ (decomposition)
L-3-(3,4-diphenylmethylenedioxy
(phenyl)-2-methylalanine hydrochloride 255g
(66.4%). Analysis value: C_{twenty three}H_{twenty one}NO._Fouragainst HCl Calculated values: C 67.07, H 5.39, N 3.40 Experimental values: C 66.91, H 5.29, N 3.34 B L-N-carbobenzyloxy-3-(3,
4-diphenylmethylenedioxyphenyl)-
Production of 2-methylalanine By slow addition of 10% sodium hydroxide solution
While adjusting the pH to 12.0, add L-3 (3,4-
Diphenylmethylenedioxyphenyl)-2-meth
Chilalanine hydrochloride 175g (0.425mol), acetate
A mixture of 1750 ml of water and 1750 ml of water was heated to a temperature below 10°C.
Stir under nitrogen at 30°C. Carbobenzyl chloride
Add 93 g (0.545 mol) of Si to the reaction mixture at 20-30℃.
Drip over 5-7 minutes. At this time, 10% hydroxy acid
Add sodium solution at the same time to adjust the pH to 12.0~
Keep it at 12.2. Addition of carbobenzyloxy chloride
After the addition was completed, the reaction mixture was stirred at 25-30°C for 3 hours.
do. Then remove most of the acetone under reduced pressure at 25-35℃
Removal of the desired N-carbobenzyloxy derivative
Precipitates sodium salts in the body. This sodium
The salts were extracted into 1.5% ethyl acetate and 5% sodium hydroxide.
200ml of sodium chloride solution and saturated sodium chloride solution
Wash with 200ml and then dry over magnesium sulfate
do. Add 17.5g of decolorizing carbon, and add sulfuric acid magne.
Solvent at 25-35℃ after passing through a bed of
Remove under reduced pressure. The residue was dissolved in ethyl ether (20
%) - twice in hexane (80%) (by volume) solution
The desired N-carboxylic acid is slurried and then filtered.
Obtain the sodium salt of benzyloxy derivative. child
Dissolve the sodium salt of 1.5 in ethyl acetate and add 10
℃, then acidified with 6N hydrochloric acid to pH 2.
Ru. Add ethyl acetate extract to saturated sodium chloride solution
Wash with 200 ml and dry over magnesium sulfate,
filtrate and then concentrate under reduced pressure at 25-35°C. N-Cal
Bobenzyloxy derivatives at 25~30℃ and 0.2~
Dry at 0.3mmHg and remove L-N-carbobenzyloxychloride.
C-3-(3,4-diphenylmethylenedioxy
phenyl)-2-methylalanine is obtained. C Succinimidomethyl L-N-carbobendi
3-(3,4-diphenylmethylene)
dioxyphenyl)-2-methylalaninate
Manufacturing of L-N- in 35 ml of dry dimethylformamide
Carbobenzyloxy-3-(3,4-diphenylene)
lumethylenedioxyphenyl)-2-methylara
13.5g (0.0265mol) of nin, 2.7g of triethylamine
g (0.027 mol) and N-bromomethylsucci
A solution of 5.19 g (0.029 mol) of imide was heated at 25-30℃.
Stir for 16 hours. Pour the reaction mixture into 400ml of ice water.
and then the product was dissolved in chloroform (50%)-di
Ethyl ether (50%) (according to solubility) mixture 200
Extract to ml. Organic extract diluted (50%) with sodium carbonate
50 ml of sodium chloride solution and 50 ml of saturated sodium chloride solution
ml and then dried over anhydrous magnesium sulfate.
Dry to remove water. under pressure and vacuum
After concentration, the residue is recrystallized. Recrystallization is the raw
Dissolve the product in ethanol, then add hexane
This is achieved by precipitating the product.
Succinimidomethyl L- with melting point 143.0-145.0℃
N-carbobenzyloxy-3-(3,4-diph)
enylmethylenedioxyphenyl)-2-methyl
12.1 g (73.6%) of alaninate are obtained. Analysis value: C₃₆H₃₂N₂O₈against Calculated values: C 69.66, H 5.20, N 4.51 Experimental values: C 69.83, H 5.14, N 4.52 D Succinimidomethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalanine
Production of hydrochloride hydrate 180ml absolute ethanol and 9.6N ethanolic
Succinimidomethyl in 9 ml of anhydrous hydrogen chloride solution
L-N-carbobenzyloxy-3-(3,4-
Diphenylmethylenedioxyphenyl)-2-meth
Suspension of 6.6 g (0.0106 mol) of tylalaninate
using 3.3g of carbon catalyst with 10% palladium.
Hydrogen under an initial pressure of 30 p.s.i until hydrogen absorption is complete.
Added. After removing the catalyst by filtration,
Concentrate under reduced pressure. Pour the residue into 50ml of benzene and then acetic acid.
Extract with 50 ml of ethyl. Then remove the insoluble solid with ethanol.
alcohol (10%) - ethyl acetate (90%) (by volume)
With 50 ml of mixture and 10 ml of saturated sodium carbonate solution
Shake both. After filtering, pour the liquid into an anhydrous sulfuric acid mug.
Dry over sodium chloride, filter, and concentrate in vacuo.
Ru. Redissolve the residue in 25 ml of absolute ethanol and
Treated with 5 ml of 9.6N ethanolic anhydrous hydrogen chloride solution
and then concentrated under reduced pressure to obtain succinimidomethyl L-
3-(3,4-dihydroxyphenyl)-2-methy
Lualaninate hydrochloride hydrate 2.5g (62.7%)
obtain. Thin layer chromatography (fluorescent silica gel)
plate, 30% methanol 70% benzene (by volume)
homogeneous due to [solvent]. Observed Rf=0.5 Analysis value: C₁₅H₁₈N₂O₆・HCl・H₂against O Calculated values: C 47.81, H 5.62, N 7.44 Experimental values: C 48.09, H 5.74, N 7.42 Reference example 2 A N-(1-chloroethyl)-succinimide
manufacturing N-vinyl succinimide 50.0g (0.40mol)
Dissolve in 1000ml of carbon tetrachloride and add 5.20g of stannic chloride.
(0.020 mol) and then chlorinated at 20-30℃ for 6 hours.
Stir the mixture while saturating with hydrogen. 24 hours later
Then, the mixture was resaturated with hydrogen chloride for 1.5 h.
At the end of 48 hours, the solution was decanted and then gummy
Wash the residue 10 times with 100 ml each of carbon tetrachloride.
The combined extract was slurried with 10 g of diatomaceous earth and filtered.
Then, concentrate the liquid under reduced pressure to about 400 ml. N
-(1-chloroethyl)-succinimide
and then dried under reduced pressure at 20-30℃ to a melting point of 83.5~
Obtain 38.4 g (59%) of a white solid at 84.5°C. B α-succinimidoethyl L-N-carbobe
ndyloxy-3-(3,4-diphenylmethy)
dioxyphenyl)-2-methylalanine
Manufacture of sheets L-N-carbobenzyloxy-3-(3,4
-diphenylmethylenedioxyphenyl)-2-
Methylalanine 30.66g (0.066mol), N-(1-
chloroethyl) succinimide 9.70g (0.060mol)
), triethylamine 6.07g (0.060mol) and
and 75 ml of dimethylformamide at 95°C.
Stir for 19 hours. Pour the reaction mixture into 750ml of water,
Next, extract the product three times with 500 ml each of ethyl acetate.
Ru. The combined organic extracts were dissolved in 5% sodium hydroxide.
3 times with 300 ml of solution and saturated sodium chloride solution
Wash 3 times with 300ml of liquid, then wash with anhydrous sulfuric acid mug.
Dry on nesium. After filtering, add 5g of charcoal to the solution.
filtration and then evaporation of the solvent under reduced pressure to remove dia.
As a mixture of stereoisomers (α and β)
α-Succinimidoethyl L-N-carbobendi
3-(3,4-diphenylmethylenedi)
Oxyphenyl)-2-methylalaninate 37.90
g (99%). C α-succinimidoethyl L-3-(3,4
-dihydroxyphenyl)-2-methylalani
Production of nate hydrochloride Absolute ethanol (25%) - ethyl acetate (75%)
α-succinimide in 275 ml of solution (by volume)
Ethyl L-N-carbobenzyloxy-3-(3,
4-diphenylmethylenedioxyphenyl)-2
- 20.18 g (0.032 mol) of methylalaninate
Using 8.5g of carbon catalyst with 10% palladium,
Hydrogenated for 23 hours at an initial pressure of 40 p.s.i. and room temperature.
do. Pass through the catalyst, then reduce the pressure of the liquid at 30-40℃
evaporates below. Residue ethanol (10%)-vinegar
Ethyl acid (90%) dissolved in solution (by volume);
Then 20ml of saturated sodium carbonate solution and anhydrous carbonic acid
Stir for 10 minutes with about 30 g of sodium. After the past
The solution was dried over anhydrous magnesium sulfate and filtered.
and then evaporated to dryness under reduced pressure. Dry the residue with chloro
Dissolve in 130 ml of foam, cool the solution in an ice bath,
Then saturate with hydrogen chloride for 15 minutes. Collect the solids and then
Washed three times with 100 ml of anhydrous ether, then washed with N₂
in 300 ml of ethyl acetate in a stoppered flask below.
Slurry at room temperature overnight. α-succinimium
Doethyl L-3-(3,4-dihydroxyphenylene)
Collect 2-methylalaninate hydrochloride into hexafluoride
Slurry in 300ml bottle for 2 hours, then vacuum desiccant.
CaCl₂dry on top and α and β
8.32 g (62%) of the hydrochloride salt was obtained as a mixture of isomers.
Ru. Thin layer chromatography [fluorescent silica gel]
plate, methanol (50%) - benzene (50%) (volume
Observation Rf = 0.7 by solvent] Analysis value: C₁₆H₂₀N₂O₆・HCl・1/2CH₃C.O.₂C₂H_Five against Calculated values: C 51.86, H 6.05, N 6.7 Experimental values: C 51.98, H 5.87, N 6.65 Reference example 3 A α-succinimidoethyl L-N-carbobe
ndyloxy-3-(3,4-diphenylmethy)
dioxyphenyl)-2-methylalanine
Production of isomers Mixture of diastereoisomers of Example 2 150.5
g to 1200 ml of benzene and 100 ml of anhydrous methanol
Dissolve in the boiling mixture, filter, and then concentrate the liquid
to make approximately 700ml. Solution with 100ml of anhydrous methanol
In addition, dilute it with 1000ml of hexane.
Add seeds to induce crystallization. mixture
Cool to 5°C for about 16 hours and then cool the crude crystalline α-isomer.
50:50 of benzene and hexane
by suspending in 200ml of the mixture (depending on volume).
Wash and then dry at 70°C. The product is 68.1
g and has a melting point of 185.5-191°C.
The sample for analysis after recrystallizing two more times is 199.5 ~
It has a melting point of 201.5℃. Analysis value: C₃₇H₃₄N₂O₃against Calculated values: C 70.02, H 5.40, N 4.41 Experimental values: C 70.22, H 5.52, N 4.29 The washings from the combined mother liquor and α-isomer were heated at 60°C.
It is evaporated to dryness under reduced pressure to form a very viscous oil.
Obtained 79.3g of solids. B α-succinimidoethyl L-3-(3,4
-dihydroxyphenyl)-2-methylalani
Production of nate hydrochloride dihydrate (β-isomer) Absolute ethanol (25%) - ethyl acetate (75%)
α-succinimide in 140 ml of solution (by volume)
Ethyl L-N-carbobenzyloxy-3-(3,
4-diphenylmethylenedioxyphenyl)-2
-Methyl alaninate (β-isomer) 10.0g
(0.016 mol) solution of 10% palladium-coated carbon catalyst
20 at an initial pressure of 40 p.s.i and room temperature using 4.2 g
Hydrogenate for an hour until hydrogen absorption is complete. catalyst
was filtered under nitrogen, and the solution was diluted with 9.4N ethanol.
acidified with 2.0 ml of hydrogen chloride and then at 30-40℃.
Evaporate to dryness under reduced pressure. Amorphous solid residue at 95% temperature
Dissolve in 50 ml of ethanol (5% water), filter, and then
Dilute the liquid with anhydrous ether (68ml) and make a cloud.
Add seeds to induce crystallization. the product
Collect, then stir in 300 ml of anhydrous ether to dilute
Remove enylmethane. Collect the solid after 1 hour.
and dried overnight at 70°C to a melting point of 123-126°C.
Obtain 3.7 g of (decomposed) material. 20ml of 95% ethanol
Melting point of 129-131℃ (decomposition) after recrystallization from
(dried overnight at 70℃) as a dihydrate of
imidoethyl L-3-(3,4-dihydroxy
Phenyl)-2-methylalaninate hydrochloride dihydrate
3.36 g (51%) of compound (β-isomer) are obtained. thin layer
Chromatography [fluorescent silica gel plate, methane
Sol (50%) - Benzene (50%) (by volume) solution
homogeneous due to Rf=0.7 Analysis value: C₁₆H₂₀N₂O₆・HCl・2H₂against O Calculated value: C47.00, H6.16, N6.85 Experimental value: C46.85, 47.09, H6.12, 6.16, N6.76, 6.61 [α]²⁴⁰ _D=+33.46゜ (C=1.5, CH₃OH) Reference example 4 A α-succinimidoethyl L-3-(3,4
-dihydroxyphenyl)-2-methylalani
Production of nate hydrochloride (α-isomer) Absolute ethanol (25%) - ethyl acetate (75%)
α-succinimide in 140 ml of solution (by volume)
Ethyl L-N-carbobenzyloxy-3-(3,
4-diphenylmethylenedioxyphenyl)-2
-Methyl alaninate (α-isomer) 10.0g
(0.016 mol) was added to a carbon catalyst coated with 10% palladium.
using 4.2 g of medium at an initial pressure of 40 p.s.i. and room temperature.
Hydrogenate for 271/2 hours until hydrogen absorption is complete. Add 2 ml of a 9.4N ethanol solution of anhydrous hydrogen chloride.
Well, then by passing the catalyst through a bed of diatomaceous earth.
Remove. After concentration under reduced pressure, the residue was dissolved in diethyl
2 times with 200 ml of ether and 200 ml of benzene, then die
by shaking twice with 200 ml of chill ether.
Extract. The materials remaining after these extractions are
α-Succinimidoethyl L-3-(3,4
-dihydroxyphenyl)-2-methylalanine
salt hydrochloride (α-isomer) diethyl ether solvent
It is Japanese. Rf=0.7 [thin layer chromatography,
Fluorescent silica gel plate, methanol (50%) - benzene
(50%) (by volume) solvent]. Diphenylmeth
Contaminated with 12% of the sample. [α]^{twenty four} _D=18.75(C=
1.68，CH₃OH). Example 1 A 2-trifluoroacetamidoethyl L-N
-carbobenzyloxy-3-(3,4-diph)
enylmethylenedioxyphenyl)-2-methy
Manufacture of lualaninate L-N- in 20 ml of dry dimethylformamide
Carbobenzyloxy-3-(3,4-diphenylene)
lumethylenedioxyphenyl-2-methylalani
5.09g (0.010mol), triethylamine 1.01g
(0.010 mol) and N-(2-chloroethyl)-
2,2,2-trifluoroacetamide 1.76g
(0.010 mol) solution at 110°C under nitrogen for 20
Stir for an hour. Pour the cooled reaction mixture into 500 ml of ice water.
and then the product in 500 ml portions of ethyl acetate.
Extract 3 times. Wash the combined extract with 200ml of water,
Drying (MgSO_Four), filtered, and then concentrated under reduced pressure.
get oil. Redissolve the residue in 100ml of ethyl acetate and
Extract twice with 50ml of 5% sodium hydroxide solution
washed with 50 ml of water, then washed with magnesium sulfate.
dry. Filter and concentrate under reduced pressure to obtain 4.92 g of oil.
Ru. Chromatograph this oil on 200g of silica gel.
After processing the methanol in the chloroform
2-trifluoride was eluted as an oil with a 5% solution of
Roacetamidoethyl L-N-carbobenzyl
xy-3-(3,4-diphenylmethylene dioxy)
4.11g of (siphenylated)-2-methylalaninate
(63.4%). Thin layer chromatography [firefly]
Optical silica gel plate, methanol (5%) - chlorophyll
Homogeneous (95%) (depending on volume).
Rf=0.8. B 2-trifluoroacetamidoethyl L-3
-(3,4-dihydroxyphenyl)-2-methy
Production of lualaninate hydrochloride 2-trifluorore in 125 ml of absolute ethanol
Cetamidoethyl L-N-carbobenzyloxy
-3-(3,4-diphenylmethylenedioxif)
enyl)-2-methylalaninate 2.0g (0.0031
mol) solution and carbon catalyst with 10% palladium
1.0 g in water for 5 2/3 hours at room temperature and initial pressure of 36 p.s.i.
