KR100968576B1 - Process of preparing 2-acyl-3-amino-2-alkenoate - Google Patents

Abstract

The present invention relates to a novel process for the preparation of 2-acyl-3-amino-2-alkenoate which can be used as an important intermediate for the synthesis of heterocyclic compounds which exhibit physiological activity. According to the preparation method of the present invention, various 2-acyl-3-amino-2-alkenoates can be easily and effectively prepared using the blaze reaction intermediate.

2-acyl-3-amino-2-alkenoate, preparation method, blaze reaction intermediate

Description

Process of preparing 2-acyl-3-amino-2-alkenoate

The present invention relates to a novel process for the preparation of 2-acyl-3-amino-2-alkenoate which can be used as an important intermediate for the synthesis of heterocyclic compounds which exhibit physiological activity. More specifically, the present invention relates to a method for easily and effectively preparing various 2-acyl-3-amino-2-alkenoates using blaze reaction intermediates.

2-acyl-3-amino-2-alkenoate represented by the following formula (1) is a multifunctional compound having three different functional groups of amines, alkenes, and esters. It is a compound that is very likely to be used as an important intermediate for the synthesis of heterocyclic compounds such as pyrazole, pyrimidine and oxazole which are used as pharmacophores.

However, until now, the method for preparing 2-acyl-3-amino-2-alkenoate has been described in which beta-keto ester and nitrile are reacted in the presence of an equivalent amount of toxic SnCl ₄ . Only methods are known [B. Corain, M. Basato, AC Veronese, J. Mol . Catalysis , 1993 , 81, 133], a method for effectively preparing 2-acyl-3-amino-2-alkenoate is not known.

On the other hand, the Blaze reaction is a method known about 100 years ago [EE Blaise, CR Hebd . Seances Acad . Sci . 1901 , 132 , 478; 1901 , 132 , 978], as shown in Scheme 1 below, a reformatsky reagent and a nitrile were reacted to synthesize an enaminozincate intermediate of formula 4, and the intermediate It is known that beta-keto ester is obtained by work-up in an acidic aqueous solution, and beta-enamino ester is synthesized by treating with a neutral or alkaline aqueous solution. [R. Pcampo, WR Dolbier, Jr., Tetrhedron 2004 , 60, 9325; J. Cason, KL Rinehart, Jr., SD Thornton, Jr., J. Org . Chem . 1953 , 18 , 1594; HB Kagan, YH Suen , Bull . Soc . Chim, Fr. 1966 , 1819; SM Hannick, Y. Kishi , J. Org . Chem . 1983 , 48 , 3833].

Scheme 1

The present inventors have diligently studied to develop an effective method for preparing 2-acyl-3-amino-2-alkenoate. The present invention has been accomplished by discovering that 2-acyl-3-amino-2-alkenoate can be easily and effectively prepared.

It is therefore an object of the present invention to provide an efficient process for the preparation of 2-acyl-3-amino-2-alkenoate.

The present invention relates to a novel process for preparing 2-acyl-3-amino-2-alkenoate of formula (1),

(i) reacting a nitrile compound of formula 2 with alkyl bromoacetate and zinc of formula 3 to obtain an enaminoginate of formula 4; And

(ii) reacting the enaminozine of formula 4 with an acylating agent in the presence of a base.

Wherein R ₁ and R ₃ are each independently an alkyl group of C ₁ -C ₁₀ , a cycloalkyl group or an aryl group of C ₃ -C ₁₀ ,

R ₂ is an alkyl group of C ₁ -C ₁₀ .

As used herein, an alkyl group of C ₁ -C ₁₀ refers to a straight or branched hydrocarbon having 1 to 10 carbon atoms, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i- Butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

As used herein, a C ₃ -C ₁₀ cycloalkyl group means a cyclic hydrocarbon composed of 3 to 10 carbon atoms, and examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. no.

As used herein, the aryl group includes both aromatic groups and heteroaromatic groups and their partially reduced derivatives. The aromatic group is a simple or fused cyclic consisting of 5 to 15 pentagons, heteroaromatic group refers to an aromatic group containing one or more oxygen, sulfur or nitrogen. Examples of representative aryl groups are phenyl, naphthyl, pyridinyl, furanyl, thiophenyl, indolyl, quinolinyl, imidazolinyl, Oxazolyl, thiazolyl, tetrahydronaphthyl, and the like, but are not limited thereto.

