Вальпроат натрия.

[yarik03]

Доброго времени суток! Уважаемые коллеги, подскажите пожалуйста, как синтезировать вальпроат натрия, а то в учебниках этого нет.

[arkansas]

По-видимому, нужна вальпроевая кислота. Тогда вот из сайфайндера 15 самых старых ссылок:

 

 

77. Pharmaceutical evaluation of hollow type suppositories. V. Preparation of valproic acid suppository and rectal absorption of valproic acid in rabbits Full Text By Watanabe, Yoshiteru; Tone, Yoshito; Nishihara, Seiko; Matsumoto, Mitsuo

From Journal of Pharmacobio-Dynamics (1986), 9(12), 953-61. | Language: English, Database: CAPLUS

Seven kinds of suppositories were constructed with oleaginous base materials (Witepsol H-15 [12699-05-7] and E-85) [61240-98-0]: a conventional type suppository contg. valproic acid (VPA) [99-66-1] mixed with E-85, (A), a conventional type suppository contg. Na salt of VPA (S-VPA) [1069-66-5] mixed with H-15 (B ), hollow type suppositories contg. VPA in the form of oily liq. (free acid) ©, Macrogol [25322-68-3] 1000 or 6000 mixt. (D or E), powder (S-VPA) (F) and aq. soln. (S-VPA was dissolved in 0.9% NaCl soln.) (G) in each cavity. The content of VPA in type A was decreased considerably by volatility and type B was hygroscopic. Therefore conventional type suppositories contg. VPA or S-VPA were not of practical use, whereas C and F prevented volatility of VPA and minimized the hydroscopic property of S-VPA. By using F, the highest values of the mean of the peak plasma VPA concn. (Cmax) (49.8 μg/mL) and the mean of the area under the plasma concn.-time curve (AUC) (90.0 h•μg/mL) were obtained in rabbits after rectal administrations of C, D, F and G. The Cmax and the AUC estd. after administration of G were not significantly different from those of F. The Cmax and the AUC were lower with C than with D, F or G but the extent of bioavailability of C was about 80%. These data on bioavailability suggested that VPA was efficiently absorbed into the rectum of rabbits after the administration of hollow type suppositories.

 

82. Development and pharmacokinetic evaluation of novel sustained-release dosage forms of valproic acid in humans and dogs Full Text By Bialer, Meir; Friedman, Michael; Dubrovsky, Joseph

From Labo-Pharma - Problemes et Techniques (1984), 341, 263-4. | Language: English, Database: CAPLUS

Several sustained-release dosage forms of valproic acid (VPA) [99-66-1] were developed by matching various matrix carriers to VPA and its Na salt [1069-66-5]. After administration to 5 dogs of the new sustained-release dosage forms, in a 400 mg dose, 4 formulations were found to exhibit a more prolonged and uniform absorption rate, yielded more sustained plasma levels after ingestion and showed an overall bioavailability of 0.84, 0.81, 0.78 and 0.4 resp., relative to an equiv. dose of conventional tablet. The optimal sustained-release formulations were administered to 6 healthy human subjects. Two novel formulations of VPA maintained therapeutic serum levels for 6 h after administration of a single 1 g dose.

 

106. Dipropylacetic acid Full Text By Chignac, Michel; Grain, Claude; Pigerol, Charles

From Belg. (1978), BE 854488 A1 19771114. | Language: French, Database: CAPLUS

The alkylation of NCCH2CO2R (R = C1-4 alkyl) by PrBr (or PrI) and NaOPr gave Pr2C(CN)CO2R, the latter were sapond. and decarboxylated (140-90°) to give Pr2CHCN, the nitrile and H2SO4 gave Pr2CHCONH2, and the amide was treated with H2SO4 and NaONO to give Pr2CHCO2H (I). Also prepd. was I Na salt; I and I Na salt are useful as anticonvulsants (no data).

 

107. Dipropylacetic acid Full Text No Inventor data available

From Span. (1976), ES 419781 A1 19760316. | Language: Spanish, Database: CAPLUS

Pentanoic acid was alkylated by PrBr, and BuLi catalyst, to give dipropylacetic acid, which is useful as an anticonvulsant, central nervous system depressant, liver protective agent, and stimulant for antibodies formation.

 

108. S-alkyl thiocarboxylates from ketones. New synthetic utilization of tosylhydrazones Full Text By Cacchi, S.; Caglioti, L.; Paolucci, G.

From Synthesis (1975), (2), 120-2. | Language: English, Database: CAPLUS

4-MeC6H4SO2NHNHCRR1CN [R1 = (CH2)5, Pr2], from 4-MeC6H4SO2NHN:CRR1 and HCN, were treated with EtSH in dry THF contg. HCl at 0° to give ≤70% 4-MeC6H4S O2NHNHCRR1C(SEt):NH2+ Cl- (I), which gave ≤75% 4-MeC6H4SO2NHNHCRR1COSEt (II) in H2O; thermal decompn. of II in refluxing PhMe gave ≤80% RCHR1COSEt (III), and steam distn. of I gave 52-5% III and 20-30% RCHR1CO2H.