Hydrogenate until elementary absorption is complete. nitrogen catalyst
Removed by filtration through a lower diatomaceous earth bed, and then
Concentrate the liquid under reduced pressure at a temperature of 20-30℃. residue
Redissolve in 25 ml of absolute ethanol and add 7.6N ethanol.
hydrochloric acid by adding 2 ml of anhydrous hydrogen chloride solution.
Convert to salt and then concentrate under reduced pressure. Ethanol residue
in a boiler, then add enough water to precipitate the product.
Precipitate twice by adding a quantity of ethyl ether.
2-Triff as an ethanol solvate after stagnation
fluoroacetamidoethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalaninate
Obtain 800 mg (66.6%) of hydrochloride. thin layer chromatog
Roughy [fluorescent silica gel plate, methanol (50
%) - Chlorophorum (50%) (by volume)]
So homogeneous. Rf=0.8. Analysis value: C₁₄H₁₇F₃N₂O_Five・HCl・C₂H_FiveOH's Calculated values: C 44.40, H 5.59, N 6.47 Experimental values: C 44.55, H 5.29, N 6.72 Reference example 5 A 2-Nicotinamide ethyl L-N-carbobe
ndyloxy-3-(3,4-diphenylmethy)
dioxyphenyl)-2-methylalanine
Manufacture of sheets L-N- in 20 ml of dry dimethylformamide
Carbobenzyloxy-3-(3,4-diphenylene)
lumethylenedioxyphenyl)-2-methylara
Nin 5.84g (0.015mol), triethylamine 1.52
g (0.015 mol) and N-(2-chloroethyl)
- a solution of 2.77 g (0.015 mol) nicotinamide,
Stir at 95° C. for 20 hours under nitrogen. cooled
Pour the reaction mixture into 200ml of ice water and then add the product to vinegar.
Extract three times with 175 ml each of ethyl acid. combined extraction
Dilute the solution with 100 ml of saturated sodium bicarbonate solution and 100 ml of water.
Washed and then dried (MgSO_Four)do. After evaporation, dissolve
The agent was removed under reduced pressure to obtain 2-nicotinamide ethyl L-
N-carbobenzyloxy-3-(3,4-diph)
enylmethylenedioxyphenyl)-2-methyl
6.28 g (85%) of alaninate are obtained. thin layer chroma
Tographie [fluorescent silica gel plate, methanol
(20%) - benzene (80%) (by volume) solution]
homogeneous by. Observed Rf = 0.45. B 2-Nicotinamide ethyl L-3-(3,4
-dihydroxyphenyl)-2-methylalani
Manufacture of nate dihydrobromide 2-nicotinamidoethyl L-N-carboben
Zyloxy-3-(3,4-diphenylmethylene
Dioxyphenyl)-2-methylalaninate 1.0
g (2.0 mmol) and anhydrous hydrogen bromide in acetic acid
Add a mixture of 10 ml of 30-32% solution until gas generation is complete.
Leave for 30 minutes at 20-25℃ until solid. Homogeneous solution 20
Concentrate in vacuo at ~25°C, then dissolve the residue in diethyl ether.
Stir with 50 ml of water for 3 days. almost white
The solid was collected and washed with 50 ml of anhydrous ether, then
Dry at 20-25℃ under high vacuum (0.1-0.3mmHg).
-Nicotinamide ethyl L-3-(3,4-dihy
(Droxyphenyl)-2-methylalaninate di
Obtain 800 mg (77%) of hydrobromide. thin layer chroma
tographie [fluorescent silica plate, n-b of equal volume part
Tanol, acetic acid, 1% aqueous acidic sodium sulfite
diluted with a solution consisting of benzene and acetone.
Observation Rf = 0.5. Analysis value: C₁₈H_{twenty one}N₃O_Five・2HBr・2H₂against O Calculated values: C 38.79, H 4.88, N 7.54 Experimental values: C 38.79, H 4.56, N 7.37 Example 2 A Production of α-chloroethyl pivalate Combining 400mg of zinc chloride under 0.2~0.5mm pressure,
Then cool to 25-30 °C under nitrogen. pivaloy chloride
Add 48 g (0.40 mol) of chlorine to the melted zinc chloride,
Next, add 19.2g (0.44mol) of acetaldehyde.
Ru. Acetaldehyde carried out as rapidly as possible
The reaction mixture was stirred during the addition of the
On the contrary, the loss of acetaldehyde due to the exothermic nature of the reaction
prevent loss. After heating under reflux for 1 hour, distill
Therefore, α-chloroethylpylene with a boiling point of 32-34℃/4mm
Obtain 36g (55%) of barreto. B α-pivaloyloxyethyl L-N-carbo
Benzyloxy-3-(3,4-diphenylmethyl)
(ethylenedioxyphenyl)-2-methylalani
Manufacture of nate L-N- in 25 ml of dry dimethylformamide
Carbobenzyloxy-3-(3,4-diphenylene)
lumethylenedioxyphenyl)-2-methylara
To a stirred solution of 9.0 g (0.018 mol) of
1.80 g (0.018 mol) of α-chloroamine
Add 2.96 g (0.018 mole) of tilpivalate.
After stirring at 90-95 °C for 20 h, the reaction mixture was poured into water.
Pour the product into 350 ml of ethyl ether 100 ml.
Extract 3 times with ml. Combine the ether extracts and then
Wash with 50ml of 5% sodium hydroxide solution and 50ml of water.
and then dried over anhydrous magnesium sulfate.
After filtration, the solvent was removed under reduced pressure to obtain the crude α-pivaloy.
oxyethyl L-N-carbobenzyloxy-
3-(3,4-diphenylmethylenedioxyphene)
7.9g (68.9%)
get. C α-pivaloyloxyethyl L-3-(3,
4-dihydroxyphenyl)-2-methylara
Production of ninate hydrochloride 140ml absolute ethanol and 8N ethanolic
α-pivaloyloxye in 11 ml of aqueous hydrogen chloride solution
Chil L-N-carbobenzyloxy-3-(3,
4-diphenylmethylenedioxyphenyl)-2
- Add a solution of 7.8 g of methylalaninate to 11% paradi
20-25℃ using 3.7g of carbon catalyst with aluminum
Water at an initial pressure of 35 p.s.i. for 19 hours until hydrogen absorption ceases.
Add element. After removing the catalyst by filtration,
Ethanol is removed under reduced pressure. Benzene the residue
Stir overnight with 80 ml of water. Decant and separate benzene
and replaced with 80ml of hexane, stirred and then replaced with hexane.
Decant and separate. Dissolve the residue in 300ml of ethyl acetate.
oak, 5 g solid sodium carbonate and saturated carbonate
Stir briefly with 5 ml of sodium solution mixture
and then dried over anhydrous magnesium sulfate.
After washing, add 3 ml of 9.6N ethanolic anhydrous hydrogen chloride.
is added and the solution is then concentrated to dryness under reduced pressure. 65℃ and
and further dried at 0.2 mm pressure to form α-pivaloyl oxychloride.
Obtained 2.16g (47.2%) of ethyl ester hydrochloride
Ru. Analysis value: C₁₇H_{twenty five}NO.₆・For HCl Calculated values: C 54.32, H 6.97, N 3.73 Experimental values: C 54.47, H 7.36, N 3.39 Example 3 A L-N-carbobenzyloxy-3-(3,
4-dihydroxyphenyl)-2-methylara
Manufacture of nin 2N kept at 0℃ under nitrogen atmosphere
L-3-(3,4
-dihydroxyphenyl)-2-methylalanine
Stirred solution of 3.0 g (0.0126 mol) sesquihydrate
Carbobenzi chloride in 10 ml of diethyl ether
Add 3 ml of the solution. Stir at 0℃ for 1 hour
and then after stirring for 1 hour at 25°C, the reaction mixture
Extract with 50 ml of diethyl ether. the aqueous part
Acidify with 6N hydrochloric acid solution to pH 3-4, then
The crude product was extracted with 100 ml of ethyl acetate, then 25 ml of water.
Wash 3 times with ml. Dry over anhydrous sodium sulfate
After drying and filtering, remove the solvent under reduced pressure.
L-N-carbobenzyloxy as a viscous oil
-3-(3,4-dihydroxyphenyl)-2-methane
1.5 g (34.5%) of chillalanine is obtained. B pivaloyloxymethyl L-3-(3,4-
dihydroxyphenyl)-2-methylalanine
Production of salt hydrochloride L-N-carbo in 60 ml acetone and 4 ml water
Benzyloxy-3-(3,4-dihydroxyph)
2.1 g (6.1 mmol)-2-methylalanine
), chloromethyl pivalate 0.93 g (6.2 mmol), chloromethyl pivalate 0.93 g (6.2 mmol)
), potassium bicarbonate 0.63 g (6.3 mmol) and
A mixture of 0.15 g of potassium iodide was heated under nitrogen for 18 hours.
Stir to reflux. After concentrating under reduced pressure, add 50ml of water and then
N-carbobenzyloxy derivative of the desired ester
Extract the conductor three times with 50 ml each of diethyl ether.
Ru. Wash the ether extract with 50 ml of water, and rinse with anhydrous sulfur.
Dry over magnesium chloride and concentrate under reduced pressure. oil
Dilute the residue with 100ml of absolute ethanol and 9.6N ethanol.
Dissolve in 4 ml of anhydrous norlic hydrogen chloride solution, then add 10
39 p.s.i. using 1 g of carbon catalyst with % palladium.
Hydrogenate for 24 hours at an initial pressure of . touch by passing
After removing the medium, the liquid is concentrated under reduced pressure. residue
Dissolve in 5 ml of water and salt with saturated sodium carbonate solution.
Basic to pH 8, then insoluble product in acetic acid
Extract into 25 ml of ethyl. anhydrous magnesium sulfate
After drying over and then filtering with 9.6N ethanol
Add 1 ml of anhydrous hydrogen chloride solution and then reduce the solution.
Concentrate under pressure to obtain pivaloyloxymethyl L-3-(3,
4-dihydroxyphenyl)-2-methylalani
0.50 g (22.6%) of nate hydrochloride is obtained.
Thin layer chromatography [fluorescent silica gel plate, n
-Butanol:acetic acid:water 5:2:3 (volume) mixture
Rf = 0.86. Analysis value: C₁₆H_{twenty three}NO.₆・For HCl Calculated values: C 53.11, H 6.69, N 3.87 Experimental values: C 53.76, H 6.64, N 3.69 Reference example 6 A 1,2-ethylenebisL-N-carbobendi
3-(3,4-dihydroxyphenylene)
Production of 2-methylalaninate L-N-cal in 20 ml of dimethyl formamide
bobenzyloxy-3-(3,4-dihydroxy
phenyl)-2-methylalanine 7.8g (0.023mol)
), 1,2-dibromoethane 1.88g (0.01mol)
and a solution of 21 g (0.021 mol) of triethylamine.
Heat the solution at 85-90℃ for 10 hours, then pour into 200ml of water.
Add. Ethyl acetate 100% occluded bisester
Extract 3 times with ml each, then saturated sodium bicarbonate
With 100 ml of solution and 100 ml of saturated sodium chloride solution
Wash. Dry over anhydrous magnesium sulfate;
After concentrating under reduced pressure at 30-40℃, 1,2-ethyl
tyrenebisL-N-carbobenzyloxy-3-
(3,4-dihydroxyphenyl)-2-methyla
5.3 g (74%) of laninate is obtained. B 1,2-ethylenebisL-3-(3,4-di
Hydroxyphenyl)-2-methylalanine
Production of todihydrochloride Methanol (25%) - Ethyl acetate (75%) (by volume
1,2-ethylenebis in 120 ml of the mixture
L-N-carbobenzyloxy-3-(3,4-
dihydroxyphenyl)-2-methylalanine
A solution of 5.0 g (6.98 mmol) of
Initial pressure of 35 p.s.i. using 2 g of carbon catalyst with aluminum
Hydrogenation is continued until hydrogen absorption is completed. Too much
After removing the catalyst, remove the solvent under reduced pressure.
Ru. The residue was dissolved in ethanol (10%)-ethyl acetate.
(90%) (by volume) dissolved in the mixture, saturated carbonic acid
5 ml of sodium solution and solid sodium carbonate
Stir with 5 g. anhydrous magnesium sulfate
Add 96N ethanol to the mixture and then filter the mixture.
Acidify with 1 ml of anhydrous hydrogen chloride solution. solvent
Remove under reduced pressure at 20-30℃ to obtain ethyl acetate solvate.
12-ethylenebisL-3-(3,4-dihydro
xyphenyl)-2-methylalaninate dihydrochloride
Get the salt. Analysis value: C_{twenty two}H₂₈N₂O₈・2HCl・2C_FourH₈O₂against
Ru Calculated values: C 51.65, H 6.65, N 4.07 Experimental values: C 50.91, H 6.69, N 4.27 Reference example 7 A 1,3-propylenebisL-N-carboben
Zyloxy-3-(3,4-dihydroxyphene)
Production of Nyl)-2-methylalaninate L-N-cal in 20 ml of dimethyl formamide
bobenzyloxy-3-(3,4-dihydroxy
Phenyl)-2-methylalaninate 7.8g
(0.023 mol), triethylamine 2.1 g (0.020 mol)
) and 2.02 g of 1,3-dibromopropane
(0.010 mol) solution at 95℃ under nitrogen for 15 hours.
Heat for a while and then pour into 200ml of water. The product is acetic acid
Extract three times with 100 ml each of ethyl, then dilute sodium bicarbonate.
50 ml of thorium solution (5%), 50 ml of water, then sodium chloride
Wash with 50 ml of a saturated solution of Rium. anhydrous sulfuric acid
After drying over magnesium and concentrating in vacuo,
1,3-propylenebisL-N-carbobenzyl
Oxy-3-(3,4-dihydroxyphenyl)-
5.4 g (73.8%) of 2-methylalaninate are obtained. B 1,3-propylene bis L-3-(3,4-
dihydroxyphenyl)-2-methylalanine
Production of dihydrochloride Ethanol (25%) - Ethyl acetate (75%) (by volume
) 1,3-propylene bis L- in 100 ml
N-carbobenzyloxy-3-(3,4-dihydroxy
Droxyphenyl)-2-methylalaninate 5.4
g (7.39 mmol) solution on charcoal coated with 10% palladium.
at 25°C using 2.5 g of elementary catalyst at an initial pressure of 35 p.g.i.
Hydrogenate until hydrogen absorption stops. due to passing
After removing the catalyst, the solvent is removed under reduced pressure. residual
The mixture was diluted with methanol (10%) - ethyl acetate (90%) (by volume).
(depending on the volume) and saturated sodium carbonate solution.
ml and 5 g of solid sodium carbonate.
Ru. Add 5g of anhydrous sodium sulfate and stir the mixture.
Filter and then dilute the solution with 9.6N ethanolic anhydrous hydrogen chloride.
Acidify with 1 ml of solution. Concentrate the solution under reduced pressure to approximately 50%
~60 ml and then decanted from the insoluble rubber.
Ru. Stir this gum with 25 ml of ethyl acetate.
filtered and dried to form ethyl acetate solvate.
1,3-propylene bis L-3-(3,4-di
Hydroxyphenyl-2-methylalaninate di
1.74 g (33%) of hydrochloride are obtained. thin layer chromatography
Fee [fluorescent silica gel plate, equal volume portion of n-button]
From alcohol, acetone, acetic acid, water and benzene
Rf = 0.56. Reference example 8 A 1-chloro-1-succinimidopropane
manufacturing Anhydrous hydrogen chloride is converted into N-propenyl succinimide.
10 g (0.072 mol) of tin chloride and 1.04 g of stannic chloride.
Introduce into the mixture for 6 hours. Leave the solution at room temperature for 10 days
do. After 3 and 4 days, the solution was poured again with hydrogen chloride gas.
saturate with water. Remove the solvent under reduced pressure at 30-40℃
1-chloro-1-succinimide as yellow oil
Get propane. B α-succinimidopropyl L-N-carbo
Benzyloxy-3-(3,4-diphenylmethyl)
(ethylenedioxyphenyl)-2-methylalani
Manufacture of nate L-N-cal in 20 ml of dimethyl formamide
bobenzyloxy-3-(3,4-diphenylmethyl)
(ethylenedioxyphenyl)-3-methylalanine
10.2g (0.020mol), Naethylamine 2.1g
(0.021 mol) and 1-chloro-1-succini
A solution of 3.51 g (0.020 mol) of midopropane was heated to 90°C.