The C ₁ -C ₁₀ alkyl group, C ₃ -C ₁₀ cycloalkyl group and aryl group is one or more hydrogen is C ₁ -C ₅ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ Alkynyl group, C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₅ alkoxy group, C ₁ -C ₅ thioalkoxy group, aryl group, acyl group, hydroxy, thio, halogen, amino, alkoxy Carbonyl, carboxy, carbamoyl, cyano, nitro and the like.

In the above production method of the present invention, R ₁ and R ₃ are each independently one or more substituents selected from the group consisting of C ₁ -C ₅ alkyl group, C ₁ -C ₅ alkoxy group, aryl group and halogen C ₁ -C ₁₀ alkyl group or aryl group which is unsubstituted or substituted by. More preferably, R ₁ and R ₃ are each independently an unsubstituted C ₁ -C ₁₀ alkyl group, a C ₁ -C ₁₀ alkyl group substituted with one or more halogens,

And, wherein X and Y are each independently hydrogen, alkoxy or halogen in the alkyl group of _{C 1 -C 5, C 1 -C} 5.

Hereinafter, the preparation method of the present invention will be described in more detail with reference to Scheme 2 below. The method described in Scheme 2 below merely illustrates the method used representatively, the order of the unit operation, the reaction reagent, the reaction conditions and the like may be changed as much as the case may be.

Scheme 2

The enaminoazineate (4), which is a blaze reaction intermediate, is prepared by reacting a nitrile compound (2) with an alkyl bromoacetate (3) and zinc, preferably zinc dust.

As the reaction solvent, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, or the like is preferably used, and the reaction temperature is preferably under reflux conditions.

The enaminoazineate (4) is directly in situ ) can be used for the following processes:

2-acyl-3-amino-2-alkenoate (1) is prepared by reacting enaminoginate (4) with an acylating agent in the presence of a base.

As the base, both inorganic and organic bases can be used. Specific examples of the inorganic base include alkyllithium such as CH ₃ Li, EtLi, n-BuLi, t-BuLi, s-BuLi, aryl lithium such as PhLi, Grignard reagent such as CH ₃ MgBr, PhMgBr, lithium Alkali metals such as hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), alkali metals such as hexamethyldisilazide (NaHMDS), potassium t-butoxide, sodium methoxide, potassium methoxide and the like Metal hydrides such as metal alkoxides, sodium hydrides, calcium hydrides, potassium hydrides and the like. Specific examples of the organic base include alkyl amines such as triethylamine and aryl amines such as pyridine. Most preferably n-BuLi is used as the base. The amount of the base used is preferably 0.1 to 1.2 equivalents, more preferably about 1.0 equivalent.

According to the preparation method of the present invention, the use of a base significantly increases the reactivity and selectivity of the acylation reaction so that only C2-acylated products without N-acylated by-products can be selectively synthesized in high yield.

As the acylating agent, it is preferable to use an acid anhydride represented by (R ₃ CO) ₂ O or an acid chloride represented by R ₃ COCl, and represented by (R ₃ CO) ₂ O. Most preferably, acid anhydrides are used.

It may also comprise the step of hydrolysis by addition of a weakly acidic, neutral or alkaline aqueous solution after the acylation reaction step.

According to the preparation method of the present invention, 2-acyl-3-amino-2-alkenoate, which can be used as an important intermediate for the synthesis of heterocyclic compounds showing physiological activity, can be easily and effectively prepared using a blaze reaction intermediate. Can be . In particular, the use of a base in the acylation reaction of the enaminoazineate 4 significantly increases the reactivity and selectivity, allowing only C2-acylated products to be selectively synthesized in high yield without N-acylated byproducts.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is apparent to those skilled in the art that these examples are only for illustrating the present invention, and the scope of the present invention is not limited to these examples.

