JP2012036131A - Dihydroxyboryl group-containing, nitrogen-containing heterocyclic derivative, medicine comprising the derivative as active ingredient and method for producing the derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new dihydroxyboryl group-containing, nitrogen-containing heterocyclic derivative, a medicine comprising the derivative as an active ingredient and a method for producing a dihydroxyboryl group-containing, nitrogen-containing heterocyclic derivative, which does not require many processes and has a slight environmental load.SOLUTION: The new dihydroxyboryl group-containing dihydroxypyrimidin-2-one (or thioketone) derivative, the dihydroxyboryl group-containing 1,4-dihydropyridine derivative and the dihydroxyboryl group-containing dihydropyrano[2,3-c]pyrazole compound are provided. The cancer therapeutic agent comprises the compound as an active ingredient. The one-pot synthesis method from a multicomponent raw material of the compound is provided.

Description

  The present invention relates to a dihydroxyboryl group-containing nitrogen-containing heterocyclic derivative, a medicament containing the derivative as an active ingredient, and a method for producing the derivative.

Compounds containing boric acid groups [RB (OH) ₂ ] and boric acid ester groups [RB (OR ') ₂ ] have recently been developed by Suzuki-Miyaura Cross Coupling (Miyaura, N .; Suzuki, A. Chem. Rev. 1995). , 95, 2457-2483.) And molecular recognition sensors (Soya, G .; Aaron, M .; Marilyn, M, O .; Christine, M ,. B .; Lacie, C, H .; Sulolit, P, R , A .; Wessling .; Bakthan, SJ Am. Chem. Soc. 2007. 129, 1278-1286.). Interestingly, boron compounds having a dihydroxyboryl group [—B (OH) ₂ ] have been found to have various biological activities. For example, the following formula:

で表されるホウ酸誘導体中、ホウ素アミノ酸誘導体(A)はhuman arginase IIに対して強い阻害活性を有する（Evis, C, D, M.; Colleluori, F, A, E.; Hyunshun, S.; Soo, W, K.; Noel N, K.; Abdulmaged, M, T.; David E. A.; David, W, C.; Biochemistry 2003. 42, 8445-8451.）。またα-アミノホウ酸はセリンプロテアーゼ阻害作用を示すものが知られており（Wenqian, Y.; Xingming, G.; Binghe, W.; Medicinal Research Reviews, 2003. 23, 346-367.）、例えばホウ素化合物(B)は血液凝固に関係するプロテアーゼのトロンビンに対して強い阻害活性を示す（Kettner, C.; Mersinger, L.; Knabb, R. J. BioChem. 1990. 265, 18289-18297.）。ホウ素化合物Bortezomib (C) はVelcadeの名で市販されており、26 S プロテアソームを強く選択的に阻害するため、抗がん剤として臨床で使用されている（Popat, U.; Carrum, G.; Heslop, H,E.Cancer Treat. Rev. 2003. 29, 3-10.）。ホウ素化合物(D)はleucyl-tRNA synthetaseを阻害する薬効範囲の広い抗真菌剤である（Fernando, L, Rock.; Weimin, M..; Anya, Y.; Mikhail T.; Thibaut, C.; Huchen Z.; Yong-Kang, Z.; Vincent, H.; Tsutomu, A.; Stephen, J, B.; Jacob J, P.; Lucy, S.; Susan, A, M.; Stephen, J, B.; Stephen C. Science. 2007. 316, 1759-1761.）。

In the boric acid derivative represented by the formula, boron amino acid derivative (A) has a strong inhibitory activity against human arginase II (Evis, C, D, M .; Colleluori, F, A, E .; Hyunshun, S. Soo, W, K .; Noel N, K .; Abdulmaged, M, T .; David EA; David, W, C .; Biochemistry 2003. 42, 8445-8451.). In addition, α-aminoboric acid is known to have a serine protease inhibitory action (Wenqian, Y .; Xingming, G .; Binghe, W .; Medicinal Research Reviews, 2003. 23, 346-367.). Compound (B) exhibits a strong inhibitory activity against the thrombin protease related to blood coagulation (Kettner, C .; Mersinger, L .; Knabb, RJ BioChem. 1990. 265, 18289-18297.). The boron compound Bortezomib (C) is marketed under the name Velcade and is used clinically as an anticancer agent because it strongly and selectively inhibits the 26 S proteasome (Popat, U .; Carrum, G .; Heslop, H, E. Cancer Treat. Rev. 2003. 29, 3-10.). Boron compound (D) is a broad-spectrum antifungal agent that inhibits leucyl-tRNA synthetase (Fernando, L, Rock .; Weimin, M ..; Anya, Y .; Mikhail T .; Thibaut, C .; Huchen Z .; Yong-Kang, Z .; Vincent, H .; Tsutomu, A .; Stephen, J, B .; Jacob J, P .; Lucy, S .; Susan, A, M .; Stephen, J, B .; Stephen C. Science. 2007. 316, 1759-1761.).