Heat for 10 hours and then pour into 200ml of water. product
was extracted three times with 100 ml of ethyl ether each time, and then
50ml of 5% sodium hydroxide, 50ml of water and sodium chloride
Wash with 50 ml of saturated solution of thorium. anhydrous sulfuric acid
After drying over magnesium and filtering,
Remove the solvent under reduced pressure to obtain α-succinimidopropyl
L-N-carbobenzyloxy-3-(3,4-
Diphenylmethylenedioxyphenyl)-2-meth
8.6 g (68%) of tylalaninate are obtained. thin layer
Romantography [fluorescent silica gel plate, chlorophyll
Expanded in Orm] Rf = 0.2. C α-succinimidopropyl-3-(3,4
-dihydroxyphenyl)-2-methylalani
Production of nate hydrochloride Ethanol (25%) - Ethyl acetate (75%) (by volume
) in 120 ml of solution
Pill L-N-carbobenzyloxy-3-(3,
4-diphenylmethylenedioxyphenyl)-2
-A solution of 8.6 g (0.014 mol) of methylalaninate
40p using 4g of carbon catalyst with 10% palladium.
Hydrogenation at initial pressure of s.i. for 18 hours until hydrogen absorption stops
Add. After removing the catalyst by filtration, the solvent
is removed under reduced pressure at 30-40℃. Ethanol the residue
(10%) - ethyl acetate (90%) (by volume)
water, then 5 ml of saturated sodium carbonate solution and filtrate.
Stir for 2 minutes with excess solid sodium carbonate.
Add 10g of anhydrous magnesium sulfate and mix the mixture.
Filter and then add 9.6N ethanolic hydrogen chloride solution to the solution.
Acidify with 2 ml. The solution was concentrated to dryness under reduced pressure and diluted with acetic acid.
Add 100ml of ethyl and then concentrate the mixture again under reduced pressure.
Dry up. Add 100ml of ethyl acetate, then at 25℃
After stirring for 1 hour, remove the product by filtration.
and then dried under reduced pressure to remove the ethanol solvate.
α-succinimidopropyl L-3-(3,
4-dihydroxyphenyl)-2-methylalani
3.0 g (51.0%) of nate hydrochloride is obtained. thin black
Matography [fluorescent silica gel plate, methanol
(30%) - developed with benzene (70%)], Rf = 0.63. Analysis value: C₁₇H_{twenty two}N₂O₆HCl・C₂H_Fiveagainst OH Calculated values: C 52.71, H 6.75, N 6.47 Experimental values: C 53.62, H 6.51, N 6.32 Reference example 33 A Production of N-chloroethylglutarimide Gradually add 8.35 g (0.070 mol) of thionyl chloride.
N-Hydroxymethylglutal in 50ml
Added to a solution of imide 9.0g (0.063mol) at 40℃
Ru. After the addition was complete, the solution was heated under reflux for 1.5 h and then
Stir for 1.5 h at room temperature. Benzene at 30-40℃
and the residue was then distilled to a boiling point of 97.
~100℃/0.1mm N-chloromethylglutarial
5.4 g (53%) of mido is obtained. B Glutarimidomethyl L-N-carboben
Zyloxy-3-(3,4-diphenylmethylene
dioxyphenyl)-2-methylalanine
Manufacture of L-N-cal in 20 ml of dimethyl formamide
bobenzyloxy-3-(3,4-diphenylmethyl)
(ethylenedioxyphenyl)-2-methylalanine
10.2 g (0.020 mol), triethylamine 2.02
g (0.020 mol) and N-chloromethylgluta
A solution of 3.23 g (0.020 mol) of limide at 70℃
5 hours, then stirred at 20-30℃ for 5 hours, then water
Pour into 200ml. Add the product to 100ml each of ethyl acetate
Extract 3 times with 50 ml of 5% sodium hydroxide solution,
Wash with 50 ml of water and 50 ml of saturated sodium chloride solution.
and then dried over anhydrous magnesium sulfate.
After evaporation, remove the solvent under reduced pressure to remove the glutarimide.
Methyl L-N-carbobenzyloxy-3-(3,
4-diphenylmethylenedioxy)-2-methyl
12.1 g (95%) of alaninate are obtained. thin layer chroma
tographie [fluorescent silica gel plate, chlorofluor
), Rf = 0.14. C Glutarimidomethyl L-3-(3,4-
dihydroxyphenyl)-2-methylalanine
Production of salt hydrochloride Absolute ethanol (25%) - ethyl acetate (75%)
Glutarimidomethyl in 130ml (by volume)
L-N-carbobenzyloxy-3-(3,4-
Diphenylmethylenedioxyphenyl)-2-meth
A solution of 12 g (0.0189 mol) of tylalaninate
20-25℃ using 5g of carbon catalyst with palladium
and hydrogen absorption ceases for 18 hours at an initial pressure of 40 p.s.i.
Hydrogenate until removing the catalyst by filtration;
After concentrating to dryness under reduced pressure, the residue was evaporated into anhydrous evaporator.
In 200 ml of ethanol (10%)-ethyl acetate (90%) solution
Comb and add 5 ml of saturated sodium carbonate solution and
Stir for 2 minutes with excess solid sodium carbonate.
Ru. Add 10g of anhydrous magnesium sulfate, and
Remove by filtration after a few minutes. Remove solvent under reduced pressure
and the residue was mixed with 25 ml of hexane and then with 25 ml of ethyl acetate.
ml and then dried under reduced pressure. before the residue
α-methane was reprocessed with sodium carbonate as described above.
Chil-3,4-dihydroxyphenylalanine
removed and 9.6N ethanolic anhydrous hydrogen chloride
Convert to hydrochloride with 3 ml and use as ethyl acetate solvate.
Glutarimidomethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalaninate
3.0 g (36%) of hydrochloride is obtained. thin layer chromatography
Fee [fluorescent silica gel plate, methanol (30%)
− developed with benzene (70%) (depending on volume)]
homogeneous, Rf = 0.56. Analysis value: C₁₆H₂₀N₂O₆・HCl・3/4C_FourH₈O₂to
against Calculated values: C 51.99, H 6.20, N 6.38 Experimental values: C 52.15, H 6.45, N 6.53 Reference example 9 A 2-[L-N-carbobenzyloxy-3-
(3,4-diphenylmethylenedioxyphenylene
)-2-methylalanyloxymethyl]-1,
2-Benzisothiazol-3(2H)-one-
Production of 1,1-dioxide L-N-cal in 15 ml of dimethyl formamide
bobenzyloxy-3-(3,4-diphenylmethyl)
(ethylenedioxyphenyl)-2-methylalanine
7.65g (0.015mol), triethylamine 1.5g
(0.015 mol) and N-chloromethylsacchulin
3.0g (0.015mol) of solution was heated at 75-80℃ for 17 hours.
Heat, then pour into 150ml of water. The product was dissolved in acetic acid.
Extracted 3 times with 100 ml of chilled water and saturated sodium bicarbonate.
50 ml of solution, 50 ml of water and saturated sodium chloride
Wash with 50 ml of solution, then anhydrous magnesium sulfate
Dry on top. After evaporation, the solvent was removed under reduced pressure and
-[L-N-carbobenzyloxy-3-(3,4
-diphenylmethylenedioxyphenyl)-2-
methylalanyloxymethyl]-1,2-benz
Isothiazol-3(2H)-one-1,1-dio
9.3 g (100%) of oxide is obtained. thin layer chromatography
PHIE [Fluorescent silica gel plate, exhibited in chlorophorum]
Open], Rf=0.32. B 2-[L-3-(3,4-dihydroxyphenylene)
)-2-methylalanyloxymethyl]-1,
2-Benzisothiazol-3(2H)-one-
Production of 1,1-dioxide hydrochloride 100ml absolute ethanol and 8N ethanolic
2-[L-N-carbobe in 5 ml of aqueous hydrogen chloride solution
3-(3,4-diphenylmethylene)
dioxyphenyl)-2-methylalanyloxy
dimethyl]-1,2-benzisothiazole-3
(2H)-one-1,1-dioxide 3.0g (0.0043
1.5 g of a 10% palladium-coated carbon catalyst solution
at 20-25 °C and an initial pressure of 35 p.s.i. using
Hydrogenate for hours until hydrogen absorption stops. It's too late
After removing the catalyst and concentrating to dryness under reduced pressure,
Then, stir the residue with 50 ml of ethyl acetate for 1 hour.
and then decant the ethyl acetate. Empty the residue
Tanol (20%) - Ethyl acetate (80%) (by volume)
), then add 10 ml of saturated sodium carbonate solution.
and excess solid sodium carbonate.
Ru. Add 10g of anhydrous magnesium sulfate, and
After a few minutes, remove by filtration and then reduce the liquid to 9.6N.
- Acidify with 1 ml of ethanolic anhydrous hydrogen chloride solution.
Ru. Remove the solvent under reduced pressure to obtain ethyl acetate solvate.
2-[L-3-(3,4-dihydroxyphenylene)
)-2-methylalanyloxymethyl]-1,2
-Benzisothiazol-3(2H)-one-1,
0.2 g (10.0%) of 1-dioxide hydrochloride is obtained.
Thin layer chromatography (fluorescent silica gel plate, etc.)
Parts by volume of benzene, water, acetic acid, n-butanol and
and acetone], Rf=0.74. Analysis value: C₁₈H₁₈N₂O₇S・HCl・1/4C_FourH₈O₂against
do Calculated values: C 49.08, H 4.55, N 6.03 Experimental values: C 49.27, H 4.76, N 5.65 Reference example 10 A 1-methyl-2-[L-N-carbobenzyl
Oxy-3-(3,4-dihydroxyphenyl)
-2-methylalanyloxymethyl]-imida
Manufacture of sol L-N-cal in 20 ml of dimethyl formamide
bobenzyloxy-3-(3,4-dihydroxy
phenyl)-2-methylalanine 7.8g (0.0226mol)
), triethylamine 4.2 g (0.042 mol) and
and 1-methyl-2-chloromethylimidazole
3.34g (0.0256mol) solution at 70-75℃ for 10 hours
Heat and then pour into 200 ml of water. Acetic acid
Extracted three times with 100 ml of ethyl and saturated sodium bicarbonate.
with 50 ml of sodium chloride solution and 50 ml of saturated sodium chloride solution.
Washed and then concentrated under reduced pressure to obtain 1-methyl-2-[L
-N-carbobenzyloxy-3-(3,4-di
hydroxyphenyl)-2-methylalanyloxy
2.2 g (22%) of dimethyl]-imidazole are obtained.
Thin layer chromatography [fluorescent silica gel plate,
Tanol (15%) - Chloroform (85%) (by volume
) homogeneous, Rf = 0.66. B L-1-methyl-2-[2-(3,4-dihydro
(roxybenzyl)-alanyloxymethyl]-i
Production of midazole dihydrochloride dihydrate 1-Methyl-2-[L in 100 ml of absolute ethanol
-N-carbobenzyloxy-3-(3,4-di
hydroxyphenyl)-2-methylalanyloxy
[cymethyl]-imidazole 2.1 g (4.78 mmol)
using 1g of carbon catalyst with 10% palladium.
and hydrogenate for 4 hours at an initial pressure of 35 p.s.i.
The catalyst was removed by filtration and concentrated under reduced pressure to 50%
ml, then 9.6N ethanolic anhydrous hydrogen chloride
2 ml is added and then the remainder of the solvent is removed under reduced pressure. Residue
Dilute the distillate with ethanol (20%) - ethyl acetate (80%)
200ml, 10ml of saturated sodium carbonate solution and excess
of solid sodium carbonate. anhydrous
Add 10g of magnesium sulfate and then filter after a few minutes.
Remove by. Add 9.6N ethanol-free solution
Acidify with 1 ml of aqueous hydrogen chloride solution. Remove solvent under reduced pressure
to give L-1-methyl as ethyl acetate solvate.
-2-[2-(3,4-dihydroxybenzyl)-
Alanyloxymethyl]-imidazole dihydrochloride
0.2 g (8.5%) of dihydrate is obtained. thin layer chromatog
Roughy [fluorescent silica gel plate, equal volume part n-b]
Tanol, acetic acid, water, benzene and acetone?
], Rf=0.3. Analysis value: C₁₈H₁₉N₃O_Four・2HCl・2H₂O・1/2
C_FourH₈O₂against Calculated values: C 44.55, H 6.34, N 9.17 Experimental values: C 44.62, H 6.84, N 8.95 Reference example 11 A 1-methyl-3-chloromethylhydantoin
Manufacturing of Under reflux, 1-methyl-3-hydroxy
25 g (0.173 mol) of methylhydantoin and
Add thionichloride to 160ml of a well-stirred mixture.
Gradually add 30 ml of the liquid over 20 minutes. under reflux
After stirring for 2 hours, the reaction mixture was concentrated to dryness under reduced pressure.
then add 70 ml of benzene and then concentrate the solution again to dryness.
dry up Repeat this method at least once with 70ml of benzene.
After repeating the above steps, add 100ml each of the residue to carbon tetrachloride.
Extract 3 times. Remove the solvent under reduced pressure to remove 1-methyl
-3-chloromethylhydantoin 15.7g (55.7
%). B 1-methyl-3-[L-N-carbobenzyl
Oxy-3-(3,4-diphenylmethylenedi)
(oxyphenyl)-2-methylalanyloxy
Production of methyl]-hydantoin L-N-cal in 23 ml of dimethyl formamide
bobenzyloxy-3-(3,4-diphenylmethyl)
(ethylenedioxyphenyl)-2-methylalanine
10.2g (0.020mol), triethylamine 2.1g
(0.021 mol) and 1-methyl-3-chloromethylene
A solution of 3.25 g (0.020 mol) of Ruhydantoin
Heat for 18 hours at °C, then pour into 230 ml of water. Living
The product was extracted three times with 100 ml each of ethyl acetate, and diluted with dilute water.
50 ml of sodium oxide solution (5%), 50 ml of water and
Wash with 50 ml of saturated sodium chloride solution, then anhydrous
Dry over magnesium sulfate. After evaporation, solvent
was removed under reduced pressure to obtain 1-methyl-3-[L-N-ka].
Lebobenzyloxy-3-(3,4-diphenyl
Methylenedioxyphenyl)-2-methylalani
Hydantoin 11.7g (92%)
get. C L-1-methyl-3-[2-(3,4-dihydro
roxybenzyl)alanyloxymethyl]-H
Production of dantoin hydrochloride hydrate With 140ml of absolute ethanol and 10% palladium
1-methyl-3-[L-N-ka in 2g of carbon catalyst
Lebobenzyloxy-3-(3,4-diphenyl
Methylenedioxyphenyl)-2-methylalani
Hydantoin 4.0g (6.3ml)
mol) solution with hydrogen for 20 hours at an initial pressure of 36 p.s.i.
Added. Remove the catalyst by filtration and reduce
After being concentrated to dryness, the residue was diluted with 100 ml of hexane.
Wash. Transfer hexane-insoluble substances to methanol (10
%)-ethyl acetate (90%), then dissolve in 150 ml of ethyl acetate (90%) and then
5 ml of sodium carbonate solution and excess sodium carbonate
Stir with aluminum, then add anhydrous magnesium sulfate.
Dry on sium. After evaporation, evaporate the liquid with 9.6N ethanol.
Acidify with 2 ml of anhydrous alcoholic hydrogen chloride, then reduce the pressure
Concentrate and dry. The residue with 80 ml of ethyl acetate
Stir for an hour, filter, then dry under reduced pressure and evaporate acetic acid.
L-1-methyl-3-[2-
(3,4-dihydroxybenzyl)-alanyl oxy
[cymethyl]-hydantoin hydrochloride hydrate 0.50g
(18%). Analysis value: C₁₅H₁₉N₃O₆・HCl・H₂O・1/2
C_FourH₈O₂against Calculated values: C 46.84, H 6.01, N 9.64 Experimental values: C 46.28, H 6.09, N 9.06 Reference example 12 A 2-Phenoxyethyl L-N-carbobendi
3-(3,4-diphenylmethylene)
Dioxyphenyl-2-methylalaninate
manufacturing L-N-cal in 15 ml of dimethyl formamide
bobenzyloxy-3-(3,4-diphenylmethyl)
Tylendioxyphenyl-2-methylalanine
4.5g (0.0088mol), triethylamine 0.90g
(0.009 mol) and 2-bromoethyl phenyl
A solution of 1.81 g (0.009 mol) of ether at 70-75℃
Heat for 24 hours, cool and then pour into 150 ml of water.
The product was extracted three times with 100 ml each of ethyl ether,
50 ml of 5% sodium hydroxide solution, 50 ml of water and saturated
Wash with 50 ml of sodium chloride solution, then with anhydrous
Dry over magnesium sulfate. After that, remove the solvent.