Example  1: 2-acyl-3-amino-2- Of alkenoate (1a)  Produce

To a zinc powder suspension (Aldrich, 10 μm, 0.65 g, 10 mmol) was added 5 mol% methanesulfonic acid dissolved in THF (2.5 mL) with stirring and the reaction mixture was heated to reflux for 10 minutes. Benzonitrile (0.52 ml, 5 mmol) was added to the reaction mixture, then ethyl bromoacetate (0.83 mL, 7.5 mmol) was added dropwise using a syringe pump for 1 hour and refluxed. After 1 hour, the reaction mixture was cooled to 0 ° C. and n-BuLi (2M in cyclohexane, 2.5 mL, 5 mmol) was added dropwise followed by the addition of acetic anhydride (0.62 mL, 6.5 mmol). The reaction temperature was allowed to stand at room temperature and stirred for 4 hours. Then, the reaction was stopped by adding a saturated NH ₄ Cl aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck 60, 230-400 mesh) to give the title compound (0.93 g, 4 mmol, 80%).

¹ H NMR (CDCl ₃ , ppm) δ 11.00 (bs, 1H), 7.45 to 7.36 (m, 5H), 5.49 (bs, 1H), 3.76 (q, J = 7.2 Hz, 2H), 2.38 (s, 3H ), 0.71 (t, J = 7.2 Hz, 3H)

¹³ C NMR (CDCl _{3 ,} ppm) δ 13.3, 29.4, 60.0, 104.1, 126.6, 128.6, 130.0, 138.4, 166.9, 169.8, 197.1

Example  2-13: 2-acyl-3-amino-2- Of alkenoate (1b-1m)  Produce

2-Acyl-3 of Chemical Formulas 1b to 1m in the same manner as in Example 1, except that the nitrile compounds shown in Table 1 below and the acid anhydrides shown in Table 1 below instead of acetic anhydride were used instead of benzonitrile. -Amino-2-alkenoate was obtained in the yields described in Table 1 below.

TABLE 1

[a] Yield of product isolated after chromatography

[b] Yield of E / Z Mixture

2-acyl-3-amino-2- Alkenoate (1b)

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.24 (bs, 1H), 7.29 ~ 7.11 (m, J = 6.8 Hz , 4H ), 5.52 (bs, 1H), 3.72 (m, 2H), 2.37 (s, 3H ), 2.32 (s, 3H), 2.08 (s, 1H). 0.69 (t, J = 6.8 Hz, 3H)

¹³ C NMR (400 MHz, CDCl ₃ ) δ 13.30, 19.20, 30.00, 59.80, 103.30, 125.60, 128.90, 129.80, 130.10, 135.90, 137.70, 165.90, 168.30, 198.30

2-acyl-3-amino-2- Alkenoate (1c)

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.96 (bs, 1H), 7.37 (dd, J = 8.0 Hz , 2H), 7.11 (dd, J = 8.0 Hz , 2H ), 5.51 (bs, 1H), 3.80 (q, J = 8.0 Hz , 2H), 2.36 (s, 3H), 0.81 (t, J = 8.0 Hz , 3H)

¹³ C NMR (400 MHz, CDCl ₃ ) δ 14.10, 29.50, 53.50, 60.10, 104.30, 115.60, 116.20, 128.50, 116.00, 134.40, 165.70, 169.70, 197.00

2-acyl-3-amino-2- Alkenoate (1d)

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.99 (bs, 1H), 8.74 (dd, J = 4.0 Hz , 1H), 8.61 (d, 1H) , 7.76 (m, J = 4.0 Hz , 1H), 7.44 ( m, J = 4.0 Hz , 1H), 6.00 (bs, 1H), 3.78 (q, J = 7.2 Hz, 2H). 2.38 (s, 3H), 0.79 (t, J = 7.2 Hz , 3H)

¹³ C NMR (400 MHz, CDCl ₃ ) δ 13.60, 30.00, 60.20, 104.50, 123.80, 134.90, 135.50, 147.10, 150.40, 163.00, 168.70, 197.80

2-acyl-3-amino-2- Alkenoate (1e)

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.26 (bs, 1H), 7.13 (d, J = 8.4 Hz , 2H), 6.89 (d, J = 7.2 Hz , 2H ), 5.57 (bs, 1H), 4.25 (q, J = 7.2 Hz , 2H), 3.90 (s, 1H), 3.78 (s, 3H), 2.28 (s, 3H). 1.33 (t, J = 7.2 Hz , 3H)

¹³ C NMR (400 MHz, CDCl ₃ ) δ 14.20, 30.00, 39.70, 55.20, 60.30, 103.20, 114.50, 126.50, 130.80, 159.00, 168.70, 169.60, 196.80