 

109. Alkylacetic acids having therapeutic properties Full Text No Inventor data available

From Span. (1971), ES 368237 A1 19710501. | Language: Spanish, Database: CAPLUS

The title compds. R2CHCO2H (R = Pr or Bu) were prepd. from R2CHCl either through their Grignard compd. and addn. of CO2, or by reaction with KCN followed by hydrolysis.

 

112. Theoretical treatment of the influence of steric effects on the reactivity of aliphatic compounds. III. Steric hindrance in the formation and hydrolysis of saturated aliphatic carboxylic esters Full Text By Becker, Friedrich

From Zeitschrift fuer Naturforschung (1961), 16b, 236-45. | Language: Unavailable, Database: CAPLUS

cf. CA 54, 22313h. The steric requirements for the esterification of RCO2H in MeOH and EtOH were quant. evaluated. Equiv. hydrocarbons were used as models, e.g. for RCO2H, RCO2R', and the transition state, RCH2Me, RCH2CH2R', and RCMe2CH2R', resp., but using a smaller repulsion parameter for the methyls used to approximate the loosely-bound oxygens in the transition state. Values for Est and In Qst' were given for 34 acids, together with corrections to Est for the effect of changes in valence angles due to steric strain in heavily branched acids. Agreement between observed and calcd. rates was good. Inductive, ponderal, and solvent effects were discussed. Acid hydrolysis can be similarly calcd., but in sapon., parameters for solvation of the alkyl-O must be included. Calcns. are given for 19 primary alkyl acetates and 17 ethyl esters.

 

113. Reactions of alkoxy radicals. I. Reactions of di-tertbutyl peroxide with n-butyric acid and ethyl n-butyrate Full Text By Beckwith, A. L. J.

From Australian Journal of Chemistry (1960), 13, 244-55. | Language: Unavailable, Database: CAPLUS

tert-Butoxy radicals from the decompn. of tert-butyl peroxide at 116° abstract mainly the α-H atoms of n-butyric acid. The tert-butoxy radical thus is not a dominantly electrophilic species; its behavior is compared with that reported for other radicals. The main products are acetone (24%), tert-butanol (60%), meso-2,3-diethylsuccinic acid (I) (22%), dl-2,3-diethylsuccinic acid (II) (20%), 2-ethyl-3-methylglutaric acid (III) (2.6%), tert-Bu butyrate (by esterification), and 2-ethyl-4-methylvaleric acid (IV) (from isobutene and HO2CCHEt radical). tert-Butoxy radicals attack Et butyrate mainly by abstraction of the α-H atoms of the acid moiety. The ratio of dicarboxylic acids on hydrolysis of the products is 5:5:1 I-II-III. Catalytic amts. of CuCl2.2H2O greatly modify the reaction of tert-butyl peroxide with butyric acid; C8-dicarboxylic acids are not formed in large quantities. Products are sepd. by partition chromatography. Monocarboxylic acids are identified on Whatman No. 1 paper with 1:1 1.5N ammoniabutanol as the solvent and bromocresol purple indicator. Sepn. is achieved on silica gel bearing 30% vol./wt. dil. aq. bromocresol green with 10:1 iso.ovrddot.octane-acetone as the moving phase. Dicarboxylic acids are sepd. on silica gel with dil. H2SO4 as the stationary phase and CCl4-acetone as the moving phase or by paper chromatography. New solvent systems are developed for paper chromatography (bromocresol green indicator) of dicarboxylic and hydroxycarboxylic acids: upper phase of 10:1:5 PhMe-BuOH-50% aq. AcOH (solvent A); upper phase of 8:1:5 PhMe-BuOH-20% aq. AcOH (solvent B ); lower phase of 10:2:1 CCl4-H2O-AcOH (solvent C). Solvents A and B are of general utility, C gives a wider sepn. of C5 to C8-acids and enables sepn. of I, II, and III. Reference compds. are synthesized. Et crotonate is added over 1 hr. to NaOEt in ether in a dry-ice bath and the mixt. neutralized with AcOH after 3 hrs. at room temp. Di-Et 2-ethylidine-3-methylglutarate, 60%, b18 136-8° is extd., distd., hydrogenated over 10% Pd-C at atm. pressure, and hydrolyzed by 5% KOH in 50% aq. EtOH to III, m. 82-7°, which is recrystd. repeatedly from ether-hexane to give an isomer, m. 97-8° (stereochemistry unknown, cf. Mumm, et al., CA 31, 53601). Crude III gives a p-phenylphenacyl ester, m. 90-2°. Di-Et 2,3-diethylsuccinate (Steinkopf, et al., CA 35, 36315) is hydrolyzed by KOH in aq. EtOH to a mixt. of I and II. The acidified aq. soln. ppts. I; I and II are sepd. from the mother liquors by fractional crystn. from acetone-CCl4. I, m. 204°, gives p-phenylphenacyl ester, m. 228° (CHCl3 or PhCH3), and p-bromophenacyl ester, m. 151-2° (acetone). II, m. 135° (ether-hexane), yields a p-phenylphenacyl ester, m. 185° (EtOAc), and a p-bromophenacyl ester, m. 121-2° (MeOH). Carbonation of 3-methyl-3-hexylmagnesium chloride gives 2-ethyl-2-methylvaleric acid, b25 132°, which with oxalyl chloride gives the acid chloride, converted to the p-toluidide, m. 92° (hexane). Successive alkylation of di-Et malonate with EtBr and PrBr, followed by hydrolysis with 50% aq. KOH and decarboxylation at 180°, yields 2-ethylvaleric acid, b20 118-20°, which gives a p-toluidide, m. 129° (hexane). Other acids are obtained similarly: 2-ethylcaproic acid, b4 102-6° [p-toluidide m. 107° (aq. methanol)]; 2-ethyl-4-methylvaleric acid, b2 84-6° [p-toluidide m. 111° (pentane)]; 2-propylvaleric acid, b10 118-20° [p-toluidide m. 154° (hexane)]; 3-methylcaproic acid, b10 101-2° (p-toluidide m. 73°). 2-Hydroxybutyric acid (8.9 g.), 20 ml. butyric anhydride, and 5 ml. pyridine are left in benzene overnight, refluxed 30 min., and poured into water to give 2-butyroxybutyric acid, b25 106-8°, n20D 1.4298; p-phenylphenacyl ester m. 53-4° (pentane).