Removed under reduced pressure to remove 2-phenoxyethyl L-N-cal.
bobenzyloxy-3-(3,4-diphenylmethyl)
(ethylenedioxyphenyl)-2-methylalanine
Obtain 4.8g (86.5%) of thin layer chromatography
PHIE [Fluorescent silica gel plate, exhibited in chlorophorum]
homogeneous by [open], Rf = 0.91. B 2-Phenoxyethyl L-3-(3,4-di
Hydroxybenzyl)alaninate hydrochloride hemi
Hydrate production 2-Phenoxyethyl in 120 ml of absolute ethanol
L-N-carbobenzyloxy-3-(3,4
-diphenylmethylenedioxyphenyl-2-methyl
Solution of 4.7 g (7.5 mmol) of tylalaninate
using 1.7g of carbon catalyst with 10% palladium.
Hydrogenate for 20 hours at an initial pressure of 20 p.s.i. catalyst
After filtration, remove the solvent under reduced pressure and sift the residue.
Chromatography on a 75g column of Lycagel
Understand. Methanol (5%) - Benzene (95%)
Esters with melting point 35-42℃ eluted with 400ml of mixture
1.42 g (58%) of base are obtained. thin layer chromatograph
E [Fluorescent silica gel plate, methanol (30%) -
homogeneous by developing with benzene (70%), Rf=
0.52. Chloroform (50%) - methanol as base
(50%) mixture to 25 ml, and 9.6N
Acidify with 2 ml of ethanolic anhydrous hydrogen chloride solution.
Convert to the hydrochloride salt by Remove solvent under reduced pressure
to give 2-phenoxyethyl L-3-(3,4-
dihydroxybenzyl)-alaninate hydrochloride
Obtain the myhydrate. Analysis value: C₁₈H_{twenty one}NO._Five・HCl・1/2H₂against O Calculated values: C 57.37, H 6.15, N 3.72 Experimental values: C 57.17, H 6.16, N 3.41 Reference example 13 A 2-succinimidoethyl L-N-carbobe
ndyloxy-3-(3,4-diphenylmethy)
dioxyphenyl)-2-methylalanine
Manufacture of sheets L-N-cal in 15 ml of dimethyl formamide
bobenzyloxy-3-(3,4-diphenylmethyl)
(ethylenedioxyphenyl)-2-methylalanine
4.5g (8.8mmol), triethylamine 0.90g
(9 mmol) and N-(2-bromoethyl)-
A solution of 1.85 g (9.3 mmol) of succinimide
Heat at 95℃ for 19 hours, cool and then pour into 150ml of water.
do. Pour the product three times with 100 ml each of ethyl ether.
Extract with 50 ml of 5% sodium hydroxide solution and 50 ml of water.
and 50 ml of saturated sodium chloride solution, then
Dry over anhydrous magnesium sulfate. past
After that, the solvent was removed under reduced pressure and 2-succinimide ethyl
L-N-carbobenzyloxy-3-(3,4
-diphenylmethylenedioxyphenyl)-2-
4.8 g (86%) of methylalaninate are obtained. thin layer
Chromatography [fluorescent silica gel plate, chloro
homogeneous, Rf = 0.27. B 2-succinimidoethyl L-3-(3,4
-dihydroxyphenyl)-2-methylalani
Production of nate hydrochloride hemihydrate 75ml methanol, 75ml ethanol and 76N
2-sacsi in 3 ml of tanolic anhydrous hydrogen chloride solution
imidoethyl L-N-carbobenzyloxy-
3-(3,4-diphenylmethylenedioxyphene)
2.5g (3.94ml)-2-methylalaninate
1.2 mol) suspension of 10% palladium-coated carbon catalyst
Hydrogenation for 20 hours using g at an initial pressure of 20 p.s.i.
do. After removing the catalyst by filtration, remove the solvent.
Remove under reduced pressure and then add 25ml of benzene to it
Stir with 25 ml of ethyl acetate. insoluble substances
Ethanol (10%) - Ethyl acetate (90%) 100
ml, 5 ml of saturated sodium carbonate solution and solid charcoal
Treat with 5 g of sodium chloride. Anhydrous organic extract
dried over magnesium sulfate, filtered and vacuumed.
Concentrate. 9.6N ethanolic anhydrous hydrogen chloride solution
Add 1ml. All solvents were removed under reduced pressure
Then, 2-succinimidoethyl L-3-(3,4
-dihydroxyphenyl)-2-methylalanine
Obtain 0.5 g (33%) of hemihydrate of ethyl hydrochloride. Thin
Layer chromatography [fluorescent silica gel plate, meta
developed with alcohol (30%)-benzene (70%)].
homogeneous, Rf = 0.4. Analysis value: C₁₆H₂₀N₂O₆・HCl・1/2H₂against O Calculated values: C 50.33, H 5.54, N 7.34 Experimental values: C 50.89, H 5.65, N 7.22 Reference example 14 A 1,2-ethylenebis[L-N-carboben
Zyloxy-3-(3,4-diphenylmethylene
dioxyphenyl)-2-methylalanine
Manufacture of L-N-cal in 35 ml of dimethyl formamide
bobenzyloxy-3-(3,4-diphenylmethyl)
(ethylenedioxyphenyl)-2-methylalanine
10.18g (0.020mol), triethylamine 2.12g
(0.021 mol) and 1,2-dichloroethane 0.99
A solution of 105 g (0.010 mol) was added under nitrogen to
Heat at ~110°C for 28 hours, then pour into 400ml of ice water
Ru. Extract the product into 800 ml of ethyl ether and
Wash with 100ml of sodium hydroxide solution and 100ml of water.
Then dry over anhydrous magnesium sulfate and filter.
Next, concentrate under reduced pressure. Pour the residue onto 800g of silica gel.
chromatography, then 1,2-ethyl
Lenbis [L-N-carbobenzyloxy-3-
(3,4-diphenylmethylenedioxyphenyl)
-2-methylalaninate 2.25g (21.5%)
Elute with Roloforme. B L,L-2-[2-(3,4-diphenylmethy)
dioxybenzyl)-alanyloxy]-ethyl
2-(3,4-dihydroxybenzyl)-ara
Production of ninate bishydrozine oxalate 1,2-ethylene bicarbonate in 100 ml of absolute ethanol
[L-N-carbobenzyloxy-3-(3,
4-diphenylmethylenedioxyphenyl)-2
-Methyl alaninate] 2.25 g (2.2 mmol)
Using 1.2g of carbon catalyst with 10% palladium
Hydrogen absorption was completed for 28 hours at an initial pressure of 30 p.s.i.
Hydrogenate until solid. Remove the catalyst by
After that, the solvent is removed under reduced pressure. Remove the residue
100 ml of alcohol (10%)-ethyl acetate (90%), saturated
2 ml of sodium carbonate solution and solid sodium carbonate
Stir for 15 minutes with 3 g of aluminum and then filter. liquid
was dried over anhydrous magnesium sulfate and filtered.
Concentrate under reduced pressure. Chroma the residue on silica gel.
treated with methanol (30%)
Elution with benzene (70%) gives 220 mg of product.
This product was dissolved in 500 ml of oxalic acid in 10 ml of ethanol.
mg and precipitated with ethyl ether.
It is converted to oxalate by of ethyl ether
Precipitate more than once from 10 ml of ethanol by adding
After that, L,L-2-[2-(3,4-diphenyl
methylenedioxybenzyl)-alanyloxy]-
Ethyl 2-(3,4-dihydroxybenzyl)-a
Laninate Bishydrozine Oxalate 246mg
(14%). Analysis value: C₃₅H₃₆N₂O₈・2C₂H₂against O Calculated values: C 59.08, H 5.08, N 3.53 Experimental values: C 59.15, H 5.18, N 3.55 Reference example 15 A 2-phthalimidoethyl L-N-carboben
Zyloxy-3-(3,4-diphenylmethylene
dioxyphenyl)-2-methylalanine
Manufacture of L-N-cal in 30 ml of dimethyl formamide
bobenzyloxy-3-(3,4-diphenylmethyl)
(ethylenedioxyphenyl)-2-methylalanine
10.18g (0.020mol), triethylamine 2.12
g (0.021 mol) and N-(2-bromoethyl)
A solution of 5.08 g (0.020 mol) of phthalimide was heated with nitrogen.
Stir overnight at 105-110°C under water, then cool in ice water.
Pour into 600ml. 100ml of the product in ethyl ether
Extract 3 times each time and then wash with 50 ml of water. A
Dry the extract over anhydrous magnesium sulfate.
filtration and concentration under reduced pressure to give a gummy solid.
Chromatography on silica gel and then
2-phthalimidoethyl by elution with chloroform
L-N-carbobenzyloxy-3-(3,4
-diphenylmethylenedioxyphenyl-2-methyl
Obtain tylalaninate. thin layer chromatography
- [Fluorescent silica gel plate, developed with chloroform],
Rf=0.53. B 2-phthalimidoethyl L-3-(3,4-
dihydroxyphenyl)-2-methylalanine
Production of salt hydrochloride 2-phthalimidoethyl in 125 ml of ethyl acetate
L-N-carbobenzyloxy-3-(3,4-
Diphenylmethylenedioxyphenyl-2-methylene
A solution of 10.88 g (0.0159 mol) of lualaninate,
31 p.s using 6g of carbon catalyst with 10% palladium.
Hydrogenation at the initial pressure of i. for 5 hours until hydrogen absorption stops
do. Remove the catalyst by filtration and remove the solvent.
After removal in vacuo, the residue was diluted with 5.15N ethanol.
Anhydrous ethanol containing 4 m of anhydrous hydrogen chloride solution
Mix to 150ml, then add 43g of palladium-coated carbon catalyst
Hydrogenate for 5 days at 27-38 p.s.i. Change
During this period, 43 g of carbon catalyst with 10% palladium was added to
Add to. Remove the catalyst by filtration and reduce
After pressure concentration, the residue was washed with 100 ml of petroleum ether.
Rinse and then dissolve in ethanol. Add it to ethyl ether
Precipitated three times from ethanol by addition of
Ru. The product was dried under reduced pressure to a melting point of 138.0-140.0.
2-phthalimidoethyl L-3- at °C (decomposition)
(3,4-dihydroxyphenyl)-2-methyla
2.80 g (41.8%) of laninate hydrochloride are obtained. thin layer
Chromatography [fluorescent silica gel plate, methane
(50%) - developed with benzene (50%)]
homogeneous, Rf=0.61 Analysis value: C₂₀H₂₀N₂O₆・For HCl Calculated values: C 57.07, H 5.03, N 6.65, Cl 8.42 Experimental values: C 56.31, H 5.62, N 6.48, Cl 8.75 Example 5 A 2-acetoxyethyl L-N-carbobendi
3-(3,4-diphenylmethylene)
dioxyphenyl)-2-methylalaninate
Manufacturing of L-N-cal in 30 ml of dimethyl formamide
bobenzyloxy-3-(3,4-diphenylmethyl)
(ethylenedioxyphenyl)-2-methylalanine
10.0g (0.0196mol), triethylamine 2.39g
(0.0235 mol) and 2-chloroethyl acetate
A solution of 2.40 g (0.0196 mol) of
Stir for 20 hours and then pour into 500 ml of ice water. Generate
Extract the sample with 200 ml of ethyl ether four times.
Combine the liquid and then add 200ml of water and 5% sodium hydroxide.
Wash 200 ml of solution then 200 ml of water. anhydrous sulfuric acid
After drying over magnesium and filtering the solvent
is removed under reduced pressure. Transfer the residue onto 700g of silica gel.
Chromatography treatment. Methanol (5
%)-chloroform (95%)
Setoxyethyl L-N-carbobenzyloxy-
3-(3,4-diphenylmethylenedioxyphene)
5.60g (48%)
get. B 2-acetoxyethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalanine
Manufacture of 2-acetoxyethyl in 100 ml of absolute ethanol
L-N-carbobenzyloxy-3-(3,4
-diphenylmethylenedioxyphenyl)-2-
Solution of 5.60 g (0.0094 mol) of methylalaninate
using 2.8g of carbon catalyst with 10% palladium.
At an initial pressure of 37 p.s.i. for 24 hours until hydrogen absorption is complete.
Hydrogenate with. Remove the catalyst by filtration and
After removing the solvent under reduced pressure, the residue was
Wash with 100ml of alcohol, then ethanol (10%)-vinegar.
Dissolve in 124 ml of ethyl acid (90%) (depending on volume).
6.2g sodium carbonate and saturated sodium carbonate
Add 4 ml of solution and stir for 20 minutes. mixture
filtered and dried over anhydrous magnesium sulfate;
Filter and concentrate under reduced pressure. the residue on silica gel
Chromatographically treated with methanol (20%)
- Elute with benzene (80%) (by volume).
Dissolve in ethyl acetate, then add cyclohexane
The melting point is determined by recrystallization by precipitation.
2-acetoxyethyl L- at 114-118℃ (decomposition)
3-(3,4-dihydroxyphenyl)-2-methy
1.01 g (36%) of lualaninate is obtained. Analysis value: C₁₄H₁₉NO.₆against Calculated values: C 56.55, H 6.44, N 4.71 Experimental values: C 56.64, H 6.63, N 4.33 Reference example 16 A 2-Benzamidoethyl L-N-carboben
Zyloxy-3-(3,4-diphenylmethylene
dioxyphenyl)-2-methylalanine
Manufacture of L-N-cal in 20 ml of dimethyl formamide
bobenzyloxy-3-(3,4-diphenylmethyl)
(ethylenedioxyphenyl)-2-methylalanine
10.0g (0.0196mol), triethylamine 2.11g
(0.021 mol) and N-(2-chloroethyl)-benzene
A solution of 3.64 g (0.0196 mol) of nzamide was heated with nitrogen.
Stir at 110℃ for 20 hours, then pour into 400ml of ice water.
Ru. Remove the precipitate by filtration and wash with 100ml of water.
Then dissolve in 200ml of ethyl ether. This a
50ml of 5% sodium hydroxide solution, 50ml of water
ml and then dried over anhydrous magnesium sulfate.
do. Remove the desiccant and then concentrate the liquid under reduced pressure.
2-Benzamidoethyl L-N-carbobenzyl
Oxy-3-(3,4-diphenylmethylenedio)
xyphenyl)-2-methylalaninate 11.21g
(87%). Thin layer chromatography [fluorescence]
Silica gel plate, methanol (5%)-chlorofluorocarbon
lum (95%) (depending on capacity)], Rf = 0.7. B 2-Benzamidoethyl L-3-(3,4-
dihydroxyphenyl)-2-methylalanine
Production of oxalate hemihydrate 2-benzamide in 100 ml of absolute ethanol
Chil L-N-carbobenzyloxy-3-(3,
4-diphenylmethylenedioxyphenyl)-2
-Dissolution of 11.21 g (0.017 mol) of methylalaninate
Using 5.5g of carbon catalyst with 10% palladium,
Hydrogenate for 7 hours at an initial pressure of 30 p.s.i. past
Remove the catalyst and remove the solvent under reduced pressure.
After washing, the residue was soaked with 100 ml of petroleum ether overnight.
Stir. Remove insoluble substances with methanol (10%) - vinegar
Dissolve in 250ml of ethyl acid (90%) and saturated sodium carbonate.
with 12 ml of solution and 12 g of sodium carbonate.
Shake and then strain. Anhydrous magnesium sulfate solution
Dry over a sieve, filter and concentrate under reduced pressure. residue
treated with 1.3 g of oxalic acid dissolved in 25 ml of absolute ethanol.
Understand. Oxalate salt added with ethyl ether
Precipitate by convert the product into ethanol
and add ethyl ether to precipitate the product.
Precipitation is carried out two or more times by
-Benzamidoethyl L-3-(3,4-dihydro
Roxyphenyl)-2-methylalaninate oxy
1.60 g (23%) of zarate hemihydrate are obtained. thin layer
Chromatography [fluorescent silica gel plate, methane
Developed with chloroform (50%) - chloroform (50%)]
Homogeneous by, Rf = 0.44. Analysis value: C₁₉H_{twenty two}N₂O_Five・1/2C₂H₂O_Four・1/2H₂to O
against Calculated values: C 58.24, H 5.86, N 6.79 Experimental values: C 58.39, H 5.73, N 6.37 Reference example 17 A naphthalimidomethyl L-N-carbobendi
3-(3,4-diphenylmethylene)
dioxyphenyl)-2-methylalaninate
Manufacturing of L-N-cal in 50 ml of dimethyl formamide
bobenzyloxy-3-(3,4-diphenylmethyl)
(ethylenedioxyphenyl)-2-methylalanine
10.2g (0.020mol), triethylamine 2.02g
(0.020 mol) and N-chloromethyl naphthalene
Stir a solution of 4.9 g (0.020 mol) of Mido at 90℃ for 20 hours.
