RU2061669C1 - Process for preparing 2-methyl-1,4-naphthaquinone - Google Patents

Abstract

FIELD: preparation of 2-methyl-1,4-naphthaquinone. SUBSTANCE: product: 2-methyl-1,4-naphthaquinone. Reagent 1: 2-methyl-1-naphthol or mixture thereof with 2,4- dimethyl-1-naphthol. Reagent 2: 0.2-0.45 molar aqueous solution of acid salt of molybdovanadophosphoric acid with transition metal consisting of Me $\genfrac{}{}{0ex}{}{\text{2+}}{\text{a}}$ H_3+n-azPV_nM_12-nO₄₀ wherein Me $\genfrac{}{}{0ex}{}{\text{2+}}{\text{a}}$ = Co²⁺, Fe³⁺, Cr³⁺, Cu²⁺, Mn²⁺ or Co²⁺+Fe³⁺,, n is more than 1 and less than 4. Reaction conditions: reaction is carried out at 40-70 C in inert gas atmosphere. EFFECT: more efficient preparation process. 3 tbl

Description

The present invention relates to the field of organic synthesis, namely, to an improved method for producing 2-methyl-1,4-naphthoquinone (menadione) of formula I having the properties of vitamin K. I is obtained by oxidation of 4-R-2-methyl-1-naphthols ( II), where R H (IIA) or CH ₃ (llb).

Менадион широко применяют в медицинской практике с целью профилактики и лечения ряда заболеваний и в животноводстве с целью повышения продуктивности всех его отраслей [1] Он также является промежуточным продуктом для получения водорастворимых и жирорастворимых препаратов, регулирующих функции крови [2]
Существует несколько способов получения I, изложенных в обзоре [3] Большинство их основано на окислении 2-метилнафталина (Ill). Недостатком этих способов является то, что при окислении III наряду с 1 образуется значительные количества 6-метил-1,4-нафтохинона, образующего с I трудно разделяемые смеси.

Menadione is widely used in medical practice for the prevention and treatment of a number of diseases and in animal husbandry in order to increase the productivity of all its branches [1] It is also an intermediate product for the production of water-soluble and fat-soluble drugs that regulate blood functions [2]
There are several ways to obtain I described in the review [3]. Most of them are based on the oxidation of 2-methylnaphthalene (Ill). The disadvantage of these methods is that during oxidation of III, along with 1, significant quantities of 6-methyl-1,4-naphthoquinone are formed, which form difficult to separate mixtures with I.

Поскольку CuCl₂ + LiCl известен и как катализатор хлорирования ароматических соединений [5, 6] их образование в реакции (1) в качестве примесей к I оказывается неизбежным. А эти примеси являются очень опасными диоксиноподобными соединениями. Другой недостаток способа-прототипа - трудность выделения целевого продукта, обусловленная сложностью состава растворителя.The oxidation of 2-methyl-1-naphthol (IIa) described in the patent [4] which is the prototype of the present invention proceeds more selectively. The catalyst for this oxidation is a solution of CuCl ₂ + LiCl in a mixed solvent containing water, toluene and C ₁ C ₄ alcohols:

Since CuCl ₂ + LiCl is also known as a catalyst for the chlorination of aromatic compounds [5, 6], their formation in reaction (1) as impurities to I is inevitable. And these impurities are very dangerous dioxin-like compounds. Another disadvantage of the prototype method is the difficulty of isolating the target product, due to the complexity of the composition of the solvent.

The objective of the invention is the creation of a chloride-free catalyst for the oxidation of II to I. This problem is solved by the fact that instead of chlorides, acid salts of the 12th row molybdovanadophosphoric acids are used having the composition H _{3 + n} PV _n Mo _12-n O ₄₀ . Their salts have the composition Me $\genfrac{}{}{0ex}{}{\text{z}}{\text{a}}$ H _{3 + n-za} PV _n Mo _12-n O ₄₀ H3 + n-za PVn Mo12-n O40 and are readily soluble in water. In oxidation II, the catalyst forms an aqueous phase, and the oxidized compound IIa (or IIa + llb) and the reaction product I
the organic phase which is not miscible with water. Thus, the oxidation reaction proceeds with mixing of the phases and stops when mixing stops.

