SU506592A1 - Method for producing tert-alkyloxycarbonyl hydrazides - Google Patents

Description

one

This invention relates to a process for the preparation of tert alkyloxycarbonic shtrazides, compounds that are of practical importance for the production of protected amino acids, using "oh" in peptide synthesis.

A known method for producing tert-butylcarbonyl hydrazide, by hydrazinolysis of nitrophenyl carbonate, the yield of the target product.

In the known synthesis, it is used as initial sources, such hazardous and harmful substances as phosgene and metallic sodium and potassium, which significantly complicates the technological design of the process. The disadvantage of this method is the low yield of the target product.

In order to increase the yield of the target product and simplify the technological process in the proposed method, the tert-alkyl-carbamate is subjected to nitration with copper nitrate in acetic anhydride, followed by treating the tert-apkil-Mnitrocarbamate obtained with this product with hydrazine hydrate, separating the excess gdraehinehydrate from the desired product with boric acid and

the selection of the target product known methods.

Presentation I: the first method developed in two versions A and B). Option A has a simpler process and gives a higher yield. Variant B gives the same output as the known method, however, it has before the latter the {the advantage that it does not use metallic sodium and ether.

For option A, the nitration of tert-alkylcarb 1mat (I) is carried out in the presence of bivalent mercury acetate. At the same time, the resulting tert-alkyl-N-nitrocarbamate is converted to the insoluble mercury salt (P). The latter is treated with hydrogen sulfide into free tert-alkyl N-nitrocarbamate 1111). Reaction with hydrazine hydrate t 111) Gives 4ret-al (iloxycarbonyl hydrazide (IV), see: Extraction using Methylene Chloride, followed by treatment of the extract with boric acid and anhydrous magnesium sulfate (to remove traces of hydrazine hydrate dichloride) and vol.HT. 55% calculated with tert-butanol}, according to variant B, nitration is carried out without the addition of mercury acetate. After the reaction, the mixture is treated with water to hydrate acetic anhydride, acidified with potassium bisulfate, tert-alkyl-N nit car Bamate (III) is extracted with methylene chloride, the extract is washed with water, filtered with anhydrous magnesium sulfate, filtered. A stream of ammonia is passed through the filtrate. A precipitate is formed consisting of a1-1 monium salt of tert-alkylN-nitrocarbamate (V) and ammonium acetate. This mixture is treated with hydrazine hydrate, and a tert-alkyloxycarbonyl hydrazide (IV) is formed, which is isolated by the same treatment as in the case of variant A (see above). The resulting product is purified by vacuum distillation. The yield of bonilcydrazide obtained according to variant B of tert-butyloxyk is 30% (based on tert-butanol). Tert-butyl-N-nitrocarbamate (TPa) as well as its salts are not described in the literature. Their structure is proved by elementary analysis, as well as by data of IR, UV, and NMR spectra. The BOC-hydrazide obtained by the described method is identified by comparing with the BOC-hydroxide a razide obtained by the previously described method by IR spectra, as well as by the absence of depression of the melting point of the mixed sample. Example. Synthesis of tert-butyloxycarbonyl hydrazide (BOC hydrazide). Option A. Mercury salt of tert-butyl-M-nitrocarbamate (II a). Into a 2.5 liter flask, 800 ml of acetic anhydride, 117.1 g (1.0 mol of tert-butylcarbamate and 171.5 g (0.5 ml) of divalent mercury acetate) are introduced, cooled, and 300 g of finely powdered copper nitrate are poured before (). Stir for 2 hours, keeping the temperature of the mixture +8 - + 13 ° C by immersing the flask in an ice bath (an exothermic reaction occurs). Then the reaction mixture is poured into 1 liter of ice water, filtered through a suction filter, the filter cake is washed water, acidified with acetic acid, and then with alcohol and ether.You get a more crystalline substance, ready Further synthesis. Yield: 212 g (81%). The analytical preparation is obtained by precipitation from the ammonium salt of tert-butyl N-nitrocarbamate (Va, see below), mercury acetate, T. dec. 172 ° C Found: N10.62; C 23.07; H 3.54., C, Calculated,%: N10.71; C 22.97; H 3.47. X (in nuoli): 3030, 3006, 2950, 1736 SI. Tert-Butyl N-nitrocarbamate (III a) 52.3 g (0.1 mol) of the mercury salt of tnpem-butyl-N-nitrocarbamate (II a) are suspended in 300 ml of acetone, cooled to -20c and, while stirring and protecting from moisture, a stream of hydrogen sulfide dried in calcium chloride until the mixture turns completely black and some ond time (mixture should have a strong odor of hydrogen sulfide). Filter through a dense glass filter; wash the filter cake with acetone. The filtrate is evaporated on a rotary evaporator at room temperature while the residue crystallizes. The crystals are dried in a Petri dish in air at room temperature. Yield colorless crystals of 28.6 g (88%), so pl. 59C. tert-Butyl N-nitrocarbamate. very soluble in alcohol, ether, insoluble in petroleum ether. In water, the solubility is limited, the solution is acidic and when heated quickly decomposes with evolution of gas. For analytical purposes, it is crystallized from diethyl ether - petroleum ether. M.p. recrystallized substance 60 ° C. Found,%: K 17.04; C, 36.61; calculated,%; Nl7.28; C 37.04 P 6.22. IR (Nuiol): 3460, 3228, 3107, 1758, 1615 cm. NMR (in chloroform): 2.7T singlet. -OH), 8.46 g {singlet, - C (CH3), Ufa (in water): 212 nm (); 262 nm (g 6000); in 0.01 N NaOH262 nm (8600). pK 4.2 (in water at, determined potentiometrically). To prove the structure of tert-butyl-N-nitrocarbamate (llla), its pure α-ammonium salt is synthesized (it is obtained by passing dry ammonia to ethereal pacTBOplIIa). These are colorless crystals. different 130 C, easily soluble in water. Found,%: N23.34; C 33.96; H 7.56. CsH ,, N, 04. Calculated,%: N23,45; C 33.52; H 7.31., IKS (in Nuyol): 3275, 3060, 2985, 2945, 1685 CM-. NMR (in BjO); 8.54 G singlet C (CH3), ret-butyloxycarbonyl hydrazide (IVa), 30 ml of hydrazine hydrate (0.6 mol) is cooled to -20 ° C, 32.4 (0.2 mol) tert-buTyl-N-nitrocarbamate is introduced. , stirred until complete dissolution, and left for 6 hours or 10-15 hours. Gas bubbles are released and the liquid is gradually separated. Then the reaction mixture is extracted with methylene chloride (ml). Boric acid and water sulfate are added to the extract, magnesium (about 30 g every day) and stirred for 10 minutes, filtered through a folded filter, and the filter cake is washed with PO ml of methylene chloride. The filtrate is evaporated on a rotary evaporator at room temperature. After a while, the formed oil crystallizes after some time; with the introduction of the BOC-hydrazide crystal, crystallization occurs immediately. T. pl. 38-39 ° C. Yield 22.8 g (86%). For analytical purposes, it is crystallized from petroleum eLire. Found,%: N21.47; C 45.06; H 9.31. C, H, N, 0 Calculated,%: N, 21.20; C 45.44; H 9.15. IR (nujol): 3343,, 2991, 2948, 1700, 1632 cm-. Option B. A Immonium salt of tgret-butyl-N nitrocarbamate (Va). 5.54 g (0.05 mol) tert-butyl carbamate (Yd) is dissolved in -40 tjui acetic anhydride, cooled to 0 ° C and 1 g of fine-grated Co copper nitrate (NO) is introduced. Stir for 6 h, maintaining the temperature of the mixture O - (immersion in a bath with ice). Then, 50 ml of ice-water are poured and the mixture is stirred for another 2 hours. Another 10 ml of a saturated solution of potassium bisulfate are added. At the same time, a precipitate of copper sulfate crystalline hydrate is precipitated, which is filtered off. The filtrate is extracted with chlorine.