  The biological activity of the boron compound containing a dihydroxyboryl group is also related to the nature of the boron atom itself. Since boron has an empty 2p orbital, it can interact with a negative atom of the donor molecule by a covalent bond as shown in the following formula.

For this reason, boron compounds can strongly interact with target molecules by hydrogen bonds and covalent bonds, and new physiological activity can be expected. Furthermore, it is expected that a preferable water solubility is imparted to the drug.
However, there are few production examples of dihydroxyboryl group-containing nitrogen-containing heterocyclic derivatives despite the expectation of the expression of physiological activity in this way, and the known production method requires many steps and has a large environmental load. There are many problems such as using a catalyst.

Miyaura, N .; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483. Soya, G .; Aaron, M .; Marilyn, M, O .; Christine, M ,. B .; Lacie, C, H .; Sulolit, P, R, A .; Wessling .; Bakthan, SJ Am. Chem Soc. 2007. 129, 1278-1286. Evis, C, D, M .; Colleluori, F, A, E .; Hyunshun, S .; Soo, W, K .; Noel N, K .; Abdulmaged, M, T .; David EA; David, W, C .; Biochemistry 2003. 42, 8445-8451. Wenqian, Y .; Xingming, G .; Binghe, W .; Medicinal Research Reviews, 2003. 23, 346-367. Kettner, C .; Mersinger, L .; Knabb, R. J. BioChem. 1990. 265, 18289-18297. Popat, U .; Carrum, G .; Heslop, H, E. Cancer Treat. Rev. 2003. 29, 3-10. Fernando, L, Rock .; Weimin, M ..; Anya, Y .; Mikhail T .; Thibaut, C .; Huchen Z .; Yong-Kang, Z .; Vincent, H .; Tsutomu, A .; Stephen, J, B .; Jacob J, P .; Lucy, S .; Susan, A, M .; Stephen, J, B .; Stephen C. Science. 2007. 316, 1759-1761.

  The present invention provides a novel dihydroxyboryl group-containing nitrogen-containing heterocyclic derivative and a novel pharmaceutical comprising the derivative as an active ingredient. The present invention also provides a method for producing a dihydroxyboryl group-containing nitrogen-containing heterocyclic derivative that does not require many steps, has a low environmental burden, and is inexpensive and readily available.

、式：

または式：

[式中、Ｒ^１はハロゲン原子を有していてよい炭素数１〜１０のアルキル基、アルキルオキシ基もしくはアルキルアミノ基、ハロゲン原子を有していてよい炭素数６〜１６のアリール基、またはハロゲン原子を表し、Ｒ^２、Ｒ^４およびＲ^５は、それぞれ独立にハロゲン原子を有していてよい炭素数１〜１０のアルキル基または炭素数６〜１６のアリール基を表し、Ｒ^３はハロゲン原子を有していてよい炭素数１〜１０のアルキル基、炭素数１〜１０のアルキルオキシ基（但し、Ｘが酸素原子のときは、エトキシ基ではない。）、ハロゲン原子を有していてよい炭素数１〜１０のアルキルアミノ基、またはハロゲン原子を有していてよい炭素数６〜１６のアリール基を表し、Ｘは酸素もしくは硫黄原子を表し、ｎは０、または１〜４の整数を表す。]で表される化合物１、７または１０である、ジヒドロキシボリル基含有含窒素複素環化合物； That is, the present invention
<1>
A nitrogen-containing heterocyclic compound containing a dihydroxyboryl group,
The compound has the formula:

,formula:

Or the formula:

[Wherein, R ¹ represents an alkyl group having 1 to 10 carbon atoms which may have a halogen atom, an alkyloxy group or an alkylamino group, an aryl group having 6 to 16 carbon atoms which may have a halogen atom, or represents a halogen ^atom, R 2, ^{R 4} and ^{R 5} each independently represent an alkyl group or an aryl group having a carbon number of 6 to 16 1 to 10 or carbon atoms have a halogen atom, ^{R 3} is halogen An alkyl group having 1 to 10 carbon atoms which may have an atom, an alkyloxy group having 1 to 10 carbon atoms (however, when X is an oxygen atom, it is not an ethoxy group), and has a halogen atom A good alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 16 carbon atoms which may have a halogen atom, X represents an oxygen or sulfur atom, n is 0, or an integer of 1 to 4 The To express. A dihydroxyboryl group-containing nitrogen-containing heterocyclic compound represented by the formula 1, 7 or 10;