 

118. Fats from fatty acids with odd numbers of carbon atoms. VI Full Text By Keil, Werner

From Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie (1947), 282, 137-42. | Language: Unavailable, Database: CAPLUS

cf. C.A. 37, 6728.1. 4-Bromoheptane (II), b18 62-3°, was prepd. from HBr and Pr2CHOH (I). II with KCN gave 4-cyanoheptane (III), b24 78-80°. 2-Propylpentanoic acid (IV), b20 128-30°, resulted from 24 h. alk. hydrolysis of III; amide, m. 123-5°. 3-Propylhexanoic acid (V), prepd. from II by the malonic ester synthesis, b8 126°; amide, m. 111°; Me ester, b6 76°; Et ester, b11 94°. 3-Propylhexanol (VI), b18 106°, b8 92-4°, resulted from hydrogenation of V Me ester over a Cu catalyst at 240°. 3-Propylhexyl bromide (VII), b18 98-100°, was prepd. from VI with HBr, and the cyanide (VIII), b12 106°, from VII and KCN. Hydrolysis of VIII gave 4-propylheptanoic acid (IX), b14 150-2°. 5-Propyloctanoic acid (X), b22 167°, resulted from the malonic ester chain-lengthening of VII; Me ester, b19 125°. 5-Propyloctanol (XI), prepd. from X Me ester by hydrogenation over a Cu catalyst at 240°, b20 129-30°. 5-Propyloctyl bromide (XII), from XI and HBr, b21 128-30°; with KCN it gave the cyanide (XIII), b16 135-6°. Alk. hydrolysis of XIII gave 6-propylnonanoic acid (XIV), b18 176-7°. XI by the malonic ester synthesis gave 7-propyldecanoic acid (XV), b25 195-6°. Similarly octyl bromide gave 2-methyldecanoic acid (XVI), whose Me ester b9 108-9°. Hydrogenation of XV Me ester over a Cu catalyst at 280° and 180 atm. of H gave 2-methyldecanol (XVII), b13 122°, which with HBr gave 2-methyldecyl bromide (XVIII), b15 127°. 4-Methyldodecanoic acid (XIX), from XVIII by the malonic ester synthesis, b15 142°. Conversion of IV, V, IX, X, XIV, XV, XVI, and XIX to their triglycerides was effected by slow heating of the acids with a 10% excess of glycerol and 1 g. Zn dust/kg. acid in vacuo for 2 h. at 170°, then 3-4 h. at 210°. Detn. of the neutral equiv. at this point showed that the slower reactions required further heating for 1 h. at 220-30°. After treating with 3% H2SO4 at 70-80°, neutralization, treatment with charcoal, and then with steam at 130°, the pure triglycerides resulted. The triglycerides of IV, V, IX, X, XIV, XV, XIX, and 3-ethylheptanoic acid (XX) in solns. of 3 parts of coconut oil were fed to dogs, the quant. collected urine acidified and extd. with Et2O for 17 h., the extd. material esterified with alc. HCl, and the esters then distd. and identified. X, IV, XX, V, and IX pass through the organism in part unchanged. By β-oxidn. IX is in part degraded to IV, X in part to V, XIV in part to IX, and XV in part to V. XIX was partly excreted as α-, or γ-methylsebacic acid, m. 82° (from CCl4 or aq. Me2CO). The Et2O-sol. acidic material appearing in the urine amounted to 10-25% of the IV, V, IX, X, XIV, and XV triglycerides fed. The existence of unidentified Pr-substituted dibasic acids in the higher-boiling fractions of the excreted products is suspected.