Synthesis Scheme.

AXIS (QOS) 2-ЗН20Q

OCNH, (CH3 CO), 0; LD (OOSN,). („,.,. 0 gI

R-OCNHNH; F

O 1 Si Shz) g ZPGOLSISSOg 0;

II

-OCNHz

ZHjO; IKHSO; 4.NH3

one

zie E-gpre a / gk /} -;

Zl (I-I) i a- (SIS) VICANT A

P

-Hgs

HzS Oh

CgNc-NgO

ROC-N NtJe

-KaOi-HzO W Option B

e / o

NH

0

Y NzlU igo

-NHj -NzO -HjO

R-OCN INll2 IE with methylene chloride (ml), the combined extracts were washed with 30 ml of water and dried with anhydrous magnesium sulphate. The temperature of the solutions during the whole treatment should not exceed + 5 ° C. After drying through the filtrate, the pro- let a stream of dry aMfmaKa be allowed up to alkaline reaction of the solution and the appearance of a white precipitate. The precipitate is used in a further synthesis. The weight of the precipitate is 14.5 g with the content of tert-butyl N-nitrocarbs1mat (Va) ammonium salt 4.5 g (determined by precipitation with mercury acetate). Output 50% of theoretical. NMR (in BjO): 8.54t singlet, -C (Preparation of tert-butyloxycarbonyl hydrazide (IV a). 14.5 g of precipitate containing 4.5 g (0.025 mol) of the ammonium salt of tert-butyl-N-nitrocarbamate, are dissolved with stirring in 15 ml of Thydrazine hydrate and incubated for 10-12 hours. Add 10 ml of water to dissolve the precipitate (hydrazine acetate) and extract with methylene chloride (ml). The extracts are treated with boric acid and anhydrous magnesium sulfate (3 g each) (Filtered and the filtrate is evaporated on a rotary evaporator at room temperature. An oil is obtained which is crystallized is distilled into a crystalline mass having a smell af "iaKa. mp. after distillation in vacuum (70-72 °), 3.5 mm. mercury.) a crystalline mass is obtained, mp 38-40 C. Output of 2.15 g (65%). X (in nuoli): 3343, 2991, 2948, 1700, 1632 cm. Other tert-alkyloxycarbonyl hydrazides are also prepared in a similar way.

Invention Formula

The method of obtaining tert-alkyloxyKarvonilhydrate, o tl and h and uP and so that, in order to increase the yield of the target product i simplify the technological process, tert-alkmlkovamat is subjected to nitration with copper nitrate in acetic anhydride ide with the subsequent processing of the resulting tert -alkyl-N-nitrocarbamate with hydraine hydrate, separation of excess hydraine hydrate from the target product with boric acid and isolation of the target product with known techniques and.