で表される化合物１ｗである、＜１＞に記載のジヒドロキシボリル基含有含窒素複素環化合物； <2>
Compound 1 has the formula 1w:

The dihydroxyboryl group-containing nitrogen-containing heterocyclic compound according to <1>, which is a compound 1w represented by:

<3>
<1> or a therapeutic drug for cancer comprising the dihydroxyboryl group-containing nitrogen-containing heterocyclic compound according to <2> as an active ingredient;

[式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｘおよびｎは、前記と同義である。]、
に従ってワンポット反応させる工程を含んでなる、ジヒドロキシボリル基含有含窒素複素環化合物１または１ｗの製造方法； <4>
A process for producing a dihydroxyboryl group-containing nitrogen-containing heterocyclic compound 1 or 1w according to <1> or <2>, comprising 3 consisting of formylphenylboronic acid derivative 4, β-diketone derivative 3 and (thio) urea 2 Ingredients
Reaction formula (1):

[Wherein R ¹ , R ² , R ³ , X and n are as defined above]. ],
A process for producing a dihydroxyboryl group-containing nitrogen-containing heterocyclic compound 1 or 1w, comprising a one-pot reaction according to

であり、得られる生成物１が１ｗである、＜４＞に記載の製造方法； <5>
Reaction formula (1) is represented by reaction formula (1-1):

The production method according to <4>, wherein the obtained product 1 is 1 w;

[式中、Ｒ^１、Ｒ^４、Ｒ^５およびｎは、前記と同義である。]、
に従ってワンポット反応させる工程を含んでなる、ジヒドロキシボリル基含有含窒素複素環化合物７の製造方法。 <6>
<3> A method for producing a dihydroxyboryl group-containing nitrogen-containing heterocyclic compound 7 according to <1>, wherein three components comprising formylphenylboronic acid derivative 4, 3-aminocrotonic acid ester 5 and β-ketoester derivative 6
Reaction formula (2):

[Wherein, R ¹ , R ⁴ , R ⁵ and n are as defined above. ],
A method for producing a dihydroxyboryl group-containing nitrogen-containing heterocyclic compound 7 comprising the step of carrying out a one-pot reaction according to FIG.

[式中、Ｒ^１、Ｒ^４、Ｒ^５およびｎは、前記と同義である。]、
に従ってワンポット反応させる工程を含んでなる、ジヒドロキシボリル基含有含窒素複素環化合物１０の製造方法、等を提供するものである。 <7>
<4> A method for producing a dihydroxyboryl group-containing nitrogen-containing heterocyclic compound 10 according to <1>, comprising four components comprising formylphenylboronic acid derivative 4, β-ketoester derivative 6, malononitrile 8 and hydrazine 9.
Reaction formula (3):

[Wherein, R ¹ , R ⁴ , R ⁵ and n are as defined above. ],
The method for producing the dihydroxyboryl group-containing nitrogen-containing heterocyclic compound 10, which comprises the step of carrying out a one-pot reaction according to the above.

  According to the present invention, a novel dihydroxyboryl group-containing nitrogen-containing heterocyclic derivative and a pharmaceutical such as a novel cancer therapeutic agent containing the derivative as an active ingredient can be obtained. The present invention can provide a method for producing a dihydroxyboryl group-containing nitrogen-containing heterocyclic derivative that does not require many steps, has a low environmental burden, and is inexpensive and easily available as a starting material.

において、Ｘは酸素又は硫黄原子である。ヒドロキシボリル基−Ｂ（ＯＨ）_２の結合位置は、ジヒドロピリミジノン（または、ジヒドロピリミジン−チオン）基が結合した位置に対してオルト、メタ、またはパラのいずれかの位置であってよい。 Dihydroxyboryl group-containing dihydropyrimidin-2-one (or thione) derivative 1, which is a novel dihydroxyboryl group-containing nitrogen-containing heterocyclic derivative of the present invention 1:

In the formula, X is an oxygen or sulfur atom. The bonding position of the hydroxyboryl group -B (OH) ₂ may be any of ortho, meta, or para with respect to the position to which the dihydropyrimidinone (or dihydropyrimidine-thione) group is bonded.