После отделения органической фазы водный слой, содержащий Н_mГПК, контактируют с воздухом или кислородом при повышенной температуре. При этом восстановленная форма катализатора окисляется в исходную форму:

Одновременно с нею окисляются (до СО₂, НСООН или СН₃СООН) и всe побочные продукты реакций (2а) и (2b), растворимые в воде. Побочные продукты, не растворимые в воде, но растворимые в органической фазе (смолы), отделяется от целевого продукта I на стадии отгонки растворителя.As molybdovanadophosphoric acids, acids containing from 1 to 4 vanadium atoms can be used; as their salts, salts of Co (II), Fe (lll), Cr (lll), Cu (ll), Mn (II). The oxidation reaction II is carried out in an inert atmosphere (CO ₂ or N ₂ ). In this case, Me $\genfrac{}{}{0ex}{}{\text{z}}{\text{a}}$ H _{3 + n-za} PV _n Mo _12-n O ₄₀ (abbreviated as HPA) is an oxidizing agent and is reduced to m electrons to form Me $\genfrac{}{}{0ex}{}{\text{z}}{\text{a}}$ H _{3 + n + m-za} PV $\genfrac{}{}{0ex}{}{\text{IV}}{\text{m}}$ V $\genfrac{}{}{0ex}{}{\text{V}}{\text{nm}}$ Mo _12-n O ₄₀ (abbreviated as H _m2 GPC):

After separation of the organic phase, the aqueous layer containing H _m HPA is contacted with air or oxygen at elevated temperature. In this case, the reduced form of the catalyst is oxidized to its original form:

Along with it, all by-products of reactions (2a) and (2b), soluble in water, are oxidized (to CO ₂ , HCOOH, or CH ₃ COOH). By-products that are not soluble in water but soluble in the organic phase (resins) are separated from the target product I in the solvent stripping step.

 The proposed method is illustrated by the following examples 2-6. Example 1 describes a method for producing catalysts used in examples 2-6.

Example 1. To obtain catalysts, which are aqueous solutions of acid salts of molybdovanadophosphoric acids, 0.4 molar aqueous solutions of the corresponding acids H _{3 + n} PV _n Mo _12-n O ₄₀ (HPA-n) were previously prepared:
H ₃ PO ₄ + (12-n) MoO ₃ + n / 2V ₂ O ₅ __ → H _{3 + n} PV _n MO _12-n O ₄₀ (4)
0.4 molar solution of H ₅ PV ₂ Mo ₁₀ O ₄₀ (HPA-2): 18.2 g of V ₂ O ₅ "pct" (0.1 mol) was introduced into 900 ml of 5% H ₂ O ₂ “chemically pure” (~ 1.35 mol) at 4 ^o C. The suspension was stirred at 5 7 ^o C for one hour until a dark red clear solution, after which stirring and cooling were stopped and left for 15 hours until an orange solution was obtained. In another glass, 6.62 ml of 15.1-molar (88.4%) Н ₃ РО ₄ (0.1 mol) and 144.0 g of MoO ₃ “chemically pure” were introduced into 500 ml of water. (1.0 mol). The resulting suspension, with vigorous stirring, was heated to boiling and boiled for one hour until a yellow color was obtained, after which, without stopping boiling, a solution of vanadium salts was introduced in small portions of 50 to 150 ml until all 900 ml of this solution was injected. After this, stirring of the suspension was continued with evaporation of water until the MoO _{3 was} almost completely dissolved. The resulting ≈ 225 ml of a clear orange solution was cooled, filtered, and the filtrate was diluted with water to 250 ml. (Remained on the filter (≈ 0.19 g of gray precipitate).

150 ml of a 0.4 molar solution of H ₆ PV ₃ Mo ₉ O ₄₀ (HPA-3) was obtained similarly using 1,500 ml of 5% H ₂ O ₂ 27.3 g V ₂ O ₅ , 6.62 ml 15, 1 molar H ₃ PO ₄ and 129.6 g of MoO ₃ . Similarly, 200 ml of a 0.4 molar solution of H ₇ PV ₄ Mo ₈ O ₄₀ (HPA-4) were obtained from 1800 ml of 4.5% H ₂ O ₂ , 29.32 g of V ₂ O ₅ , 5.30 ml 15.1 molar H ₂ PO ₄ and 92.16 g MoO ₃ and 125 ml of a 0.4 molar solution of H ₅ PVMo ₁₁ O ₄₀ HPA 1) from 250 ml of 6% H ₂ O ₂ , 4.55 g V ₂ O ₅ , 3.31 ml of 15.1 molar H ₃ PO ₄ and 79.2 g of MoO ₃ .

 Catalysts, which are aqueous solutions of the acid salts Co (ll), Un (ll), Cu (ll), as well as magnesium, were prepared by dissolving a calculated sample of basic cobalt carbonate (respectively, manganese, copper, magnesium) in a certain volume of the previously obtained HPA solution -n (i.e., GPK-2, GPK-Z, etc.). The resulting suspension was heated to complete dissolution of the carbonate.

Catalysts, which are aqueous solutions of acidic salts of Fe (lll) and Cr (lll), were prepared by dissolving the calculated weighed portion of Me (NO ₃ ) ₃ • 9H ₂ O nitrate in a certain volume of the previously obtained HPA-n solution. The resulting solutions containing HNO ₃ were evaporated until HPA-n crystals appeared and placed in a vacuum desiccator over ascarite. The resulting dry residue was dissolved in hot water and cooled. The compositions of the obtained catalysts are shown in table 1.