Stir and then pour into 500 ml of ice water. The product is acetic acid
Extracted into 200 ml of ethyl 5% sodium hydroxide
50 ml of solution, 50 ml of water and saturated sodium chloride solution
Wash with 50ml and then over anhydrous magnesium sulfate.
dry. After filtration, remove the solvent under reduced pressure and remove the naphthalene.
imidomethyl L-N-carbobenzyloxy-3
-(3,4-diphenylmethylenedioxyphenylene
)-2-methylalaninate 13.1g (91%)
obtain. B Naphthalimidomethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalanine
Production of hydrochloride Absolute ethanol (25%) - ethyl acetate (75%)
(depending on volume) Naphthalimidomethyl L in 150ml
-N-carbobenzyloxy-3-(3,4-di
phenylmethylenedioxyphenyl)-2-methy
A solution of 13 g (0.0181 mol) of lualaninate was added to
% palladium-coated carbon catalyst at 25℃ and 5g.
Hydrogen absorption is completed for 24 hours at an initial pressure of 40 p.s.i.
Hydrogenate until The catalyst is gradually removed by
After concentrating the liquid under reduced pressure, remove the residue using anhydrous evaporator.
Tanol (10%) - Ethyl acetate (90%) in 200ml
oak, and 5 ml of saturated sodium carbonate solution and
Stir for 10 minutes with 5 g of solid sodium carbonate.
Filter the mixture and remove the liquid with anhydrous magnesium sulfate.
Dry on top, filter again and concentrate under reduced pressure. residual
Wash the item with 100ml of hexane and diphenylmethane.
Remove and dissolve in 25ml of absolute ethanol and then 8N
Acidify with 5 ml of ethanolic anhydrous hydrogen chloride. workman
Naphthalimidomethylene by addition of thyl ether
L-3-(3,4-dihydroxyphenyl)-2
- Precipitating methylalaninate. Example 6 A racemic N-carbobenzyloxy-3-(3,
4-dihydroxyphenyl)-2-methylara
Manufacture of nin 60ml of 2N sodium hydroxide solution under nitrogen
racemic DL-3-(3,4-dihydroxyphene)
8.0g (0.0378mol)
of potassium chloride in 25 ml of diethyl ether.
Add a solution of 9 ml of lebobenzyloxy. at 0℃
After stirring for 1 hour and then for 1 hour at 25°C, the reaction mixture was
The compound is extracted with 50 ml of diethyl ether. Aqueous part
Acidify with 6N hydrochloric acid to PH3, then crude
The material was extracted into 100 ml of ethyl acetate and then with 35 ml of water.
Wash 3 times. Dry over anhydrous magnesium sulfate
After filtration, the solvent is removed under reduced pressure and the laceration is performed.
mi-N-carbobenzyloxy-3-(3,4-di
Hydroxyphenyl)-2-methylalanine 4.5g
(34%) is obtained as a viscous oil. B racemic pivaloyloxymethyl 3-(3,4
-dihydroxyphenyl)-2-methylalani
Production of nate hydrochloride Racemic N-ca in 20 ml of dimethylformamide
Lebobenzyloxy-3-(3,4-dihydroxy)
Cyphenyls)-2-methylalanine 4.2g (0.012
mol), triethylamine 1.3g (0.013 mol) and
and chloromethyl pivalate 1.26g (0.013mol)
The solution was stirred at 90 °C for 20 h, then poured into 200 ml of water.
Add. The product was extracted into 100 ml of ethyl acetate and then
with 25 ml of saturated sodium bicarbonate solution and 25 ml of water.
Wash. Dry over anhydrous magnesium sulfate;
After filtering, concentrate the liquid under reduced pressure to obtain the desired
N-carbobenzyloxy derivative of Stell was obtained.
Ru. Add this material to 9.6N ethanolic anhydrous hydrogen chloride.
Dissolve in 100 ml of absolute ethanol containing 10 ml of liquid,
Next, using 3g of carbon catalyst with 10% palladium,
Hydrogenate for 24 hours at an initial pressure of 35 p.s.i. too much
After removing the catalyst, the liquid is concentrated under reduced pressure.
Dissolve the residue in 25 ml of water and add saturated sodium carbonate solution.
Make basic with liquid to pH 8, then remove insoluble product
Extract with 100ml of ethyl acetate. anhydrous sulfuric acid mug
After drying and passing over nesium, 9.6N
Add 5 ml of ethanolic anhydrous hydrogen chloride solution, then
Concentrate the solution under reduced pressure to obtain racemic pivaloyloxymethylene.
3-(3,4-dihydroxyphenyl)-2-methane
Obtained 1.5g (22.6%) of tylalaninate hydrochloride
Ru. Thin layer chromatography [fluorescent silica gel]
plate, 5-2-3 (volume) of n-butanol-acetic acid-water
homogeneous, Rf=
0.86. Example 7 2-acetamidoethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalanine
Production of hydrochloride Under nitrogen, L-3-(3,4-dihydro
xyphenyl)-2-methylalanine hydrochloride eta
Nol solvate (ethanol solution of hydrochloride under reduced pressure)
) 88.3 g (0.30 mol) and N-A
Cetylethanolamine 146.4g (1.42mol)
Warm the slurry to 104-108°C. Thioni chloride
84.8 g (0.713 mol) of chlorine was heated for 15 minutes while stirring.
Add it up. The reaction mixture will rise vigorously during the addition.
foam. After the addition is complete, bring the reaction mixture to 104-108°C.
Stir for 18 hours. Additionally, 42.4g of thionyl chloride
(0.357 mol) over 7 minutes. reaction mixture
Stir the mixture at 104-108°C for an additional 3 1/2 hours, then bring to 30°C. Cool and then concentrate under reduced pressure to obtain a viscous oil. this oil
slurry with 100 ml of chloroform and then
Remove the Rolophorum under reduced pressure. Repeat this three times or more.
Then, wash the oil with 100ml of benzene and then remove the benzene.
Decant and separate the zen. Isopropanol the residue
Dissolve to 700ml, then add to ethyl ether 6
Ru. Wash the formed precipitate with 500 ml of ethyl ether.
and then ethanol (10%)-ethyl acetate (90%)
6. 150ml of saturated sodium carbonate solution and carbonic acid
Shake with 100 g of sodium. organic extract
Dry over anhydrous magnesium sulfate, filter and then
Concentrate under reduced pressure to liberate acetamidoethyl ester
Get the base. Add this base to 300ml of isopropanol.
treated with 15 g of fumaric acid in a
Precipitate by adding thyl ether. Fumare
salt by adding sufficient amount of ethyl ether.
Precipitate one or more times from isopropanol and then precipitate from isopropanol.
Ethanol (10%)-ethyl acetate as described
(90%) 200ml, 20ml of saturated sodium carbonate solution and
shake with 20 g of solid sodium carbonate.
Convert back to the free base by . Anhydrous free base
Dissolve in 100ml of ethanol and add 10ml of 9.6N HCl.
, then precipitated by addition of ethyl ether 1
It is converted to the hydrochloride salt by mentioned above
from ethanol-ethyl ether by carrying out as
After three precipitations, 2-acetamide as the hydrochloride
Ethyl L-3-(3,4-dihydroxyphenyl)
-2-Methylalaninate hydrochloride 15.1g (15
%). Thin layer chromatography [fluorescence chromatography]
Kagel plate, methanol (50%) - benzene (50%)
(depending on capacity)], Rf = 0.57. Analysis value: C₁₄H₂₀N₂O_Fiveagainst HCl Calculated values: C 50.52, H 6.36, N 8.41 Experimental values: C 50.49, H 6.69, N 8.49 Example 8 3-acetamidopropyl L-3-(3,4-
dihydroxyphenyl)-2-methylalanine
hydrozine oxalate hydrate Add 275 ml of thionyl chloride to L-3-(3,4-
dihydroxyphenyl)-2-methylalanine
Add to 250g of Toseski hydrate and then steam the mixture.
Heat over the bath. After heating for 2 hours, the reaction mixture
Dimethylformamide dissolved in 25ml of benzene
dilute with 7.5 ml of water, then place on a steam bath to stop gas generation.
Stir until smooth. Add 100ml of benzene and then
The sulfuric acid ester was removed by filtration and the benzene
100ml, chloroform 100ml and ether 100ml
ml and then dried under reduced pressure to a melting point of 199°C.
(Decomposition) 280 g of sulfite ester intermediate is obtained. Crude sulfite intermediate 13.7g, N-acetyl
24.98 g (0.212 mol) of propanolamine and
Steam a mixture of 2 g of anhydrous dimethyl formamide.
Stir on a gas bath for 20 hours, then cool. reaction mixture
6 times with 200 ml of ethyl ether and diluted with methychloride.
Wash 4 times with 200 ml of water each time, then dry under reduced pressure.
Ru. The remaining semi-solid material was dissolved in ethanol (20%).
Ethyl acetate (30%) (by volume) 200ml, saturated charcoal
20 ml of sodium acid solution and solid sodium carbonate
Stir with 20g of mussels. Organic extract with anhydrous sulfuric acid
Dry over magnesium, filter and evaporate the liquid.
Add to a solution of 3.2 g of oxalic acid in 50 ml of alcohol. next
Achieve solvent removal under reduced pressure, and then
Dissolve the product in 50 ml of ethanol and then evaporate.
the product by adding 500 ml of ether
Let it settle. Add the product to 50ml of ethanol again.
and then by adding 500 ml of ethyl acetate.
3-acetaminyl by precipitating the product.
Dopropyl L-3-(3,4-dihydroxyphene)
)-2-methylalaninate hydrozine
Quizalate hydrate is obtained. thin layer chromatography
- [Fluorescent silica gel plate, methanol (25%) -
Exhibited by Roloforum (75%) (by volume)
Open], Rf=0.45. Analysis value: C₁₅H_{twenty two}N₂O_Five・C₂H₂O_Four・H₂against O Calculated values: C 48.80, H 6.26, N 6.69 Experimental values: C 48.73, H 6.85, N 6.68 Example 9 2-Methylthioethyl L-3-(3,4-dihydrogen
Droxyphenyl)-2-methylalaninate
Production of hydrozine oxalate Add 275 ml of thionyl chloride to L-3-(3,4-
dihydroxyphenyl)-2-methylalanine
Add to 250g of Toseski hydrate and then steam the mixture.
Heat over the bath. After heating for 2 hours, the reaction mixture
Dimethyl formamide 7.5 in 25 ml of benzene
ml, then on a steam bath until gas evolution stops.
Stir. Add 100ml of benzene, then crude sulfite
Remove the ester by filtration, add 100ml of benzene,
Wash with 100 ml of chloroform and 100 ml of ether.
and then dried under reduced pressure to obtain a solution with a melting point of 199°C (decomposition).
280 g of sulfite intermediate are obtained. Crude sulfite ester 30g, 2-hydroxyethyl
Methyl sulfide 34.6g (0.375mol) and
Steam a mixture of 6 g of anhydrous dimethylformamide.
Stir on air bath for 28 hours, then cool. reaction mixture
4 times with 100 ml of ethyl ether and diluted with methychloride.
Wash 3 times with 100ml each. Empty the remaining material.
Tanol (20%) - Ethyl acetate (80%) (by volume)
) 250 ml, 30 ml of saturated sodium carbonate solution and
Stir with 60 g of solid sodium carbonate, then filter
do. Insoluble materials were dissolved in ethanol (20%)-acetic acid.
Chill (80%) (depending on volume) Wash 3 times with 250ml each
and combined with the first ethanol-ethyl acetate extract.
and then dried over anhydrous magnesium sulfate.
After filtration, the solvent was removed under reduced pressure and the residue was silched.
Chromatography on Kagel. product
2.3g methanol (25%) - chloroform (75%)
%) (by volume) elute with the mixture. This generation
was added to a solution of 1.3 g of oxalic acid in 25 ml of ethanol,
Next, precipitate with a sufficient amount of ethyl ether.
It is then converted to oxalate. to dissolve the product
Ethanol and ethyl alcohol to precipitate the product.
After 3 or more precipitations using ether, 2
-Methylthioethyl L-3-(3,4-dihydro
xyphenyl)-2-methylalaninate hydride
Obtain 300 mg of Rosin Oxalate. thin layer chromatography
Graphie [fluorescent silica gel plate, methanol (25
%) - developed with chloroform (75%)]
Homogeneous, Rf = 0.83. Melting point 85-90℃ (decomposition) Analysis value: C₁₃H₁₉NO._FourS・C₂H₂O_Fouragainst Calculated values: C 47.99, H 5.64, N 3.73 Experimental values: C 48.00, H 6.10, N 4.07 Reference example 18 A DL-3-(3,4-diphenylmethylenedio)
xyphenyl)-2-methylalanine hydrochloride
manufacturing Racemic-3-(3,4-dihydroxyphenyl)
-2-Methylalanine hydrochloride 38.6g (0.155mol)
and dichlorodiphenylmethane 74g (0.312mol)
) was preheated with gradual stirring.
Place in an oil bath at 190℃. After starting the reaction, the reaction mixture
Stir rapidly at 190℃ for 6 minutes and remove from hot oil bath.
Then cool to 25-30°C. Raw from 6 times method
Combine the ingredients and make a slurry with diethyl ether 2
filtered, washed with diethyl ether 2 and then
Dry at 30 °C under 50 mm pressure. Ethanol the product
by stirring and then adding ethyl acetate.
Recrystallize to obtain DL-3-(3,4-diphenylmethylene)
dioxyphenyl)-2-methylalanine hydrochloride
Get the salt. B DL-N-carbobenzyloxy-3-(3,
4-diphenylmethylenedioxyphenyl)-
Production of 2-methylalanine By gradual addition of 10% sodium hydroxide solution
While keeping the pH at 120, add racemic-3-(3,4
-diphenylmethylenedioxyphenyl)-2-
Methylalanine hydrochloride 175g (0.425mol), acetic acid
A mixture of 1750 ml of ton and 1750 ml of water at below 10℃
Stir under nitrogen at room temperature. Carbobenzyl chloride
Add 93 g (0.545 mol) of oxygen to the reaction mixture at 20-30°C.
dropwise over 5 to 7 minutes. At this time, set the pH to 12.0.
10% sodium hydroxide solution to hold ~12.2
Add liquid at the same time. Carbobenzyloxy chloride
After the addition of
Stir. Next, remove most of the acetone at 25-35℃.
The desired N-carbobenzyloxy derivative is removed by pressure removal.
Precipitates sodium salts in the body. sodium salt
Extracted into 1.5% ethyl acetate and 5% sodium hydroxide
200 ml of solution and 200 ml of saturated sodium chloride solution
and then dried over magnesium sulfate. Detachment
Add 17.5g of colored charcoal and a bed of magnesium sulfate.
After filtration, remove the solvent under reduced pressure at 25-35℃
do. The residue was dissolved in ethyl ether (20%)-hexa
Slurrying (80%) (depending on capacity) 2 times in 1
do. Next, the desired N-carbobenzyl
Obtain the sodium salt of the xy derivative. This Natoriu
Dissolve the salt in 1.5 ml of ethyl acetate and cool to 10°C.
Next, acidify to PH2 with 6N hydrochloric acid. Ethyl acetate
Wash the extract with 200ml of saturated sodium chloride solution.
dried over magnesium sulfate and filtered for 25 min.
Concentrate under reduced pressure at ~35°C. N-carbobenzyloki
Further dry the derivative at 25-30℃ and 0.2-0.3mmHg.
Dry to give DL-N-carbobenzyloxy-3-
(3,4-diphenylmethylenedioxyphenyl)
-2-Methylalanine is obtained. C D,L-succinimidomethyl N-carbobe
ndyloxy-3-(3,4-diphenylmethy)
dioxyphenyl)-2-methylalanine
Manufacture of sheets D, L- in 35 ml of dry dimethylformamide
N-carbobenzyloxy-3-(3,4-diph)
enylmethylenedioxyphenyl)-2-methyl
Alanine 13.5g (0.0265mol), triethylamine
27 g (0.027 mol) and N-bromomethyl saline
A solution of 5.19 g (0.029 mol) of succinimide was added to
Stir at ~30 °C for 16 h. Pour the reaction mixture into ice water 400 ml
ml and then the product in chloroform (50
%) - diethyl ether (50%) (by volume) mixture
Extract the mixture into 200ml. Dilute organic extract (5%)
50 ml of sodium carbonate solution and saturated sodium chloride
Wash with 50 ml of anhydrous magnesium sulfate solution.
Remove water by drying on a vacuum. filtration and vacuum concentration
After shrinkage, the residue is recrystallized. Ethanol the product
and then add hexane to precipitate the product.
Recrystallization is performed by
Cinimidomethyl N-carbobenzyloxy-3
-(3,4-diphenylmethylenedioxyphenylene
)-2-methylalaninate is obtained. D D,L-succinimidomethyl-3(3,4
-dihydroxyphenyl)-2-methylalani
Production of nate hydrochloride hydrate 180ml absolute ethanol and 9.6N ethanolic
Racemic succinimide in 9 ml of anhydrous hydrogen chloride solution
Methyl N-carbobenzyloxy-3-(3,4
-diphenylmethylenedioxyphenyl)-2-
Suspension of 6.6 g (0.0106 mol) of methylalaninate
Using 3.3g of carbon catalyst with 10% palladium,
water at an initial pressure of 30 p.s.i. until hydrogen absorption is complete.