 

119. Dehydration of symmetrical dipropenylglycol. Formation of a disubstituted aldehyde (hydrobenzoin rearrangement) and of a non-transposed ketone (vinylic dehydration) Full Text By Tiffeneau, Marc; Deux, Yves

From Compt. rend. (1941), 212, 105-8. | Language: Unavailable, Database: CAPLUS

When s-dipropenylglycol is dehydrated by heating it with 5 parts of boiling 30% H2SO4 a mixt. of unsatd. compds., probably dipropenylacetaldehyde and 2,6-octadien-4-one, is obtained, b14 71-2°. This mixt., which could not be sepd., was hydrogenated with H and Raney Ni at room temp. till the product was satd. to Br; and the aldehyde fraction oxidized with AgNO3-NH4OH. The acid fraction was identified as dipropylacetic acid, b22 126° (amide, m. 125-6°; anilide, m. 102°); the neutral fraction as BuCOPr, b26 70°.

 

120. 1-Azabicyclo[1.3.3]nonane Full Text By Prelog, Vlado; Heimbach, Suzana; Seiwerth, Rativoj

From Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1939), 72B, 1319-25. | Language: Unavailable, Database: CAPLUS

cf. C. A. 33, 5851.3. Attempts to prep. 1-azabicyclo[1.3.3]nonane (I) from (BrCH2CH2CH2)2CHCH2Br (II) and NH3 in MeOH by the method employed in the synthesis of the 1,4-bridged piperidine deriv. were no more successful than those of earlier workers to obtain this cyclic system by the Dieckmann condensation or by distn. of the alk. earth salts of the corresponding piperidinedicarboxylic acids. II was prepd. from 1,7-diphenoxyheptane-4,4-dicarboxylic acid (III) through the heptane-4-carboxylic acid (IV) and heptane-4-carbinol (V). I was successfully synthesized, however, by catalytically reducing in alc. with the Adams Pt oxide catalyst Et nicotinoylacetate-HCl, which took up 6-8 atoms H; considerable Et β-(3-piperidyl)propionate (VI) was formed and this on redn. with Na and alc. gave γ-(3-piperidyl)propyl alc. (VII), which was converted by fuming HBr into 3-('γ-bromopropyl)piperidine-HBr (VIII). This with dil. NaOH gave I in good yield by intramol. alkylation. The neg. results of the 1st expts. led to the following attempts to find another method of synthesis. 1,4-Diethoxyheptane-4-carbinol (IX), obtained by redn. of the Et 4-carboxylate (X), was converted with PBr3 and pyridine into bromo(1,7-diethoxy-4-heptyl)methane (XI) and thence through the cyano compd. (XII) into 1,7-diethoxy-4-heptoylacetic acid (XIII), which was degraded by the Curtius-Schmidt method to amino(1,4-diethoxy-4-heptyl)methane (XIV). This with fuming HBr gave amino(1,7-dibromo-4-heptyl)methane-HBr (XV), which by double intramol, alkylation smoothly yielded I. PhO(CH2)2CH(CO2Et)2 (84% from PhO(CH2)3Br, CH2(CO2Et)2 and Na in alc.), b7, 207-8°, gave with NaOEt and PhO(CH2)2Br in boiling alc. 66.3% of the di-Et ester, b0.07 245-50°, m. 42-3.5°, of III (obtained in 70.8 g. yield from 82.5. g. ester), m. 123-3.5°, which was quant. decarboxylated at 180-200° to IV, m. 65°, whose Et ester (95% yield), b0.05 248°, gave with Na and alc. 74% V, b0.3 255°. 1,7-Dibromo-4-methylheptane (II) (70% from V and 68% HBr in sealed tubes at 100°), yellowish, b0.03 175-7°. VI (33.5%), b10 141-2°; HBr salt, m. 229°. VI (81%), b10 154°. VIII (87%), m. 154°. X (93.5% from 87.14 g. of the acid esterified by azeotropic distn. with 135 cc. abs. alc., 68 cc. toluene and 1 cc. concd. H2SO4), b20 166-8°. IX (83.2%), b15 158-61°. XI (66.4%), b11 153°. XII (96% from XI refluxed with KCN in aq. alc.), b12 171-2° hydrolyzed by KOH in boiling aq. alc. to XIII (83.5%), b12 206°. XIV (85%), b10 150-1°. XV (96%), m. 159°. I (77-9%), b. 175°, m. 114° does not decolorize KMnO4 in H2SO4; HCl salt, sublimes above 350°; chloroplatinate, orange, m. 226°; picrate, yellow, m. 283°; picrolonate, brown, m. 231°; methiodide, m. 351°.