Example 2. In a three-necked flask, 200 ml was charged with 50 ml of a Co-2 catalyst solution, the flask was purged with carbon dioxide and the solution was heated to 51 ^° C with stirring. Then, while stirring, a solution of 0.8 g of 2 was pinned to the catalyst solution for 70 minutes methyl-1-naphthol (2MH1) in 60 ml of n-hexane (molar ratio [2MH1] [Co-2] 0.25). (2MH1 contains 76.3% of the basic substance, see table 2). After the introduction of only 2MH1, the mixture was stirred for another 10 minutes, after which it was cooled and the resulting 2 layers were separated. The hexane layer was washed with water to extract water-soluble resins from it, dried with anhydrous CaCl ₂ , and then the hexane was distilled off. The resulting oil was distilled with water vapor, and 0.64 g of 2-methyl-1,4-naphthoquinone (1) was obtained in distillation in 74% yield (see table 2). The aqueous layer (reduced catalyst) was oxidized in an autoclave with oxygen at 120 ^o C and used in repeated experiments (see table. 2).

раза избирательность реакции упала в 1,4 раза (таблица 2).In the first of the repeated experiments carried out under the same conditions, 0.8 g of an oxidizable substance and 37.5 ml of catalyst were used (molar ratio [2MH1] [Co-2] 0.34); the yield of the target product l 72% In further experiments with an increase in the molar ratio [2MN1] [Co-2] to 0.4 and 0.8, yield 1 was 67.5% and 52.6%, respectively. Thus, with an increase in the load on catalyst in

times the selectivity of the reaction fell 1.4 times (table 2).

Example 3. By the method described in example 2, experiments were carried out on the oxidation of 2-methyl-1-naphthol in the presence of catalysts containing iron salts (Ill) Fe-3 and Fe-2 (see table. 2). The reaction temperature is 40-60 ^o C, the dropping time of a solution of 2MH1 in n-hexane to a solution of the catalyst is 80-90 minutes. The resulting 2-methyl-1,4-naphthoquinone was recovered from the mixture as described in Example 2. The reduced catalyst was regenerated in the same manner as in Example 2. Yields 1 were 67 75% and only slightly decreased with increasing molar ratio [2MH1] [Fe salt (lll)]
Example 4. By the method described in example 2, experiments were carried out on the oxidation of 2-methyl-1-naphthol in the presence of catalysts containing Cr (lll), Mn (ll) or Cu (ll) (Cr-3, Mn-3 and Cu -3). Yields l from 32 to 45% (table 3).

Example 5. By the method described in example 2, experiments were carried out in the presence of catalysts, which are salts of Co or Fe with GPK-1, GPK-3 and GPK-4 (table 3). Yields l from 51.2 to 67.5%
Example 6. By the method described in example 2, experiments were carried out on the oxidation of 2MH1 in the presence of catalysts, which are aqueous solutions of mixed salts of HPA-2 with two transition metals Co (ll) and Fe (lll). With the ratio of [2MH1] [catalyst] 0.4, a quite satisfactory selectivity of reaction (2) is achieved (table 3).

The above examples show that the method of producing 2-methyl-1,4-naphthoquinone proposed by the present invention allows to obtain the target product with impurities of resins, but without the admixture of chlorinated compounds, which ensures its ecological purity. The side-forming water-soluble resins are oxidized during the regeneration of the reduced form of the НmГПК-n catalyst with oxygen; by-products remaining after distillation of the organic solvent and isolation of the target product and insoluble in water (resins) can be burned with the formation of CO ₂ and water. TTT1 TTT2 TTT3

Claims (1)

1. The method of producing 2-methyl-1,4-naphthoquinone by catalytic oxidation of 2-methyl-1-naphthol or a mixture thereof with 2,4-dimethyl-1-naphthol in a two-phase system in which the oxidizable substance is part of the organic phase, and the catalyst is an aqueous solution, not miscible with the organic phase, with vigorous stirring of the phases at a temperature of 40-70 ^o C in an inert gas atmosphere, characterized in that 0.2-0.45 M aqueous solution of molybdovanadophosphoric acid salt is used as a catalyst transition metal acids having becoming
Me $\genfrac{}{}{0ex}{}{\text{z +}}{\text{a}}$ H _{3 + p-az} PV _n M _12-n O ₄₀ ,
Where
Me $\genfrac{}{}{0ex}{}{\text{z}}{\text{a}}$ = Co ²⁺ , Fe ³⁺ , Cr ³⁺ , Cu ²⁺ , Mn ²⁺ or
Co ²⁺ + Fe ³⁺ ;
1 ≅ n ≅ 4.
2. The method according to claim 1, characterized in that the molar ratio of oxidizable substance: catalyst is used from 0.125 to 0.8.

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