Add element. After removing the catalyst by filtration,
Concentrate the liquid under reduced pressure. 50ml of benzene to the residue, then
Extract with 50 ml of ethyl acetate. Remove insoluble solids
50 ml of ethanol (10%)-ethyl acetate (90%) mixture
and 10 ml of saturated sodium carbonate solution.
Ru. After filtration, the solution was poured over anhydrous magnesium sulfate.
Dry, filter and concentrate under reduced pressure to obtain D,L-succinimide.
imidomethyl 3-(3,4-dihydroxyphene)
Nyl)-2-methylalaninate was obtained as the base.
Ru. E. Succin by recrystallization of diastereomeric salts
imidomethyl L-3-(3,4-dihydroxy
Phenyl)-2-methylalaninate hydrochloride water
manufacturing of chemicals Absolute ethanol (50%) - ethyl acetate (50%)
(-)Tartaric acid 0.47g in 10ml of solution (by volume)
(3.1 mmol) solution for 20-25 min under nitrogen.
D,L-succinimate in 10 ml of absolute ethanol at °C.
Midomethyl 3-(3,4-dihydroxyphenyl)
-2-methylalaninate 1.0g (3.1 mmol)
Add to the solution. After warming the solution to 40-60℃,
Add ethyl acetate to cloud, then gradually warm to 25°C.
Cool and then stand at 5-10°C for 12 hours. insoluble
Crude tartrate was removed by filtration and 20-25
Dry at °C and 0.2-0.5mm pressure. This recrystallization
The melting point and optical rotation of tartrate are essentially
Repeat until it becomes constant. 15-20mm and 40-45mm of mother liquor from initial crystallization
Concentrate at °C. Residue ethanol (10%)-vinegar
25 ml of ethyl acid (90%) mixture and saturated sodium carbonate
Shake with 10 ml of solution. After that, drain the liquid.
Dry over anhydrous magnesium sulfate, filter and then
Concentrate at 15-20 mm and 40 °C to obtain a gum.
Dissolve the residue in 5 ml of absolute ethanol and dilute with nitrogen.
Anhydrous ethanol (50%) - ethyl acetate under
(+) liquor in 11 ml of solution (50%) (by volume)
Add to a solution of 0.3 g of taric acid. Heat the solution to 40-60℃.
After warming, add ethyl acetate to cloud, then
Gradually cool to 25℃ and leave at 5-10℃ for 14 hours
do. Insoluble crude tartrate is removed by filtration.
Ru. By repeating this recrystallization method, succinimide
Methyl 3-(3,4-dihydroxyphenyl)-2
- Other optical enantiomers of methylalaninate are tartaric.
Obtained as an acid salt. The optically active tartrate is prepared by the following method:
Converted to optically active hydrochloride. Sakshini
Mido L-3-(3,4-dihydroxyphenyl)-
2-Methylalaninate tartrate with ethanol
(10%)-ethyl acetate (90%) mixture and 50 ml of saturated
Shake with 10 ml of Japanese sodium carbonate. After that,
The solution was dried over anhydrous magnesium sulfate and filtered.
Then concentrate under reduced pressure. 25% of the residue in absolute ethanol
Redissolve in 9.6N ethanolic anhydrous hydrogen chloride
Treat with 5 ml of solution and then concentrate under reduced pressure to saccharinate.
Midomethyl L-3-(3,4-dihydroxyphene)
Nyl)-2-methylalaninate hydrochloride hydrate
obtain. Thin layer chromatography [fluorescent silica gel]
Plate, methanol (30%) - benzene (70%) (volume
homogeneous, Rf=0.5 Reference example 19 Racemic pivaloyloxy by direct recrystallization
Methyl 3-(3,4-dihydroxyphenyl)-
Resolution of 2-methylalaninate Racemic pivaloyloxymethyl 3-(3,4-
dihydroxyphenyl)-2-methylalanine
The hydrochloride salt is prepared as in Example 23. Racemic pivaloyloxymethyl 3-(3,4-
dihydroxyphenyl)-2-methylalanine
Slurry 30g of hydrochloride in 100ml of 1.0N hydrochloric acid at 35°C.
- to become Strain off excess solids. 35 saturated solution
pivaloyloxymethyl D-3-(3,4-
dihydroxyphenyl)-2-methylalanine
Add the seeds of hydrochloride hydrate. mix 30 minutes 20
Cool to 20°C and leave at 20°C for 0.5 hours. precipitation
The resulting material was isolated by filtration and washed twice with 5 ml of cold water.
Washed, then 0.1-0.5mm and 20-25℃ for 20 hours
Dry to give pivaloyloxymethyl D-3-(3,
4-dihydroxyphenyl)-2-methylalani
Obtain nate hydrochloride hydrate. The mother liquor from the previous step was heated to 35°C and 35°C
pavaloyloxymethyl L-3-(3,4-
dihydroxyphenyl)-2-methylalanine
Add the seeds of hydrochloride. Then boil the mixture for 30 minutes.
Cool to 20°C and then leave at 20°C for 05 hours.
The precipitated material was isolated by filtration and diluted with 5 ml of cold water.
Wash and then dry for 20 hours at 0.1-0.5mm and 20-25℃
After drying, pivaloyloxymethyl L-3-(3,4
-dihydroxyphenyl)-2-methylalanine
to obtain salt hydrochloride hydrate. Reference example 20 A α-succinimideethyl L by fractional crystallization
-3-(3,4-dihydroxyphenyl)-2-
Methylalaninate hydrochloride dihydrate (β-isomer
body) manufacturing Succinimidoethyl L-3-(3,4
-dihydroxyphenyl)-2-methylalanine
10 g of salt hydrochloride (α- and β-isomer mixture)
Dissolve in 50 ml of warm 95% ethanol (5% water),
Fill with water ether, cloud, add seeds and crystallize.
induce change. After cooling to 5-10℃ for 12 hours,
The precipitated solid is collected and then dried at 70°C. Eta
From alcohol (95%) - water (5%) - ethyl ether
By similar recrystallization of
solution). Final from 95% ethanol
Melting point (70℃) of 129-131℃ (decomposed) by recrystallization
α-sacsi as a dihydrate with (dried overnight)
imidoethyl L-3-(3,4-dihydroxy
Phenyl)-2-methylalaninate hydrochloride dihydrate
(β-isomer). thin layer chromatograph
E [Fluorescent silica gel plate, methanol (50%) -
Homogeneous with benzene (50%) solvent, Rf = 0.7. B α-succinimidoethyl L-3-(3,4
-dihydroxyphenyl)-2-methylalani
Production of nate hydrochloride hydrate (α-isomer) α-succines enriched in the corresponding α-isomer
imidoethyl L-3-(3,4-dihydroxyph)
enyl)-2-methylalaninate hydrochloride hydrate
The mother liquor from the first crystallization of the β-isomer of
Concentrate at 20 mm and 40-45 °C. Heat the residue to 95%
Dissolve in 20ml of ethanol (5% water) and add ethyl acetate.
Dilute to a cloudy point, add seeds and stir
Midoethyl L-3-(3,4-dihydroxyphene)
Nyl)-2-methylalaninate hydrochloride hydrate
The α-isomer is precipitated. Plus 95% ethanol
(5% water) and acetic acid by precipitation from ethyl acetate.
The α-isomer is obtained as an ethyl solvate. Rf＝
0.7 [Thin layer chromatography, fluorescent silica gel
Plate, methanol (50%) - benzene (50%) solution
agent]. Example 10 pivaloyloxymethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalanine
Production of hydrochloride L-3-(3,
4-dihydroxyphenyl)-2-methylalani
0.95 g (4.0 mmol) of sesquihydrate and
Baloyloxymethyl chloride 0.61g (4.06ml)
Stir the solution of limol) at 20-25°C for 23 hours. melt
Dilute the solution with 10ml of distilled water, then use the base cycle.
A container containing 5 g of weakly basic anion exchange resin.
Pass it through the ram. Positive chloride after elution with water fraction
Combine the fractions to give the ferric test, and
3g of weakly acidic cation exchange resin as an acid cycle
column. Unreacted L-3-(3,4-di
Steaming hydroxyphenyl)-2-methylalanine
Elute with standing water until a negative ferric chloride test is obtained.
and then the ester is eluted with 1N acetic acid. beauty salon
Acidify 50ml of Refluxion (PH3.2) with 1N hydrochloric acid.
Freeze to pH2.0 and then freeze dry at 0.1~0.3mm for 20 hours
After drying, pivaloyloxymethylene is obtained as acetic acid solvate.
L-3-(3,4-dihydroxyphenyl)-2
- Obtaining methylalaninate hydrochloride. Analysis value: C₁₆H_{twenty three}NO.₆・HCl・1/3HC₂H_FourO₂against
do Calculated values: C 52.11, H 6.69, N 3.58 Experimental values: C 52.11, H 6.49, N 3.73 Reference example 21 α-succinimidoethyl L-3-(3,4-
dihydroxyphenyl)-2-methylalanine
Production of salt hydrochloride L-3-(3,
4-dihydroxyphenyl)-2-methylalani
0.95 g (4.0 mmol) of N sesquihydrate and N
-(α-chloroethyl)-succinimide 0.65g
(4.0 mmol) was stirred at 20-25℃ for 23 hours.
Ru. Dilute the solution with 10ml of distilled water, then wash with base.
Contains 5g of weakly basic anion exchange resin as a base.
Pass it through the column. Positive after elution with water fraction
Combine the fractions that give the ferric chloride test and
Weakly acidic cation exchange resin 3 as an acid cycle
g column. Unreacted L-3-(3,4-
dihydroxyphenyl)-2-methylalanine
Elute with distilled water until a negative ferric chloride test is obtained.
and then the ester is eluted with 1N acetic acid. beauty salon
Treat 55ml of refluxion (PH3.2) with 1N hydrochloric acid.
PH2.0 and then freeze-dried at 0.1-0.3mm for 20 hours.
α-succinimidoethyl L-3-(3,4
-dihydroxyphenyl)-2-methylalanine
to obtain an acetic acid solvate of hydrochloride. Analysis value: C₁₆H₂₀N₂O₆・HCl・1/3C₂H_FourO₂against
do Calculated values: C 50.96, H 5.73, N 7.13 Experimental values: C 50.48, H 6.13, N 6.77 Example 11 3-acetamidopropyl L-3-(3,4-
dihydroxyphenyl)-2-methylalanine
Production of hydrozine oxalate hydrate Add 275 ml of thionyl chloride to L-3-(3,4-
dihydroxyphenyl)-2-methylalanine
Add to 250g of Toseski hydrate and then steam bath the mixture.
Heat on top. After heating for 2 hours, the reaction mixture
Dimethyl formamide dissolved in 25 ml of benzene
Dilute with 7.5ml, then put on a steam bath to stop gas generation.
Stir until Add 100ml of benzene and then
The sulfuric acid ester was removed by filtration and the benzene
100ml, chloroform 100ml and ether 100ml
ml and then dried under reduced pressure to a melting point of 199°C.
(Decomposition) 280 g of sulfite ester intermediate is obtained. Crude sulfite intermediate 13.7g, N-acetyl
24.98 g (0.212 mol) of propanolamine and
Steam a mixture of 2 g of anhydrous dimethyl formamide.
Stir on a gas bath for 20 hours, then cool. reaction mixture
6 times with 200 ml of ethyl ether and diluted with methichloride.
Wash 4 times with 200ml each, then dry under reduced pressure.
do. Ethanol (20%) the remaining semi-solid material
- Ethyl acetate (80%) (by volume) 200 ml, saturated
20ml of sodium carbonate solution and solid sodium carbonate
Stir with 20g of um. Anhydrous organic extract
Dry over magnesium sulfate, filter, then drain
is added to a solution of 32 g of oxalic acid in 50 ml of ethanol.
Achieve the removal of the solvent under reduced pressure and then remove the product
Dissolve in 50 ml of ethanol, then add ethyl ether.
Precipitate the product by adding 500 ml of
Ru. Dissolve the product again in 50 ml of ethanol, then
Remove the product by adding 500 ml of ethyl acetate.
Let it settle. Thereby, 3-acetamidopro
Pill L-3-(3,4-dihydroxyphenyl)-
2-Methylalaninate hydrozine oxale
Obtain a hydrate. Thin layer chromatography [fluorescence]
Silica gel plate, methanol (25%)-chlorofluorocarbon
lum (75%) (depending on capacity)], Rf=0.45 Analysis value: C₁₅H_{twenty two}N₂O_Five・C₂H₂O_Four・H₂against O Calculated values: C 48.80, H 6.26, N 6.69 Experimental values: C 48.73, H 6.85, N 6.68 Example 12 2-acetamidoethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalanine
Production of hydrochloride L-3-(3,4-dihydroxyphenyl)-2
- Methylalanine hydrochloride ethanol solvate (reduced)
(by concentration of ethanolic solution of hydrochloride under pressure) 88.3
g (0.30 mol) and N-acetylethanola
A slurry of 146.4 g (1.42 mol) of
Heat to 104-108℃. Thionyl chloride 84.8
g (0.713 mol) over 15 minutes with stirring.
Add. The reaction mixture foams vigorously during the addition.
After the addition was complete, the reaction mixture was heated at 104-108 °C for 18 h.
Stir. Furthermore, 42.4 g (0.357 mole) of thionyl chloride
) over 7 minutes. reaction mixture 104
Stir for an additional 31/2 hours at ~108°C, cool to 30°C, It is then concentrated under reduced pressure to obtain a viscous oil. this oil
Slurry with 100ml of chloroform, then chloroform.
Remove the foam under reduced pressure. Repeat this 3 or more times
Then wash the oil with 100ml of benzene and then
Decant and separate the zen. Isopropanol the residue
Dissolve to 700ml, then add to ethyl ether 6
Ru. Wash the formed precipitate with 500 ml of ethyl ether.
and then ethanol (10%)-ethyl acetate (90%)
(by volume) 6, saturated sodium carbonate solution 150
ml and 100 g of sodium carbonate.
Dry the organic extract over anhydrous magnesium sulfate.
filtered, then concentrated under reduced pressure to obtain acetamide ethyl
The free base of the ether is obtained. This base is
treated with 15 g of fumaric acid in 300 ml of lopanol,
Then the humer is added by adding ethyl ether.
Precipitate the lunate. Adding ethyl ether
1 fumarate from isopropanol depending on
Precipitate more times and then ethanol as described above.
(10%) - Ethyl acetate (90%) (by volume) 200
ml, 20 ml of saturated sodium carbonate solution and solid charcoal
By shaking with 20 g of sodium chloride
Convert back to free base. Convert this free base into anhydrous ether.
Dissolve in 100ml of alcohol, then add 10ml of 9.6N HCl.
and then convert this into the hydrochloride salt by
was precipitated by addition of 1 part of ethyl ether.
Ru. Perform ethanol-ethyl as previously described.
After three precipitations from ether, the 2-acetamide
Doethyl L-3-(3,4-dihydroxyphenylene)
)-2-methylalaninate hydrochloride is obtained. Thin
Layer chromatography [fluorescent silica gel plate, meta
Developed with nol (50%)-benzene (50%)], Rf
=0.57 Analysis value: C₁₄H₂₀N₂O_Five・For HCl Calculated values: C 50.52, H 6.36, N 8.41 Experimental values: C 50.40, H 6.69, N 8.49 Reference example 22 A L-3-(3,4-diacetoxyphenyl)-
Production of 2-methylalanine hydrochloride A mixture of 320ml glacial acetic acid and 24ml acetyl chloride
L-3-(3,4-dihydroxyph)
enyl)-2-methylalanine sesquihydrate 69.4
g (0.291 mol). The temperature of the reaction mixture is
The temperature rises to about 50°C and a clear solution is obtained.
At this temperature, add 85 ml of acetyl chloride for 10 minutes.
Add it. The resulting clear pale yellow solution is heated for 20~
Leave at 25°C for 14 hours. anhydrous ethyl ether
Add 400ml over 15 minutes. Mostly added
When complete, a white solid begins to precipitate.
Stir the mixture at 20-25°C for 30 minutes and at 5-10°C for 1 hour.
and then cooled at -10°C for 2 hours. over solid
Remove acetic acid (30%)-ethyl ether
(70%) Suspend in 150ml (depending on volume) and then
Wash with 500ml of ethyl ether. 2 hours at 70℃
After drying for a while, L-3- with a melting point of 196.0-197.0℃
(3,4-diacetoxyphenyl)-2-methyla
83.7 g (88%) of ranin hydrochloride are obtained. B L-3-(3,4-diacetoxyphenyl)-
Production of 2-methylalanyl chloride hydrochloride L-3-(3,4-diacetoxyphenyl)-2
- Methylalanine hydrochloride 6.60g (0.020mol)
and 40 ml of thionyl chloride at 60℃ for 2 hours.