 

121. Temperature coefficient of adsorption from solutions. II Full Text By Mishin, V. P.; Polochanskaya, E. E.

From Kolloidnyi Zhurnal (1936), 2, 317-22. | Language: Unavailable, Database: CAPLUS

Dipropylmalonic ester was obtained by boiling 11.9 g. Na in alc. with 41.5 g. malonic ester and then with 113 g. PrI or 81.7 g. PrBr; 2 hrs. was used for each. Alc. was boiled off and the aq. soln. extd. with ether, dried and distd. giving 21 g. of ether b. 248-50°. Dipropylmalonic acid was obtained by hydrolysis of 21 g. of the ester by 27 g. KOH in 340 g. alc. boiled for 3 hrs. The aq. soln. was acidified, extd. with ether and crystd. from CHCl3. Dipropylacetic acid was obtained from the malonic acid by heating at 180-200°. The yield of Ca salt obtained was 9.5 g. The adsorption isotherms of Ca dipropylacetate were measured at, 26.5°, 50° and 75° on birch charcoal by detn. of the salt left in soln. The ratios of the adsorptions for all concns. at these temps. are about 1:1.2:1.3:1.3.

 

122. Configurational relationship of hydrocarbons. IV. Optical rotations of hydrocarbons of the isoamyl series. The configurational relationship of substituted carboxylic acids containing an isobutyl and an isoamyl group to those of the corresponding normal carboxylic acids Full Text By Levene, P. A.; Marker, R. E.

From Journal of Biological Chemistry (1932), 95, 1-24. | Language: Unavailable, Database: CAPLUS

cf. C. A. 25, 5137; 26, 716. The members of the iso-Am series of hydrocarbons examd. had approx. the same rotation as the corresponding members of the Am series. The iso-Bu series, however, like the iso-Pr hydrocarbons previously examd., had a more neg. rotation than the corresponding Bu series. In the disubstituted carboxylic acids the same effect occurs, the iso-Bu derivs. being more neg. than the Bu derivs., while the iso-Am and Am derivs. are not very different. The following compds. were prepd. and the rotations detd., the theoretical max. rotation (M calcd.) being calcd. from the observed value by multiplying by the ratio max. rotation/observed rotation of the parent substance: d-2-ethylvaleric acid (I), b16 115°, [α]D22 3.09°, M calcd. from the parent 2-ethylbutyric acid of M 3.04° was 13.59°; Et ester of I, b20 80°, d422 0.888, [α]D20 2.38°, [M]D20 3.76°. From 3-methylcaproic acid, by reduction with Na in toluene, d-4-methyl-1-hexanol (II), b20 77°, d428 0.818, [α]D28 2.19°, [M]D28 calcd. 11.9°. d-4-Methyl-1-bromohexane (III), b44 78°, [α]D28 2.61°, [M]D28 calcd. 21.9°. d-Methylethylpropylmethane, b. 92°, d428 0.681 [α]D28 1.64°, [M]D28 calcd. 9.67°. The Et ester of I with MeMgI gave a carbinol, reduced to an unsatd. hydrocarbon by (CO2H)2; reduction of this with H2 and Adams' catalyst or treatment of the HBr compd. with NaOH and H2 in presence of colloidal Pd gave d-methylethylisoamylmethane, b. 134°, [α]D22 2.72°, [M]D22 3.48°. d-2-Propylvaleric acid (IV), from 1-bromo-3-methylhexane, b22 132° d424 0.882, [α]D24 2.11°, [M]D24 3.04°; Et ester of IV b32 104°, d424 0.859, [α]D24 1.41°, [M]D24 2.43°. Treatment of this with MeMgI, distn. from (CO2H)2 and reduction with Pt catalyst as above yielded d-methylpropylisoamylmethane, b. 156°, d425 0.725, [α]D25 1.09°, [M]D25 1.55°. 1-2-Butylvaleric acid (V), from 1-bromo-3-methylheptane, b22 149°, d425 0.871, [α]D25 -1.34°, [M]D25 -2.13°; Et ester of V, b23 112°, d425 0.861, [α]D25 -0.64°, [M]D25 -1.19°; 1-methylbutylisoamylmethane, from this with MeMgI as above, b100 109°, d425 0.738, [α]D25 -0.49°, [M]D25 -0.76°. 1-Amylvaleric acid (VI), from 1-bromo-3-methyloctane, b22 156°, d425 0.871, [α]D25 -0.60°, [M]D25 -1.03°; Et ester of VI, b22120°, d425 0.862, [α]D25 -0.12°, [M]D25 -0.23°; 1-methylisoamylmethane, b100 122°, d425 0.739, [α]D25 -0.05°, [M]D25 -0.09°. By crystg. the quinine salts from Me2CO, 1-2-butylbutyric acid, [α]D27 -4.21°, [M]D27 -6.06° 1-2-amylbutyric acid, [α]D27 -5.14°, [M]D27 -8.12°, d-2-isobutylbutyric acid (VII), b20 124°, d430 0.899, [α]D30 1.65°, [M]D30 2.37° and d-2-isoamylbutyric acid (VIII), b25 140°, d426 0.901, [α]D26 2.44°, [M]D26 3.86°, were obtained. The Et ester of VII, b20 85°, d430 0.856, [α]D30 1.13°, [M]D30 1.95°, was reduced to d-3,5-dimethylhexanol, b45 105°, d430 0.815, [α]D30 1.90°, and from this was prepd. l-1-bromo-3,5-dimethylhexane, b45 91°, d430 1.099, [α]D30 -0.50°, [M]D30 -0.97°,and thence d-3,5-dimethylhexane, b. 111-2°, d430 0.696, [α]D30 2.99°, [M]D30 3.41°. Similarly, the Et ester of VIII, b30 112°, d425 0.862, [α]D25 1.39°, [M]D25 2.59°, gave d-2,5-di-methylheptanol, b18 102°, d427 0.823, [α]D27 2.21°, [M]D27 3.18° thence l-7-bromo-2,5-dimethylheptane (IX), b23 108°, d427 1.090, [α]D27 -2.20° [M]D27 -4.56°, and thence d-2,5-dimethylheptane, b. 134°, [α]D27 4.19°, [M]D27 5.37°. Also 60 g. IX and 12 g. paraformaldehyde gave 31 g. d-2,5-dimethyloctanol, b15, 115°, d427 0.824, [α]D27 0.81°, [M]D27 1.29°, and thence d-2,5-dimethyloctane, b. 156°, [α]D28 1.02°, [M]D28 1.45°. From 1-bromo-4-methylnonane (C. A. 25, 3626) was prepd. l-4-methylnonane, b30 76°, d427 0.726, [α]D27 -1.56°, [M]D27 -2.21°, [M]D27 calcd. -2.47°.