The substituent R ¹ is an alkyl group having 1 to 10 carbon atoms which may have a halogen atom, an alkyloxy group or an alkylamino group, an aryl group having 6 to 16 carbon atoms which may have a halogen atom, or a halogen atom. Represents an atom. n is any integer of 0 or 1-4. Although the halogen atom of the C1-C10 alkyl group which may have a halogen atom does not have a restriction | limiting in particular, For example, they are a fluorine atom or a chlorine atom. Examples of the alkyl group having 1 to 10 carbon atoms include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, 2-methylbutyl, n-hexyl, 2 -Methylpentyl, n-heptyl, 2-methylhexyl, 5-methylhexyl, n-octyl, 2-ethylhexyl, 5-ethylhexyl, n-nonyl, 2-methyloctyl, n-decyl, 2-ethyloctyl and the like It is done. As a C1-C10 alkyloxy group or alkylamino group which may have a halogen atom, the alkyloxy group or alkylamino group corresponding to the said alkyl group is mentioned, for example. There are no particular restrictions on the substitution position and number of halogen atoms.
The halogen atom of the aryl group having 6 to 16 carbon atoms which may have a halogen atom is not particularly limited, and is, for example, a fluorine atom or a chlorine atom. Examples of the aryl group having 6 to 16 carbon atoms include a phenyl group, a naphthyl group, an indenyl group, an anthranyl group, an alkyl group-substituted phenyl group, an alkyl group-substituted naphthyl group, an alkyl group-substituted indenyl group, and an alkyl group-substituted anthranyl group. Can be mentioned. There are no particular restrictions on the substitution position and number of halogen atoms.
There is no particular restriction on the halogen atom as R ¹ itself, for example, fluorine, chlorine, bromine atom and the like.

R ² in Compound 1 represents an alkyl group having 1 to 10 carbon atoms or an aryl group having 6 to 16 carbon atoms which may have a halogen atom, and the halogen atom is not particularly limited. Is an atom.
Examples of the alkyl group having 1 to 10 carbon atoms include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, 2-methylbutyl, n-hexyl, 2 -Methylpentyl, n-heptyl, 2-methylhexyl, 5-methylhexyl, n-octyl, 2-ethylhexyl, 5-ethylhexyl, n-nonyl, 2-methyloctyl, n-decyl, 2-ethyloctyl and the like It is done. Preferred are, for example, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl and the like.
The halogen atom of the aryl group having 6 to 16 carbon atoms which may have a halogen atom is not particularly limited, and is, for example, a fluorine atom or a chlorine atom. Examples of the aryl group having 6 to 16 carbon atoms include phenyl, naphthyl, indenyl, anthranyl, alkyl-substituted phenyl, alkyl-substituted naphthyl, alkyl-substituted indenyl, and alkyl-substituted anthranyl. There are no particular restrictions on the substitution position and number of halogen atoms. Preferable examples of the aryl group having 6 to 16 carbon atoms which may have a halogen atom include phenyl and alkyl-substituted phenyl.

及び、式：

で表される化合物は既知であり、含まない。
ハロゲン原子を有していてよい炭素数１〜１０のアルキルアミノ基としては、Ｒ^１における例と同様なアルキルアミノ基が挙げられる。
ハロゲン原子を有していてよい炭素数６〜１６の（ヘテロ）アリール基の例としては、Ｒ^１における例と同様なアリール基に加えて、フリル基、ピロリル基、イミダゾリル基、チエニル基、ピリジル基、ピリミジル基等のヘテロアリール基が挙げられる。 R ³ in Compound 1 is an alkyl group having 1 to 10 carbon atoms which may have a halogen atom, an alkyloxy group having 1 to 10 carbon atoms (particularly a methoxy group) (however, when X is an oxygen atom, an ethoxy group) Not an alkyl group having 1 to 10 carbon atoms which may have a halogen atom, or a (hetero) aryl group having 6 to 16 carbon atoms which may have a halogen atom.
Examples of alkyl groups of the alkyl group having 1 to 10 or carbon atoms have a halogen atom include the same alkyl groups and examples of R ^1.
Examples of the alkyloxy group having 1 to 10 carbon atoms include alkyloxy groups corresponding to the same alkyl groups as those in R ¹ , for example, methoxy, ethoxy (however, when X is an oxygen atom, And alkyloxy groups such as n-propoxy, i-propoxy, n-butoxy and i-butoxy, particularly preferably a methoxy group. When X is an oxygen atom, it is not an ethoxy group. For example, the formula:

And the formula:

The compound represented by is known and is not included.
Examples of the alkylamino group having 1 to 10 carbon atoms which may have a halogen atom include the same alkylamino groups as in the examples for R ¹ .
Examples of the (hetero) aryl group having 6 to 16 carbon atoms which may have a halogen atom include, in addition to the same aryl group as in R ¹ , a furyl group, a pyrrolyl group, an imidazolyl group, a thienyl group, a pyridyl group. A heteroaryl group such as a group and a pyrimidyl group.

Specific examples of these dihydroxyboryl group-containing dihydropyrimidin-2-one (or thione) derivatives 1 are shown in Table 1:

で表される１ｗが挙げられる。 In the above table, preferable dihydroxyboryl group-containing dihydroxypyrimidin-2-one (or thioketone) derivatives include, for example, the following formula:

1w represented by the following.