2-acyl-3-amino-2- Alkenoate (1f)

¹ H NMR (CDCl _{3 ,} ppm) δ 11.37 (bs, 1H), 7.41 to 7.21 (m, 5H), 5.56 (bs, 1H), 4.24 (q, J = 7.2 Hz, 2H), 3.96 (s, 2H ), 2.32 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H)

¹³ C NMR (CDCl _{3 ,} ppm) δ 14.2, 30.1, 40.6, 60.3, 103.4, 127.6, 128.6, 129.8, 134.6, 168.0, 169.6, 196.9

2-acyl-3-amino-2- Alkenoate (1 g)

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.23 (bs, 1H), 5.62 (bs, 1H), 4.23 (q, J = 7.2 Hz , 2H), 2.53 (q, J = 6.8 Hz , 2H), 2.23 ( s, 3H). 1.33 (t, J = 7.2 Hz , 3H), 1.18 (t, J = 7.2 Hz , 3H)

¹³ C NMR (400 MHz, CDCl ₃ ) δ 12.50, 14.20, 28.90, 29.90, 60.30, 102.90, 169.80, 171.50, 197.00

2-acyl-3-amino-2- Alkenoate (1h)

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.26 (bs, 1H), 5.57 (bs, 1H), 4.24 (q, J = 7.2 Hz , 2H), 3.12 (q, J = 6.8 Hz , 1H), 2.24 ( s, 3H). 1.33 (t, J = 6.8 Hz , 3H), 1.19 (d, J = 6.8 Hz , 6H)

¹³ C NMR (400 MHz, CDCl ₃ ) δ 14.20, 20.90, 29.90, 31.20, 60.00, 103.00, 170.10, 173.90, 196.30

2-acyl-3-amino-2- Alkenoate (1i)

¹ H NMR (CDCl _{3 ,} ppm) δ 10.68 (bs, 1H), 7.76 to 7.73 (m, 2H), 7.54 to 7.20 (m, 8H), 5.72 (bs, 1H), 3.62 (q, J = 7.1 Hz , 2H), 0.63 (t, J = 7.1 Hz, 3H) minor

¹ H NMR (CDCl _{3 ,} ppm) δ 9.04 (bs, 1H), 7.76 to 7.73 (m, 2H), 7.54 to 7.20 (m, 8H), 5.27 (bs, 1H), 4.04 (q, J = 7.1 Hz , 2H), 0.95 (t, J = 7.1 Hz, 3H) -major

minor  : major  = 0.5: 1.0

¹³ C NMR (CDCl _{3 ,} ppm) δ 13.2, 13.9, 59.5, 60.2, 100.0, 103.7, 126.5, 126.8, 127.4, 127.9, 128.0, 128.6, 128.9, 129.9, 130.0, 130.1, 131.8, 137.0, 137.3, 140.7, 142.5, 164.7, 167.2, 168.8, 169.4, 194.6, 195.5

2-acyl-3-amino-2- Alkenoate (1j)

¹ H NMR (CDCl _{3 ,} ppm) δ 10.74 (bs, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.42 to 7.19 (m, 5H), 6.86 (d, J = 8.7 Hz, 2H), 5.49 (bs, 1H), 3.86 (s, 3H), 3.71 (q, J = 7.1 Hz, 2H), 0.70 (t, J = 7.1 Hz, 3H) -minor

¹ H NMR (CDCl _{3 ,} ppm) δ 8.96 (bs, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.42 to 7.19 (m, 5H), 6.80 (d, J = 8.7 Hz, 2H), 5.18 (bs, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H) -major

minor  : major  = 0.3: 1.0

¹³ C NMR (CDCl _{3 ,} ppm) δ 13.4, 14.1, 55.4, 59.5, 60.2, 99.9, 103.6, 113.1, 113.2, 126.8, 127.4, 128.5, 128.8, 130.0, 131.3, 133.4, 134.8, 137.0, 137.6, 161.4, 162.7, 163.5, 166.5, 168.7, 169.7, 193.5, 194.0

2-acyl-3-amino-2- Alkenoate (1k)

¹ H NMR (CDCl _{3 ,} ppm) δ 11.22 (bs, 1H), 7.45 to 7.37 (m, 5H), 5.47 (bs, 1H), 3.75 (q, J = 7.2 Hz, 2H), 3.35 to 3.24 (m , 1H), 1.16 (d, J = 6.8 Hz, 6H), 0.72 (t, J = 7.2 Hz, 3H)