 

123. Monoglycerides of the lower fatty acids Full Text By Gilchrist, Philippa G.; Schuette, H. A.

From Journal of the American Chemical Society (1931), 53, 3480-4. | Language: Unavailable, Database: CAPLUS

Direct esterification has been found unsuitable as a method for prepg. monoglycerides of acids of more than 4 C atoms. It is also impractical for the prepn. of monoformin because of the proximity of the b. ps. of HCO2H and H2O. The monochlorohydrin method of Guth (Z. Biol. 44, 78(1903)) has been employed in the prepn. of monoisobutyrin, b2 128-30°, 70% yield (crude product); monovalerin, b2 129-31°, 60%; monoisovalerin, b3.5 145-7°, 59%; and monocaproin, b2 132-4°, 54%. The following phys. consts. (d., n, surface tension in dynes/cm. and coeff. of viscosity in centipoises, resp.) at 20° are reported: acetin 1.2060, 1.4517, 41.27, 96.83; propionin 1.1537, 1.4503, 36.63, 89.59; butyrin 1.1344, 1.4531, 35.29, 122.65; isobutyrina 1.1073, 1.4478, 31.58, 104.65; isobutyrinb 1.1084, 1.4478, 32.19, 101.36; valerin 1.0803, 1.4515, 30.91, 90.57; isovalerin 1.0830, 1.4498, 32.85, 142.64; caproin 1.1352, 1.4591, 30.59, 198.85. (a Prepd. by esterification method, b Prepd. by chlorohydrin-alkali salt method.) The data are also shown graphically and discussed in relation to the no. of C atoms in the compds.

 

124. Preparation of optically active fats. III. Synthesis of the four possible optically active butyrins. Inversion of the three-carbon system into the optical antipodes Full Text By Abderhalden, Emil; Eichwald, Egon

From Berichte der Deutschen Chemischen Gesellschaft (1915), 48, 1847-65. | Language: Unavailable, Database: CAPLUS