Stir until solution is complete. excess thionyl chloride
is removed at 15-20 mm and 40-45°C. methylene chloride
Add 50ml of water and mix the mixture with 15-20mm
Reconcentrate to 50°C. Add this to 50ml of methylene chloride.
Iterate one or more times using 0.2~0.5mm and
After drying at 40℃ for 30 minutes, L-3-(3,4-dia
Setoxyphenyl)-2-methylalanylchlora
get id. C Succinimidomethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalanine
Production of hydrochloride hydrate L-3-(3,4-di) in 20 ml of chloroform
Acetoxyphenyl)-2-methylalanylchloro
A solution of 3.50 g (10 mmol) of Ride hydrochloride, 25
N-Hydroxymethane in 20 ml of chloroform at
Solution of 3.87 g (30 mmol) of tilsuccinimide
Add to. After stirring for 20 minutes under reflux, most of the
Removes chloroform at 15-20mm and 30-40℃
do. Dilute the residue with 10 ml of 1N hydrochloric acid, then ethyl
Extract twice with 20 ml of ether. aqueous extract
Stir at 20-25°C under nitrogen for 5 hours. 0.1~0.3mm
After freeze-drying for 20 hours in ethanol, the residue
(10%) - ethyl acetate (90%) (by volume) solution
50 ml, 5 ml of saturated sodium carbonate solution and solid
Treat with 5 g of sodium carbonate. After that, drain the liquid.
Dry over anhydrous magnesium sulfate, filter, and then
Concentrate at 15-20 mm and 30-40 °C. residue
Dissolve in 25ml of absolute ethanol again and add 9.6N ethanol.
treated with 5 ml of anhydrous hydrogen chloride solution and then reduced under reduced pressure.
Concentrate to succinimidomethyl L-3-(3,4
-dihydroxyphenyl)-2-methylalanine
to obtain salt hydrochloride hydrate. thin layer chromatography
- [Fluorescent silica gel plate, methanol (30%) -
(70%) (by volume) solvent]
quality. Rf=0.5 Reference example 23 A L-3-(3,4-dihydroxyphenyl)-
N-carboxylated 2-methylalanine
Manufacture of Drydo L-3-(3,4
-dihydroxyphenyl)-2-methylalanine
A mixture of 9.0 g (0.038 mol) of sesquihydrate
Introduce sugen gas for 25 minutes until the solution is saturated.
During the addition, the temperature of the reaction mixture rises to 45°C. melt
The solution was stirred for an additional 50 minutes while nitrogen gas was introduced.
Insoluble materials are removed by filtration through a bed of diatomaceous earth
and then concentrate the liquid at 15-20mm pressure and 30-35℃.
Shrink to obtain oil. Dissolve the residue in 75ml of ethyl acetate.
and add hexane to cloud point. 0~ for several days
After cooling to 5°C, filter the precipitated solid.
and then dry at 0.1-0.3 mm pressure and 25 °C.
Dried to L-3-(3,4-dihydroxyphenyl)
-N-carboxyamyl of 2-methylalanine
Get Drydo. B Succinimidomethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalanine
Production of hydrochloride hydrate L-3-(3,4-dihydroxyphenyl)-2
-N-carboxyanhydra of methylalanine
2.37 g (10 mmol) and N-hydroxy
Dissolution of 1.29 g (10 mmol) of methyl succinimide
All N-carboxylic anhydride is removed from the liquid.
Heat to reflux until reaction occurs. 15~20mm pressure and
After concentration at 30-40°C, the residue was dissolved in benzene 50°C.
ml, then extracted with 50 ml of ethyl acetate. Next,
The soluble solid was dissolved in ethanol (10%) - ethyl acetate (90%).
%) (by volume) mixture 50ml and saturated sodium carbonate
Shake with 10 ml of thorium solution. After that,
The solution was dried over anhydrous magnesium sulfate and filtered.
and then concentrated under reduced pressure. Remove the residue with absolute ethanol
Redissolve in 25ml 9.6N ethanolic anhydrous chloride water
5 ml of the original solution, then concentrated under reduced pressure and sacrificed.
Cinimidomethyl L-3-(3,4-dihydroxy
Cyphenyls)-2-methylalaninate hydrochloride water
Get a monster. Thin layer chromatography [fluorescence chromatography]
Kagel board, methanol (30%) - benzene (70%)
(by volume) homogeneous by solvent], Rf = 0.5 Reference example 24 A L-3-(3,4-diphenylmethylenedio)
xyphenyl)-2-methylalanine hydrochloride
manufacturing L-3-(3,4-dihydroxyphenyl)-2
-Methylalanine hydrochloride 19.3g (0.0777mol)
and dichlorodiphenylmethane 37g (0.156mol)
The mixture was preheated to 190°C under slow stirring.
Immerse in a hot oil bath. Initiation of reaction (violent moth)
(as indicated by the evolution of gas), the reaction mixture was heated to 190°C.
Stir rapidly for 6 minutes, remove from hot oil bath, then heat for 25~
Cool to 30°C. The crude products from the 12 steps were combined.
slurried with diethyl ether 3 and filtered.
Wash with diethyl ether 2 and then apply a pressure of 50 mm.
Dry at 30℃. convert the product into ethanol
and then add ethyl acetate to precipitate the product.
Recrystallization is achieved by this. This method
L-3-(3,4-
Diphenylmethylenedioxyphenyl)-2-meth
255 g (66.4%) of tylalanine hydrochloride are obtained. B α-succinimidoethyl L-3-(3,4
-diphenylmethylenedioxyphenyl)-2
-Production of methylalaninate L-3-(3,
4-diphenylmethylenedioxyphenyl)-2
- 1.4 g (4.0 mmol) of methylalanine and N
-(α-chloroethyl)-succinimide 0.65g
(4.0 mmol) solution was stirred at 20-25°C for 23 hours.
do. 150ml of water then saturated sodium carbonate solution
Add until pH8 is obtained. The product is converted into ethyl ether.
Extract into 500 ml of water, wash 4 times with 25 ml of water each,
Dry over anhydrous magnesium sulfate, then filter
Ru. Concentrate at 15-20mm and 35-40℃ for next step
Crude α-saccharide of sufficient purity for use in
imidoethyl L-3-(3,4-diphenylmethyl
(ethylenedioxyphenyl)-2-methylalanine
get a discount. C α-succinimidoethyl L-3-(3,4
-dihydroxyphenyl)-2-methylalani
Production of nate hydrochloride Absolute ethanol (25%) - ethyl acetate (75%)
α-succinimide in 25 ml of solution (by volume)
Ethyl L-3-(3,4-diphenylmethylene di
Oxyphenyl)-2-methylalaninate 1.0g
(2.0 mmol) suspension on charcoal coated with 10% palladium.
Initial pressure and chamber of 40 p.s.i using 1.0 g of elementary catalyst
Hydrogenate for 23 hours at room temperature. pass through the catalyst and then
Evaporate the liquid under reduced pressure at 30-40°C. ethanol residue
(10%) - Ethyl acetate (90%) (by volume) solution
Dissolve in 50ml of solution, then add 50ml of saturated sodium carbonate solution.
ml and with about 5 g of anhydrous sodium carbonate
Stir for 1 minute. After cooling, pour the liquid into anhydrous sulfuric acid mag- netic
Dry over nitrogen, filter, then evaporate to dryness under reduced pressure.
Ru. Dissolve the residue in 20 ml of dry chloroform,
The solution was cooled in an ice bath and then heated with hydrogen chloride gas for 15 min.
saturate. Collect the solid and dissolve in 25 ml of anhydrous ether.
Wash by resuspending twice and then at room temperature.
N in 25 ml of ethyl acetate in a flask with a stopper.₂below
Make slurry. Remove insoluble solids by filtration
slurried with 30 ml of hexane for 2 hours, then
CaCl in an empty desiccator₂Dry on top
α-succin as a mixture of - and β-isomers
imidoethyl L-3-(3,4-dihydroxyph)
(enyl)-2-methylalaninate hydrochloride is obtained.
Thin layer chromatography [fluorescent silica gel plate,
Tanol (50%) - Benzene (50%) (depending on volume)
) Solvent], Rf=0.7 Reference example 25 A L-3-(3,4-diacetoxyphenyl)-
Production of 2-methylalanine hydrochloride A mixture of 320ml glacial acetic acid and 24ml acetyl chloride
L-3-(3,4-dihydroxyph)
enyl)-2-methylalanine sesquihydrate 69.4
g (0.291 mol). The temperature of the reaction mixture is
The temperature rises to about 50°C and a clear solution is obtained.
At this temperature, add 85ml of acetyl chloride for 10 minutes.
Add over a period of time. The resulting clear pale yellow solution
Leave at 20-25℃ for 14 hours. anhydrous ethyl ether
Add 400 ml of water over 15 minutes. Addition
When almost done, a white solid will start to precipitate.
Melt. Heat the mixture at 20-25°C for 30 minutes, then at 5-10°C.
Stir for 1 hour, then cool at -10°C for 2 hours. solid
The body was removed by filtration and acetic acid (30%)-ethyl
Suspended in 150 ml of ether (70%) (depending on volume);
Filter and then wash with 500 ml of ethyl ether.
After drying at 70℃ for 2 hours, the melting point is 196.0-197.0℃.
L-3-(3,4-diacetoxyphenyl)-2-
83.7 g (88%) of methylalanine hydrochloride are obtained. B α-succinimidoethyl L-3-(3,4
-diacetoxyphenyl)-2-methylalani
Production of nate hydrochloride L-3-(3,
4-Diacetoxyphenyl)-2-methylalani
1.66 g (5 mmol) of triethylamine hydrochloride,
0.51 g (5 mmol) of N-(α-chloro
ethyl)-succinimide 0.81g (5 mmol)
Stir the solution at 20-25 °C for 20-24 h. ethyl
Stir for a few minutes with 20 ml of ether, then add ethyl ethyl ether.
dimethyl sulfur by decanting the
Remove fluoride. Perform this extraction method three times.
Ru. Dissolve the residue in 10 ml of absolute ethanol, then
Precipitate the product by adding excess ethyl ether.
Let it stagnate. This precipitation method is repeated two or more times to obtain pure
α-succinimidoethyl L-3-(3,4-di
Acetoxyphenyl)-2-methylalaninate
Obtain the hydrochloride. Reference example 26 α-succinimidoethyl L-3-(3,4-
dihydroxyphenyl)-2-methylalanine
Production of salt hydrochloride α-succinimide ethyl L in 10 ml of 1N hydrochloric acid
-3-(3,4-diacetoxyphenyl)-2-meth
Chilalaninate hydrochloride (Example 37) 18g (3.94ml)
mol) solution was stirred at 20-25°C for 5 hours under nitrogen.
do. After freeze-drying for 20 hours at 0.1-0.3mm, residual
The mixture was diluted with ethanol (10%) - ethyl acetate (90%) (by volume).
(depending on volume) solution 50 ml, saturated sodium carbonate solution 5
ml and 5 g of solid sodium carbonate.
After filtration, dry the liquid over anhydrous magnesium sulfate.
filtered and then evaporated to dryness under reduced pressure. Dry the residue
Dissolve in 20 ml of dry chloroform and place the solution in an ice bath.
Cool and then saturate with hydrogen chloride gas for 15 minutes. solid
The body was collected and suspended in 25 ml of anhydrous ethyl ether three times.
Wash by letting it cool, then leave it in a stoppered lid overnight at room temperature.
N in 25 ml of ethyl acetate in a flask₂Slurry below
become α-succinimidoethyl L-3-(3,
4-dihydroxyphenyl)-2-methylalani
Collect the nate hydrochloride and then place it in a vacuum desiccator.
CaCl₂α- and β-isomers by drying on
The hydrochloride salt is obtained as a mixture of thin layer chromatography
Fee [fluorescent silica gel plate, methanol (50%)
−Benzene (50%) (by volume) solvent], Rf=
0.7 Reference example 27 A Production of N-(1-chloroethyl)-maleimide 5.20 g (0.020 mol) of stannic chloride to carbon tetrachloride
49.2g (0.40mol) of n-vinylmaleimide in 1
) and then saturate the mixture with hydrogen chloride.
while stirring at 20-30°C for 6 hours. 24 hours later
Then, the mixture was resaturated with hydrogen chloride for 1.5 h.
At the end of 48 hours, the solution was decanted and then gummy
Wash the residue 10 times with 100 ml each of carbon tetrachloride.
The combined extract was slurried with 10 g of diatomaceous earth and filtered.
Then, concentrate the liquid under reduced pressure to about 400 ml. N
-(1-chloroethyl)-maleimide and
and dry at 20-30℃. B α-maleimidoethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalanine
Production of hydrochloride L-3-(3,
4-dihydroxyphenyl)-2-methylalani
0.95 g (4.0 mmol) of N sesquihydrate and N
-(α-chloroethyl)-maleimide 0.64g (4.0
(mmol) solution is stirred at 20-25 °C for 23 h.
Dilute the solution with 10ml of distilled water, then use the base cycle type
Color containing 5g of weakly basic anion exchange resin
Pass it through the program. After elution with water fraction, positive chloride
Combine the fractions giving the ferrous test and add the acid saline.
3g column of cycle-type weakly acidic cation exchange resin
Add to. Unreacted L-3-(3,4-dihydroxy
Distilled water
Elute until a ferric chloride test is obtained, then
Elute the stellate with 1N acetic acid. esterfraxi
Treat 55 ml of water (PH3.2) with 1N hydrochloric acid to adjust the pH to 2.0.
Next, lyophilize to 0.1-0.3 mm for 20 hours to obtain α-male.
imidoethyl L-3-(3,4-dihydroxyph)
(enyl)-2-methylalaninate hydrochloride is obtained. C α-succinimidoethyl L-3-(3,4
-dihydroxyphenyl)-2-methylalani
Production of nate hydrochloride α-maleimidoethyl in 25 ml of absolute ethanol
L-3-(3,4-dihydroxyphenyl)-2-
Methylalaninate hydrochloride 1.0g (2.7mmol)
solution using 1.0 g of 10% palladium-coated carbon catalyst.
One equivalent of hydrogen is absorbed at atmospheric pressure and 25°C using
Hydrogenate until saturated. Pass the catalyst, then the liquid
Evaporate under reduced pressure at 30-40℃. Ethanol the residue
(10%) - Ethyl acetate (90%) (by volume) 50ml
and then saturated sodium carbonate solution 5
ml and with about 5 g of anhydrous sodium carbonate
Stir for 1 minute. After filtration, dissolve the solution in anhydrous magnesium sulfate.
Dry over a vacuum, filter, then evaporate to dryness under reduced pressure.
Dissolve the residue in 20 ml of dry chloroform and add the solution.
cooled in an ice bath and then saturated with hydrogen chloride for 15 min.
Ru. Collect the solid and suspend it three times in 25 ml of anhydrous ether.
Wash at 20-25℃ overnight.
N in 25 ml of ethyl acetate in a stoppered flask.₂Below
Make it into a rally. Remove insoluble solids by filtration
and stirred with 30 ml of hexane for 2 hours, then
CaCl in an empty desiccator₂Dry on top
-succinimidoethyl L-3-(3,4-dihy
Droxyphenyl)-2-methylalaninate salt
The acid salt is obtained as a mixture of α- and β-isomers.
Ru. Thin layer chromatography [fluorescent silica gel]
plate, methanol (50%) - benzene (50%) (volume
) Solvent], Rf=0.7 Example 13 A α-chloroethyl 3-chloro-2,2-dime
Production of chillpropionate Combining 400mg of zinc chloride under a pressure of 0.2-0.5mm,
and then cooled to 25-30°C under nitrogen. 3-k
Rolo-2,2-dimethylpropionyl chloride
Add 62 g (0.40 mol) to the melted zinc chloride and then
Add 19.2g (0.44mol) of acetaldehyde to
Ru. Acetaldehyde carried out as rapidly as possible
Stir the reaction mixture during the addition of the
Prevents pyrogenic acetaldehyde loss
to cool down. After heating under reflux for 1 hour, distill
Therefore, α-chloroethyl 3-chloro-2,2-di
Obtain methyl propionate. B α-(3-chloro-2,2-dimethylpropyl)
onyloxy)ethyl L-3-(3,4-dihydroxy)
Droxyphenyl)-2-methylalaninate
Production of hydrochloride L-3-(3,
4-dihydroxyphenyl)-2-methylalani
0.95 g (4.0 mmol) of sesquihydrate and α
-Chloroethyl 3-chloro-2,2-dimethylpropylene
A solution of 0.81 g (4.06 mmol) of ropionate
Stir at ~25 °C for 23 h. Cover the solution with 10ml of distilled water.