で表されるジヒドロキシボリル基含有１，４−ジヒドロピリジン誘導体７におけるヒドロキシボリル基−Ｂ（ＯＨ）_２の結合位置は、ジヒドロピリジル基が結合した位置に対してオルト、メタ、またはパラのいずれかの位置であってよい。置換基Ｒ^１としては、前記の化合物１におけるＲ^１と同様な置換基が挙げられる。ｎは０又は１〜４のいずれかの整数である。 A novel dihydroxyboryl group-containing nitrogen-containing heterocyclic derivative of the present invention represented by the following formula:

In the dihydroxyboryl group-containing 1,4-dihydropyridine derivative 7 represented by formula (7), the bonding position of the hydroxyboryl group -B (OH) ₂ is any of ortho, meta, or para with respect to the position to which the dihydropyridyl group is bonded. It may be a position. The substituent R ^1, include the same substituents as R ¹ in the compound 1 of the. n is any integer of 0 or 1-4.

The substituents R ⁴ and R ⁵ each independently represent an alkyl group having 1 to 10 carbon atoms or an aryl group having 6 to 16 carbon atoms, which may have a halogen atom. The alkyl group having 1 to 10 carbon atoms which may have a halogen atom is not particularly limited as the halogen atom, but is, for example, a fluorine or chlorine atom. Examples of the alkyl group having 1 to 10 carbon atoms include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, 2-methylbutyl, n-hexyl, 2 -Methylpentyl, n-heptyl, 2-methylhexyl, 5-methylhexyl, n-octyl, 2-ethylhexyl, 5-ethylhexyl, n-nonyl, 2-methyloctyl, n-decyl, 2-ethyloctyl and the like It is done. Preferred are, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and the like. Although the halogen atom with the C1-C10 alkyl group which may have a halogen atom, or a C6-C16 aryl group does not have a restriction | limiting in particular, For example, they are a fluorine atom or a chlorine atom. Examples of the aryl group having 6 to 16 carbon atoms include a phenyl group, a naphthyl group, an indenyl group, an anthranyl group, an alkyl group-substituted phenyl group, an alkyl group-substituted naphthyl group, an alkyl group-substituted indenyl group, and an alkyl group-substituted anthranyl group. Can be mentioned. There are no particular restrictions on the substitution position and number of halogen atoms.

Specific examples of these dihydroxyboryl group-containing 1,4-dihydropyridine derivatives 7 are shown in Table 2:

で表されるジヒドロキシボリル基含有ジヒドロピラノ[２，３−ｃ]ピラゾール化合物１０における置換基Ｒ^１はハロゲン原子を有していてよい炭素数１〜１０のアルキル基、アルキルオキシ基もしくはアルキルアミノ基、ハロゲン原子を有していてよい炭素数６〜１６のアリール基、またはハロゲン原子を表す。Ｒ１の例としては、前記化合物１及び７における置換基Ｒ^１と同様な置換基が挙げられる。ヒドロキシボリル基−Ｂ（ＯＨ）_２の結合位置は、ジヒドロピラノ[2,3-c]ピラゾール基が結合した位置に対してオルト、メタ、またはパラのいずれかの位置であってよい。ｎは０又は１〜４のいずれかの整数である。
化合物１０の好ましい例として、下式：

で表される化合物１０ａが挙げられる。 A novel dihydroxyboryl group-containing nitrogen-containing heterocyclic derivative of the present invention represented by the following formula:

The substituent R ¹ in the dihydroxyboryl group-containing dihydropyrano [2,3-c] pyrazole compound 10 represented by the formula ( ¹⁾ is an alkyl group having 1 to 10 carbon atoms which may have a halogen atom, an alkyloxy group or an alkylamino group, An aryl group having 6 to 16 carbon atoms which may have a halogen atom, or a halogen atom. Examples of R1 include the same substituents as the substituents R ¹ in the compound 1 and 7. The bonding position of the hydroxyboryl group —B (OH) ₂ may be any of ortho, meta, or para with respect to the position to which the dihydropyrano [2,3-c] pyrazole group is bonded. n is any integer of 0 or 1-4.
Preferred examples of compound 10 include the following formula:

The compound 10a represented by these is mentioned.

で表される化合物１ｗが挙げられる。 Next, a novel pharmaceutical comprising the dihydroxyboryl group-containing nitrogen-containing heterocyclic derivative of the present invention as an active ingredient will be described.
It has been found that the dihydroxyboryl group-containing nitrogen-containing heterocyclic derivative of the present invention exhibits an effect of suppressing the growth of human cancer cells. The dihydroxyboryl group-containing nitrogen-containing heterocyclic derivative of the present invention showed an inhibitory effect particularly in a cell growth inhibition test against a human cervical cancer cell HeLa.S3 cell line. Examples of derivatives that have shown particularly excellent cell growth inhibitory effects include:

The compound 1w represented by these is mentioned.