cf. C. A. 9, 310, 1058. As was forecast in the earlier papers, it has been found possible, by improving the methods, to obtain material of higher rotation in the prepn. of active epihydrin alc. and aminoglycerol, but the attempts to obtain active aminoglycerol and fats by a shorter method from active dibromohydrin have not all been successful. Amination of d-dibromohydrin (replacement of both Br atoms by NH2) never gave an active product, probably because the Br is not directly replaced but HBr is first split off, with formation of a glycide ring which then adds NH3. Treatment of active epibromohydrin with alc. KI, with KOAc or with Ag or alkali salts of fatty acids also led to inactivation, so that the methods used chiefly by Gr.ovrddot.un for the prepn. of fats of a definite constitution lose much of their value in proving structures. A method free from doubt consists of treating the hydrochlorides or sulfates of the aminoglycerols with excess of fatty acid chlorides, removing the NH2 with NaNO2 and fractionating in a high vacuum to remove the chlorinated glycerols which are always formed as a result of the violent reaction. Even in a high vacuum, however, distn. of active fats often results in complete inactivation, so that it is better to esterify the aminoglycerol in concd. H2SO4 with excess of fatty acid and then treat with NaNO2. l-Epihydrin alc., which is l-rotatory in substance, gives by addition of PrCO2H a monobutyrin which is d-rotatory in alc., while on the other hand it yields a d-aminoglycerol giving a butyrin which is l-rotatory in alc. Although the 2 butyrins cannot be directly compared, as 1 is a mono- and the other a dibutyrin, there is no doubt that an optical inversion has occurred. The case with which compds. of both the d- and l-series are formed probably is the reason why no active fats have thus far been found in nature, and it is also very probable that the lipolytic ferments are not specifically adapted to 1 of the possible configurations. As a genetic designation is meaningless in the case of the fats, the prefixes d- and l- are now used according as the particular compd. is d- or l-rotatory in substance or in alc., thus involving some changes in the earlier designations. It has been found that if aminodibromopropane d-tartrate is heated some time with H2O on the H2O bath, HBr is split off and there is considerable loss, so that in recrystg. large amts. (8 kg.) the concn. must be effected in vacuo; smaller amts. (2-3 kg.) may be recrystd. on the H2O bath by adding the required amt. of boiling H2O and stirring vigorously until the salt dissolves; the latter is thus exposed only 5-10 min. to the higher temp. and the loss of HBr is insignificant. A d-epibromohydrin with [α]D18 23.06° is obtained by slowly pouring, in the course of 5-10 min., 50 g. KOH in 100 cc. cold H2O into 100 g. active dibromohydrin, at once extg. with Et2O, drying with Na2SO4, evapg. up to 60°, letting stand at this temp. for some time and distg. in vacuo at 40°. d-Dipropionyl-α-bromohydrin, from 2 g. d-α-bromohydrin ([α]D18 4.10° in H2O) and 6 g. (EtCO)2O, [α]D18 -2.21° in alc. d-Dibutyryl-α-bromohydrin, from d-α-bromohydrin and excess of PrCOCl, [α]D18 -2.19° in alc. l-Epihydrin alcohol (a) (formerly designated as the d-compd.), d. 1.1050, [α]D18 -8.55°, is obtained in 38 g. yield from 110 g. d-α-bromohydrin, [α]D18 4.38° in H2O (prepd. by hydrolysis of the HCO deriv. with HCl and freed from HCl by twice evapg. the crude oil with a little alc. and finally heating 0.5 hr. in vacuo at 70°) poured into a little more than the calcd. amt. of KOH in the least possible cold alc. and neutralized after 24 hrs. to phenolph. with alc. HCl. From 38 g. of (a) is obtained 34 g. d-aminoglycerol (B ), b0.1 134°, b15 163° without racemization, [α]D18 2.42 in H2O, 17.70° in dil. HCl. The following monoglycerides were prepd. in preliminary expts. from a d-(a) with [α] 4.02°, 1 g. of which with 1 mol. of the fatty acid was allowed to stand 2 weeks at 37°, treated with Et2O (except in the case of the monoacetin, which is insol. in Et2O), filtered, and freed from Et2O, unchanged acid and (a) in vacuo. All the resulting fats except the monoformin were active; why the latter was inactive has not been detd. l-α-Monoacetin, -propionin, -butyrin, -valerin and -caproin showed [α]D18 -1.14°, -0.83°, -0.63°, -0.530 and -0.40°, resp., in alc. d-α-Monobutyrin, from an (a) with [α] -8.55°, showed [α]D18 0.83°. An l-α,β-dibutyrin, still containing some Cl, with [α]D18 -1.67° in alc., -1.86° in Et2O, sapon. no. 632.4, is obtained from 1.5 g. (B ) in alc. neutralized with alc. HCl, evapd. in vacuo, heated 0.5 hr. at 70° in vacuo, then 0.5 hr. longer with P2O5 in the receiver, then treated with 3 g. PrCOCl, poured into H2O, filtered, treated cold with NaNO2, extd. with Et2O, washed with soda and dried with Na2SO4; fractionation in a high vacuum gives a product practically free from Cl but wholly inactive, b0.5 134-6°. When cooled mixts. of 5 g. (B ) with 15 cc. PrCO2H and 10 cc. PrCO2H with 15 cc. concd. H2SO4 are brought together, heated 4 hrs. at 65° (protected with a CaCl2 tube), allowed to stand 2-3 days, poured into 100 cc. ice H2O, covered with Et2O and treated with concd. aq. KOH, there is obtained 2 g. of d-γ-amino-α,β-dibutyrin, basic oil sol. in dil. acids, [α]D18 1.09° in dil. HCl, 0.47° in alc., at once converted in acids by NaNO2 into l-α,β-dibutyrin (best obtained (4 g. yield) without isolating the NH2 compd.), d. 1.0890, [α]D18 -1.10° in substance, -2.31° in alc., the [α] and sapon. nos. varying somewhat in different prepns. l-α,β-Dicaproin, obtained in the same way in 6 g. yield from 5 g. (B ), 25 cc. caproic acid and 15 cc. H2SO4, sapon. no. 359.2, [α]D18 -0.30° in substance, -0.46° in Et2O, -0.25° in CCl4, -0.44° in petr. ether, 0.57° in CHCl3. l-α-Lauro-β,γ-dibutyrin, sapon. no. 372.8, α -0.15° in a 1 dcm. tube, is obtained in 0.8 g. yield from 1 g. l-dibutyrin (α - 1.05°) and 1.1 g. lauryl chloride heated 0.5 hr. on the H2O bath, allowed to stand over moist KOH, extd. with Et2O, washed with H2O, treated with an equal vol. of alc., neutralized with alc. KOH, evapd. in vacuo, extd. with Et2O, boiled with charcoal and dried with Na2SO4. l-α-Stearo-β,γ-dibutyrin, m. 15°, inactive. l-α-Oleo-β,γ-dibutyrin, sapon. no. 351.9, α -0.07° in a 1 dcm. tube. In crystg. aminodibromopropaned-tartrate d-epihydrin alc. with at most α -4.02° in a 1 dcm. tube was obtained from the mother liquors. With l-tartaric acid, the l-aminodibromopropane, α -0.15° in Et2O was obtained from the dl-compd. after several crystns. l-Aminoglycerol © is best obtained by inversion of d-epibromohydrin (d) into the l-series; 55 g. (d), α 37.25°, is slowly poured into 500 cc. of 15% HCl below 20°, then shaken 1 hr. with 100 cc. concd. HCl, extd. with Et2O, washed with soda, dried with Na2SO4 and fractionated in vacuo; this gives 62 g. d-α-bromo-γ-chloropropan-2-ol, b15, 88°, d. 1.7069, [α]D18 0.64°; 62 g. of this are shaken with 30 g. KOH in 60 cc. cold H2O and extd. with Et2O, giving 23 g. l-epichlorohydrin, d. 1.2007, [α]D18 -25.61°, best distd. under 360° (b. 92-3°) to 260 mm. (b. 80-90°). This gives a d-formyl-α-chlorohydrin with α 4.10°, hydrolyzed by 15% HCl to a l-chlorohydrin, [α]D18 -1.88° in H2O, 25 g. of which yields 8 g. of a d-epihydrin alc. with d. 1.1054, [α]D 7.69°; 1.5 g. of this with 2 g. PrCO2H gives 1.1 g. of a l-monobutyrin, sapon. no. 347.9, [α]D18 -0.84° in alc., while 6.5 g. of the alc. yields 6 g. ©, [α]D18 -14.08° in dil. HCl. d-Dibutyrin, sapon. no. 495.8, d. 1.0890, [α]D18 1.01°.