Next, the weak basic anion exchanger of the base cycle type
Pass through a column containing 5 g of catalytic resin. water flax
gives a positive ferric chloride test after elution with
Combining fractions and acid cycle type weak acid
Add 3 g of cation exchange resin to the column. unrebelled
Compound L-3-(3,4-dihydroxyphenyl)-2
-Negative ferric chloride test for methylalanine in distilled water
The ester was then eluted with 1N acetic acid until a
Elute. Ester fraction 50ml (PH3.2)
Acidify with 1N hydrochloric acid to PH2.0, then 0.1~
Freeze-dry at 0.3 mm for 20 hours as acetic acid solvate
α-(3-chloro-2,2-dimethylpropioni
L-3-(3,4-dihydroxy)-ethyl
Cyphenyls)-2-methylalaninate hydrochloride
obtain. C α-pivaloyloxyethyl L-3-(3,
4-dihydroxyphenyl)-2-methylara
Production of ninate hydrochloride α-(3-chloro-2,
2-dimethylpropionyloxy)-ethyl L-
3-(3,4-dihydroxyphenyl)-2-methy
1.5 g (3.66 mmol) of lualaninate hydrochloride,
20~ using 1.0g of carbon catalyst with 10% palladium
Until one equivalent of hydrogen is absorbed at 25°C and atmospheric pressure.
Hydrogenate with. After removing the catalyst by
Remove ethanol at 15-20 mm and 30-35 °C.
Ru. Dissolve the residue in 40 ml of ethyl acetate and add solid carbonate.
2g sodium and 2g saturated sodium carbonate solution
Stir briefly with ml of mixture, then add anhydrous sulfur
Dry over magnesium acid. After 9.6N
Add 1 ml of ethanolic anhydrous hydrogen chloride and then add the solution.
Concentrate and dry. Further under 65℃ and 0.2mm pressure
Dried α-pivaloyloxyethyl ester salt
Obtain the acid salt. Reference example 28 A. Production of benzyl succinamate Succinamic acid 23.4g (0.20mol), sodium chloride
25.4g (0.20mol), triethylamine 20.2
g (0.20 mol) and dimethyl formamide
Stir 250 ml of the mixture at 95° C. for 20 hours. reaction mixture
Dilute the mixture with 500ml of water, then dissolve the product in ethyl ethyl
Extract twice with 200ml each. combined aete
extract in 50 ml portions of saturated sodium bicarbonate solution.
Wash twice, then twice with 50 ml of water, then with anhydrous water.
Dry over magnesium sulfate. After evaporation, remove the solution
Benzyl succina by concentrating at 15-20mm and 40℃
get mate. B Benzyl N-hydroxymethyl succinamate
Manufacture of Benzyl succina in 150 ml of ethyl acetate at 25 °C
Add paraffin to a stirred solution of mate 20.7 g (0.10 mol).
3.0g omaldehyde and ethanolic hydroxyl
Add 1 ml of a 20% (by weight) solution of calcium chloride.
I can do it. After stirring at 25°C for 20 hours, the hexane was brought to the cloud point.
and then cool the mixture at 5° C. for 24 hours.
The solvent was decanted and the residue was dissolved in 25 ml of hexane.
Washed with benzyl N-hydroxymethyl succina
get mate. C benzyl N-chloromethyl succinamate
manufacturing Benzyl N-hydroxy in 500 ml of carbon tetrachloride
24.2 g (0.10 mol) of methyl succinamate and
Triphenylfuosphine 28.9g (0.11mol)
The solution is stirred under reflux for 12 hours. passed, and
After washing the precipitate with benzene, remove the organic solvent for 15~20 min.
mm and removed at 30-40℃ and used in the next process.
benzyl N-chloromethyl with sufficient purity to
Obtain succinamate. D benzylsuccinamidomethyl L-N-cal
bobenzyloxy-3-(3,4-diphenyl
methylenedioxyphenyl)-2-methylara
Manufacture of nin L-N carbo in 20 ml of dimethyl formamide
benzyloxy-3-(3,4-diphenylmethy)
dioxyphenyl)-2-methylalanine
10.2g (0.020mol), triethylamine 2.02g
(0.020 mol) and benzyl N-chloromethyl saline
A solution of 5.12 g (0.020 mol) of kushinamate was added to the
℃ for 5 hours, then stirred at 20-30℃ for 5 hours, then
Pour into 200ml of water. Pour the product into 100ml of ethyl acetate.
Extract 3 times with 5% sodium hydroxide solution
ml, in 50 ml of water and 50 ml of saturated sodium chloride solution
Wash and then dry over anhydrous magnesium sulfate.
Ru. After evaporation, remove the solvent at 15~20mm and 30~40℃.
and benzylsuccinamidomethyl L-N-ka.
Lebobenzyloxy-3-(3,4-diphenyl
Methylenedioxyphenyl)-2-methylalani
get the results. E Succinamidomethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalanine
Production of hydrochloride Absolute ethanol (25%) - ethyl acetate (75%)
Benzylsuccinamide in 180ml (by volume)
Methyl L-N-carbobenzyloxy-3-(3,
4-diphenylmethylenedioxyphenyl)-2
-A solution of 13.8 g (0.0189 mol) of methylalanine
using 5 g of carbon catalyst with 10% palladium.
Hydrogen absorption for 18 hours at ~25 °C and initial pressure of 40 p.s.i.
Hydrogenate until stopped. Remove catalyst by filtration
After concentrating to dryness under reduced pressure, the residue was evaporated into anhydrous evaporator.
Tanol (10%) - Ethyl acetate (90%) (by volume)
) Dissolve the solution in 200 ml, then add saturated sodium carbonate.
5 ml of solution and excess solid sodium carbonate.
Stir for 2 minutes. 10g of anhydrous magnesium sulfate
added and then removed by filtration after a few minutes. solvent
Remove the residue under reduced pressure and add 25ml of hexane and then vinegar.
Wash with 25 ml of ethyl acid and then dry under reduced pressure.
Reprocess the residue with sodium carbonate as described above.
α-methyl-3,4-dihydroxyphenyl
Remove alanine and then 9.6N ethanolic anhydrous
Convert to hydrochloride with 3 ml of hydrogen chloride to obtain succinamide.
Methyl L-3-(3,4-dihydroxyphenyl)
-2-Methylalaninate hydrochloride is obtained. F Succinimidomethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalanine
Production of hydrochloride hydrate Succinamidomethyl L-3-(3,4-dihy
Droxyphenyl)-2-methylalaninate salt
3.95 g (10 mmol) of acid salt and acetyl chloride
Stir 100 ml of the mixture at 25° C. for 6 hours. 15-20
After concentration at 35 °C and 35 °C, the residue was dissolved in 1N hydrochloric acid 25
ml and then incubated at 20-25℃ under nitrogen for 5 hours.
Stir for a while. Freeze-dried for 20 hours at 0.1-0.3mm
After that, the residue was dissolved in ethanol (10%)-ethyl acetate.
(90%) (by volume) solution 50ml, saturated sodium carbonate
with 5 ml of sodium carbonate solution and 5 g of solid sodium carbonate.
Process. After evaporation, the solution is diluted with anhydrous magnesium sulfate.
Dry on a sieve, strain, then 15~20mm and 30~
Concentrate at 40°C. Dissolve the residue in 25ml of absolute ethanol.
Redissolve in 9.6N ethanolic anhydrous hydrogen chloride solution
5 ml and then concentrated under reduced pressure to remove succinimide.
Methyl L-3-(3,4-dihydroxyphenyl)
-2-Methylalaninate hydrochloride hydrate is obtained.
Thin layer chromatography [fluorescent silica gel plate,
Tanol (30%) - Benzene (70%) (depending on volume)
homogeneous due to solvent), observed Rf = 0.5 Reference example 34 A 2-hydroxyethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalanine
Production of hydrochloride L-3-(3,
4-dihydroxyphenyl)-2-methylalani
0.95 g (4.0 mmol) of sesquihydrate and 2
- Dissolution of 0.51 g (4.06 mmol) of bromoethanol
The solution was stirred at 60°C for 5 hours, then for 23 hours.
Cool to 20-25°C. Dilute the solution with 10ml of distilled water.
And base cycle type weak basic anion exchange tree
Pass through a column containing 5 g of fat. water fraction
The ferric chloride test gives a positive ferric chloride test after elution with
Combine the cushions, then use an acid cycle type weak acid cation.
Add 3 g of on-exchange resin to the column. unreacted L
-3-(3,4-dihydroxyphenyl)-2-methane
A negative ferric chloride test was obtained for tylalanine with distilled water.
Elute the ester with 1N acetic acid.
Ru. 50ml of ester fraction (PH3.2) with 1N salt
Acidify with acid to PH2.0, then 0.1 to 0.3 mm at 20 hours.
Freeze-dry for 2-hydroxyethyl L-3-
(3,4-dihydroxyphenyl)-2-methyla
Obtain laninate hydrochloride. B 2-acetoxyethyl L-3-(3,4-di
Hydroxyphenyl)-2-methylalanine
Manufacture of 2-Hydroxyethyl L-3-(3,4-dihydryl
Droxyphenyl)-2-methylalaninate salt
acid salt 1.0 g (3.4 mmol) and acetyl chloride 50
ml of the mixture is stirred at 25° C. for 6 hours. 15~20mm
After concentration at 35°C, the residue was dissolved in 25ml of 1N hydrochloric acid.
Strain and then stir for 5 hours at 20-25°C under nitrogen.
After freeze-drying at 0.1-0.3 mm for 20 hours, the residue was
Tanol (10%) - Ethyl acetate (90%) (by volume)
) solution, 5 ml of saturated sodium carbonate solution and
and 5 g of solid sodium carbonate. past
After that, the liquid was dried over anhydrous magnesium sulfate,
filtrate and then concentrate at 15-20 mm and 30-40 °C.
Ru. Chromatograph the residue on silica gel.
then methanol (20%) - benzene (80%)
(depending on volume). The ester was dissolved in warm acetic acid.
Dissolve in chill and then add cyclohexane to obtain desired
2-acetoxyethyl L-3-(3,4-dihydrogen)
Droxyphenyl)-2-methylalaninate
Recrystallization is carried out by precipitation. melting point
114-118℃ (decomposition). Reference example 35 2-acetoxyethyl L-3-(3,4-dihydrogen
Droxyphenyl)-2-methylalaninate
Manufacturing of 2-Hydroxyethyl L-3-(3,4-dihydryl
Droxyphenyl)-2-methylalaninate salt
1.0 g (3.4 mmol) of acid salt and methane sulfur
Heat a mixture of 50 ml of nil chloride at 25°C for 6 hours.
do. Concentrate at 15-20 mm and 35 °C, then 0.1
By drying at ~0.5mm and 40°C,
A methanesulfonyl derivative is obtained. In addition to this, there is a lot of moisture.
Thirsulfoxide 10ml and lithium acetate 6.6
g (10 mmol) and then stirred the mixture at 60°C for 6 hours.
Stir for an hour. Excess ethanolic anhydrous hydrogen chloride
After adding the solution, add 3 times with 50 ml of ethyl ether.
Stirring and then decanting the ethyl ether
Dimethyl sulfoxide is removed by.
Dissolve the residue in 24 ml of 1N hydrochloric acid and under nitrogen
Stir at 20-25°C for 1 hour. 0.1~0.3mm
After freeze-drying for 20 hours, the residue was dissolved in ethanol (10
%) - Ethyl acetate (90%) (by volume) solution 50
ml, 5 ml of saturated sodium carbonate solution and solid charcoal
Treat with 5 g of sodium chloride. After that, drain the liquid.
Dry over magnesium sulfate in water, strain and then
Concentrate at 15-20 mm and 30-40 °C. Chromatograph the residue on silica gel.
then methanol (20%) - benzene (80%)
(depending on volume). Dissolve in ethyl acetate,
Then, by adding cyclohexane to precipitate
Achieves recrystallization of ester with melting point of 114-118℃
(Decomposition) of the desired 2-acetoxyethyl L-3-
(3,4-dihydroxyphenyl)-2-methyla
Get laninate. Reference example 29 hard gelatin capsule g Succinimidomethyl L-3-(3,
4-dihydroxyphenyl)-2-meth
Chilalaninate hydrochloride hydrate 200 Corn starch 150 Magnesium stearate (powder) 50 Talc 50 The finely ground ingredients are mixed thoroughly and then 1000
Place into two hard gelatin capsules. That's it
This capsule contains succinimidomethyl L-3-
(3,4-dihydroxyphenyl)-2-methyla
Contains 200mg of laninate hydrochloride hydrate. Reference example 30 tablet Each of the following components is α-succinimide.
Chil L-3-(3,4-dihydroxyethyl)-2
-Methylalaninate hydrochloride dihydrate (β-isomer
body) obtain 1000 tablets containing 100 mg. g α-Succinimidoethyl L-3-
(3,4-dihydroxyphenyl)-2
-Methylalaninate hydrochloride dihydrate 100 Lactose 50 starch 50 Calcium stearate 10 Talc 10 Mix the finely ground ingredients thoroughly and then beat
According to the law, it is made into tablets. Reference example 31 hard gelatin capsule Each of the following components is α-pivaloyloxy
Ethyl L-3-(3,4-dihydroxyphenyl)
-Containing 400mg of 2-methylalaninate hydrochloride
5,000 two-piece hard gelatin capsules
Ru. g α-pivaloyloxyethyl L-3
-(3,4-dihydroxyphenyl)-
2-Methylalaninate hydrochloride 2000 Lactose 3000 Magnesium stearate 1000 Talc 1000 Thoroughly mix the finely ground ingredients, then mix normally
into capsules using this technique. Reference example 32 Anti-hypertensive activity A method for evaluating the anti-hypertensive activity of active agents is to
Orally or intraperitoneally, Wistar
Okamoto strain spontaneously administered to hypertensive rats.
It consists of giving. Caudal artery
by an indwelling aortic catheter introduced through the
to record arterial pressure continuously in these animals.
Ru. Animals were allowed to move freely in metabolic cages during measurements.
Ru. When the compounds of this invention are tested orally, significant
Significant anti-hypertensive activity is observed. Compound intraperitoneal
It also shows anti-hypertensive activity when tested. a certain place
In some cases, the compound is similar to L-α-methyldopa.
It also shows substantially higher activity. The foregoing description without departing from the concept of the invention
Many other equivalent variations are available to those skilled in the art.
It is obvious to those who do.

Claims (1)

[Claims] 1 Formula: or an acid addition salt thereof (wherein, Y is -COOH or a carboxylic acid salt,
A ₁ and A ₂ are each H) with the formula: [In the formula, m and n are each 0, 1 or 2; R ₁ and R ₂ are each H or lower alkyl; R ₃ is a group X-R ₄ (wherein X is -O-, -S- or -NH -; R ₄ is an alkyl containing up to 5 carbon atoms or an unsubstituted or halogen-substituted acyl group of an organic acyclic carboxylic acid; X ₁ is hydroxyl or halogen. A formula characterized by esterification with a compound of: [In the formula, m, n, R ₁ , R ₂ , R ₃ , A ₁ , and A ₂
is as described above] or its acid addition salt. 2 formula: An acid derivative or an acid addition salt thereof (wherein Y is -COOH, R ₅ and R ₆ are each hydrogen or together are diphenyl ketal, and R ₇ is carbobenzyloxy) of the formula: [In the formula, m and n are each 0 or 1; R ₁ and R ₂ are each H; R ₃ is a group X-R ₄ (wherein, X is -O- or -NH-; R ₄ is 5 is an unsubstituted or halogen-substituted acyl group of an organic acyclic carboxylic acid containing up to ₁ carbon atoms; [In the formula, m, n, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ and
A formula characterized in that R ₇ is as described above] or an acid addition salt thereof is obtained and reduced: [In the formula, n, m, R ₁ , R ₂ , A ₁ and A ₂ are as described above] or an acid addition salt thereof. 3 formula: or an acid addition salt thereof (wherein Y is -COOH, _R5 , _R6 are each hydrogen or taken together diphenyl ketal, and _R7 is carbobenzyloxy) of the formula: [In the formula, m and n are each 0 or 1; R ₁ and R ₂ are each H: R ₃ is a group X-R ₄ (wherein, X is -O- or -NH-; R ₄ is 5 is an unsubstituted or halogen-substituted acyl group of an organic acyclic carboxylic acid containing up to ₁ carbon atoms; [In the formula, m, n, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ and
R ₇ is as described above] or an acid addition salt thereof is obtained, and this is hydrolyzed: [In the formula, A ₁ and A ₂ are respectively H; m, n,
R ₁ , R ₂ and R ₃ are as described above] or an acid addition salt thereof.