[式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｘおよびｎは、前記と同義である。]
に従ってワンポット反応で合成することができる。 Next, the manufacturing method of the dihydroxyboryl group containing nitrogen-containing heterocyclic derivative of this invention is demonstrated.
The dihydroxyboryl group-containing dihydropyrimidin-2-one (or thione) derivative 1 or 1w comprises three components consisting of formylphenylboronic acid derivative 4, β-diketone derivative 3 and (thio) urea 2,
Reaction formula (1):

[Wherein R ¹ , R ² , R ³ , X and n are as defined above]. ]
Can be synthesized in a one-pot reaction.

に従ってワンポット反応で合成することができる。 Among compounds 1, particularly compound 1w is represented by the following reaction formula (1-1):

Can be synthesized in a one-pot reaction.

Conventionally, in the synthesis of a nitrogen-containing heterocyclic derivative not containing a dihydroxyboryl group, a protonic acid such as HCl or BF ₃ · OEt ₂ , FeCl _3, LaCl ₃ · 7H ₂ O, La (OTf) ₃ , Yb ( OTf) ₃ , ZrCl ₄ , BiCl ₃ , Mn (OAc) ₃ , LiClO ₄ etc. have been said to require acid catalysts such as Lewis acids (Adibi, H .; Heshmat, A, S .; Mojtaba B. Catalysis Communications. 2007. 8. 2119-2124 and Bose, D, S .; Liyakat, F .; Hari, B, MJ Org. Chem. 2003. 68, 587-590.).

  Surprisingly, however, in the synthesis of the dihydroxyboryl group-containing dihydropyrimidin-2-one (or thione) derivative 1 or 1w in the present invention, when these acid catalysts are present, side reactions occur rather than by-products. Therefore, it was found that compound 1 can be obtained by a one-pot reaction with high selectivity by simply mixing the three starting materials and stirring and mixing for a predetermined time without using any catalyst. This is presumed that the dihydroxyboryl group of the formylphenylboronic acid derivative 4 which is one of the raw materials fulfilled the Lewis acid function, but the present invention is not bound by this mechanism.

In the three-component one-pot reaction according to the formula (1) or (1-1) of the present invention, the mixing order of the components is not particularly problematic. Usually, after mixing the three components in the presence of a solvent, the reaction is continued with stirring at a predetermined reaction temperature. If the mixing ratio of each component is based on the utilization rate of the formylphenylboronic acid derivative 4, the β-diketone derivative 3 and the (thio) urea 2 are independent with respect to 1 mole of the formylphenylboronic acid derivative 4 respectively. In the range of usually 1 to 2 mol, preferably 1.1 to 1.6 mol, more preferably 1.2 to 1.4 mol.
In the production method of the present invention, it is preferable to use a polar organic solvent in the one-pot reaction step. As the polar solvent, a protic polar solvent such as methanol, ethanol or 2-propanol or an aprotic polar organic solvent such as acetonitrile, propionitrile, methylene dichloride or ethylene dichloride is used. Of these, acetonitrile, propionitrile, methanol, ethanol and the like are preferable. These polar organic solvents are suitable for dissolving raw materials and products, and promote the reaction to proceed efficiently in a homogeneous system. The amount of the polar organic solvent is preferably used in an amount that is equal to or higher than the amount that uniformly dissolves all the raw materials at a predetermined reaction temperature. 000 parts by weight, preferably 500 to 4,000 parts by weight, more preferably 1,000 to 3,000 parts by weight.

In the production method of the present invention, the reaction vessel is replaced with an inert gas such as nitrogen, a polar organic solvent is charged into the reaction vessel, and under stirring, the formylphenylboronic acid derivative 4, β-diketone derivative 3 and (Thio) 3 components comprising urea 2 are added and mixed with stirring. Next, the reaction is continued with stirring at a predetermined temperature for a predetermined time. Here, there is no restriction | limiting in particular in the addition order of a solvent and a reaction substrate. The reaction temperature is usually 25 ° C to 200 ° C, preferably 40 ° C to 150 ° C, particularly preferably 50 ° C to 100 ° C. It is also preferable to react at a reaction temperature near the boiling point of the solvent, and there is an advantage that the reaction temperature is kept constant. For example, when acetonitrile is used as a solvent, a reaction at a boiling point around 82 ° C. is preferable. Although the reaction time depends on the reaction temperature and the concentration of the reaction substrate, it is usually 15 minutes to 72 hours, preferably 5 hours to 60 hours, particularly preferably 10 hours to 50 hours. After confirmation by TLC), gas chromatograph (GC), liquid chromatograph (LC) or the like, the solvent is concentrated, and distilled water is added to precipitate crystals. The crystals are separated into furnaces and washed with distilled water and ether. When this is dissolved in a small amount of methanol, purified by a silica gel column (CHCl ₃ : MeOH = 19: 1) and dried, dihydroxyboryl group-containing dihydropyrimidin-2-one (or thione) derivative 1 can be obtained as crystals. I can do it.