 

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Application Number: 201010177052

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Bibliographic Data：

Title： ［MT］ Composing technology of a kind of sodium valproate

Application Number： 201010177052 Application Date： 2010.05.10

Publication Number： CN102241582A Publication Date： 2011.11.16

IPC： C07C53/128(2006.01)I;C07C51/41(2006.01)I

Applicant： ［MT］ Ming Fang Pharmaceutical Co., Ltd. Shandong

Inventor： ［MT］ Wang Xinglu;Fan Xingshan;Wang Feilong;Mu Ziqi

Priority Information：

Abstract： ［MT］ The patent refers to the field of 'acyclic or carbocyclic compounds'. The invention is in the field of medicament synthetic technology, disclose the composing technology of a kind of sodium valproate.Including the following processes: Diethyl malonate and 1-the n-propane of bromide is dissolved each other, mixture adds alcoholic solution of sodium ethoxide slowly at 40-80 隆忙, the the temperature rising reflux is 3 hours, recycle ethyl alcohol to 120 隆忙, lower the temperature to below 90 隆忙, add sodium bromide of quantitative dissolving, several layers add 15-20% sodium hydrate aqueous solution after laminating, in 4 hours for aquolysis of 70-90 隆忙, heat 99 隆忙 to gas phase temperature up and recycle ethyl alcohol, lower the temperature to below 90 隆忙, add hydrochloric acid to neutralize and reacidify, add crude valproic acid dissolve di propylmalonic acid, use get mixed acid, mixed acid heats up and decarboxylates and produces crude valproic acid slowly at 140-180 隆忙.Add crude valproic acid into the quantitative sodium hydrate solution neutralization after the rectification is refined, add methylbenzene backflow water taking, make sodium valproate de water crystallization, filter, chloroform wash dry to get finished products.This process is safe and environment-friendly, high quality, with low costs, are suitable for the commercial process.

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Legal Status Publication Date： 2011.11.16

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