¹³ C NMR (CDCl _{3 ,} ppm) δ 13.3, 19.6, 36.6, 60.2, 103.7, 126.6, 128.7, 130.0, 138.4, 166.4, 170.0, 203.5

2-acyl-3-amino-2- Alkenoate (1l)

¹ H NMR (CDCl _{3 ,} ppm) δ 11.39 (bs, 1H), 7.47 to 7.35 (m, 5H), 5.58 (bs, 1H), 3.73 (q, J = 7.2 Hz, 2H), 2.58 (d, J = 7.0 Hz, 2H), 2.22-2.11 (m, 1H), 0.95 (d, J = 6.6 Hz, 6H), 0.70 (t, J = 7.2 Hz, 3H)

¹³ C NMR (CDCl _{3 ,} ppm) δ 13.3, 22.8, 25.5, 49.4, 60.1, 104.6, 126.6, 128.6, 130.0, 138.4, 166.4, 169.9, 199.1

2-acyl-3-amino-2- Alkenoate (1m)

¹ H NMR (CDCl _{3 ,} ppm) δ 10.68 (bs, 1H), 7.51 to 7.35 (m, 5H), 6.15 (bs, 1H), 3.88 (q, J = 7.2 Hz, 2H), 0.93 (t, J = 7.2 Hz, 3H)

¹³ C NMR (CDCl _{3 ,} ppm) δ 13.4, 61.2, 100.7, 126.1, 126.6, 128.9, 129.2, 131.0, 135.9, 166.9, 170.7

Example  14-18: 2-acyl-3-amino-2- Of alkenoate (1a)  Produce

The title compound was obtained in the yield described in Table 2 in the same manner as in Example 1, except for using the base shown in Table 2 below in the equivalents shown in Table 2 instead of n-BuLi.

TABLE 2

[a] Yield of product isolated after chromatography

Comparative example  1: 2-acyl-3-amino-2- Of alkenoate (1a)  Produce

The title compound (18%) was obtained in the same manner as in Example 1 except that no base was used. 27% N-acylated byproducts were produced.

Claims (9)

(i) reacting a nitrile compound of formula 2 with alkyl bromoacetate and zinc of formula 3 to obtain an enaminoginate of formula 4; And

(ii) a process for preparing 2-acyl-3-amino-2-alkenoate of formula 1 comprising reacting an enaminoginate of formula 4 with an acylating agent in the presence of a base:

Wherein R ₁ and R ₃ are each independently an alkyl group of C ₁ -C ₁₀ , a cycloalkyl group or an aryl group of C ₃ -C ₁₀ , R ₂ is an alkyl group of C ₁ -C ₁₀ . The method of claim 1, wherein, R ₁ and R ₃ are each independently C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy groups, aryl groups and optionally substituted by one or more substituents selected from the group consisting of halogen, It is a C ₁ -C ₁₀ alkyl group or an aryl group. The alkyl group of claim 1, wherein each of R ₁ and R ₃ is independently an unsubstituted C ₁ -C ₁₀ alkyl group, an alkyl group of C ₁ -C ₁₀ substituted with one or more halogens,

And, wherein X and Y are each independently a production process, characterized in that hydrogen, an alkyl group of C ₁ -C _5, an alkoxy group or a halogen C ₁ -C _5. The (right in claim 1, without the separation of the amino yen binary Kate process of formula (IV) obtained in step (i) situ ) process according to claim (ii). The method of claim 1, wherein in step (ii) the base is alkyllithium, aryl lithium, Grignard reagent, alkali metal hexamethyldisilazide, alkali metal alkoxide, metal hydride, alkyl amine or aryl amine. Characterized in the manufacturing method. A process according to claim 5, wherein the base is n-butyllithium. The process according to claim 1, wherein the acylating agent in step (ii) is an acid anhydride represented by (R ₃ CO) ₂ O or an acid chloride represented by R ₃ COCl. The process according to claim 7, wherein the acylating agent is an acid anhydride represented by (R ₃ CO) ₂ O. A process according to claim 1, characterized in that it is reacted with an acylating agent in step (ii) and then hydrolyzed by addition of a weakly acidic, neutral or alkaline aqueous solution.