The obtained product has an IR spectrum: JASCO FT / IR-460Plus (absorption wavelength in the examples is shown in cm ⁻¹ ), 1H, or 13C-NMR spectrum: JEOL JMTC-400 / 54 / The structure was specified by SS 400 MHz (unless otherwise specified, TMS was used as an internal standard), melting point (measurement apparatus was BUCHI Melting Point B-545), and the like.

[式中、Ｒ^１、Ｒ^４、Ｒ^５およびｎは、前記と同義である。]
に従って、ホルミルフェニルボロン酸誘導体４、３−アミノクロトン酸エステル５およびβ−ケトエステル誘導体６からなる３成分をワンポット反応することによって合成することができる。（２）式による３成分のワンポット反応において、各成分の混合順序は特に問題とはならない。通常は溶媒の存在下、３成分を混合後、所定の反応温度で撹拌下反応を継続する。各成分の混合比は特に制限はないが、ホルミルフェニルボロン酸誘導体４の利用率を主体に置くならば、例えば、各成分が等モル付近の場合に生成物７の収率は良好となる。具体的には、ホルミルフェニルボロン酸誘導体４が１〜１．３モルに対して、３−アミノクロトン酸エステル５が０．８〜１．２モル、および（チオ）尿素２が０．８〜１．１モル、より好ましくは、ホルミルフェニルボロン酸誘導体４が１〜１．２モルに対して、３−アミノクロトン酸エステル５が０．８〜１．１モル、および（チオ）尿素２が０．８〜１．０モル、より好ましくは、例えば、ホルミルフェニルボロン酸誘導体４が１〜１．１モルに対して、３−アミノクロトン酸エステル５が０．９〜１．０モル、および（チオ）尿素２が０．８〜０．９５モルの範囲である。 The dihydroxyboryl group-containing 1,4-dihydropyridine derivative 7 has the following reaction formula (2):

[Wherein, R ¹ , R ⁴ , R ⁵ and n are as defined above. ]
Thus, the three components consisting of formylphenylboronic acid derivative 4, 3-aminocrotonic acid ester 5 and β-ketoester derivative 6 can be synthesized by one-pot reaction. In the three-component one-pot reaction according to the formula (2), the mixing order of the components is not particularly problematic. Usually, after mixing the three components in the presence of a solvent, the reaction is continued with stirring at a predetermined reaction temperature. The mixing ratio of each component is not particularly limited. However, if the utilization factor of the formylphenylboronic acid derivative 4 is mainly used, for example, the yield of the product 7 is good when each component is in an equimolar vicinity. Specifically, 3-aminocrotonic acid ester 5 is 0.8 to 1.2 mol and (thio) urea 2 is 0.8 to 1.3 mol with respect to 1 to 1.3 mol of formylphenylboronic acid derivative 4. 1.1 moles, more preferably, 1 to 1.2 moles of formylphenylboronic acid derivative 4 is 0.8 to 1.1 moles of 3-aminocrotonate 5 and (thio) urea 2 is 0.8 to 1.0 mol, more preferably, for example, 1 to 1.1 mol of formylphenylboronic acid derivative 4 is 0.9 to 1.0 mol of 3-aminocrotonic acid ester 5, and (Thio) urea 2 is in the range of 0.8 to 0.95 mol.

As the solvent to be used, it is preferable to use a polar organic solvent as in the case of the formula (1). As the polar solvent, a protic polar solvent such as methanol, ethanol or 2-propanol or an aprotic polar organic solvent such as acetonitrile, propionitrile, methylene dichloride or ethylene dichloride is used. Of these, methanol, ethanol, 2-propanol and the like are preferable. As in the case of the formula (1), the reaction temperature is usually 25 ° C. to 200 ° C., preferably 40 ° C. to 150 ° C., particularly preferably 50 ° C. to 100 ° C. It is also preferable to react at a reaction temperature near the boiling point of the solvent, and there is an advantage that the reaction temperature is kept constant. For example, when 2-propanol is used as a solvent, a reaction at a boiling point of about 82 ° C. is preferable. Although the reaction time depends on the reaction temperature and the concentration of the reaction substrate, it is usually 15 minutes to 72 hours, preferably 5 hours to 60 hours, particularly preferably 10 hours to 50 hours. After confirmation by TLC), gas chromatograph (GC), liquid chromatograph (LC) or the like, the solvent is concentrated, and distilled water is added to precipitate crystals. The crystals are separated into furnaces and washed with distilled water and ether. When this is dissolved in a small amount of methanol, purified by a silica gel column (CHCl ₃ : MeOH = 19: 1) and dried, a dihydroxyboryl group-containing nitrogen-containing heterocyclic derivative (compound 7) can be obtained as crystals. The analysis of the product is performed in the same manner as in the reaction formula (1), and the product is specified.

The dihydroxyboryl group-containing dihydropyrano [2,3-c] pyrazole compound 10 has the following reaction formula (3):

For this type of reaction, Yuri et al. Have developed a synthesis method by condensing four components of aromatic aldehyde, hydrazine, malononitrile, and ethyl acetoacetate in one pot (Yuri, M, L .; Alexander, A, S .; Lyudmila, A, R .; Anatoliy, M, SJ Comb. Chem. 2009, 11, 914-919.). However, no example using a boric acid group-containing component has been reported, and since it is necessary to use two types of bases, triethylamine and pyridine, as the condensation accelerator, the reaction conditions can be basic. . Then, the dihydroxyboryl group -B (OH) _{2 of} the acidic component reacts with these base components, and there is a high possibility that the overall reaction will not proceed. Surprisingly, however, the dihydroxyboryl group-containing nitrogen-containing heterocyclic compound 10 can be obtained in a high yield by carrying out a one-pot reaction in an alcohol solvent in the presence of two types of bases, triethylamine and pyridine as a condensation accelerator. I found out that I could get it.

  In the one-pot reaction between the four components according to the formula (3), the mixing order of the components is not particularly problematic. Usually, after mixing the four components in the presence of a solvent, the reaction is continued with stirring at a predetermined reaction temperature. The mixing ratio of each component is not particularly limited. However, if the utilization factor of formylphenylboronic acid derivative 4 is mainly used, for example, 1 mol of formylphenylboronic acid derivative 4 is independent of each other component. In the range of 0.8 to 2.0 mol, preferably 1.0 to 1.5 mol, more preferably 1.1 to 1.2 mol can be selected. Triethylamine and pyridine as the base can each independently select a molar amount in the same range as described above with respect to 1 mol of formylphenylboronic acid derivative 4.

As the solvent to be used, it is preferable to use a polar organic solvent as in the case of the formula (1). As the polar solvent, a protic polar solvent such as methanol, ethanol or 2-propanol or an aprotic polar organic solvent such as acetonitrile, propionitrile, methylene dichloride or ethylene dichloride is used. Of these, methanol, ethanol, 2-propanol and the like are preferable. As in the case of the formula (1), the reaction temperature is usually 25 ° C. to 200 ° C., preferably 40 ° C. to 150 ° C., particularly preferably 50 ° C. to 100 ° C. It is also preferable to react at a reaction temperature near the boiling point of the solvent, and there is an advantage that the reaction temperature is kept constant. For example, when ethanol is used as a solvent, the reaction at around 73 ° C., which is the boiling point, is preferable. Although the reaction time depends on the reaction temperature and the concentration of the reaction substrate, it is usually 15 minutes to 24 hours, preferably 30 minutes to 12 hours, more preferably about 45 minutes to 5 hours. (TLC), gas chromatograph (GC), liquid chromatograph (LC), etc., and then confirming the concentration, the solvent is concentrated, and distilled water is added to precipitate crystals. The crystals are separated into furnaces and washed with distilled water and ether. When this is dissolved in a small amount of methanol, purified by a silica gel column (CHCl ₃ : MeOH = 19: 1) and dried, a dihydroxyboryl group-containing nitrogen-containing heterocyclic derivative (compound 7) can be obtained as crystals. The analysis of the product is performed in the same manner as in the reaction formula (1), and the product is specified.

EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited to these.
The product is IR spectrum: JASCO FT / IR-460Plus (absorption wavelength in the examples is shown in cm ⁻¹ ), 1H, or 13C-NMR spectrum: JEOL JMTC-400 / 54 / SS 400 MHz ( Unless otherwise specified, TMS was used as an internal standard.) The chemical structure was specified by melting point (measurement apparatus was BUCHI Melting Point B-545).

に従って、ジヒドロキシボリル基含有ジヒドロピリミジン−２−オン（又はチオン）誘導体１−１を以下の様にして合成した。
２５ｍｌの二口フラスコに、下式： Example 1
Reaction formula:

Thus, a dihydroxyboryl group-containing dihydropyrimidin-2-one (or thione) derivative 1-1 was synthesized as follows.
In a 25 ml two-necked flask, the following formula:

に示すホルミルフェニルホウ酸誘導体（４−１、４−２又は４−３；各１ｍｍｏｌ）のいずれか一種、β-ケトエステル（又はβ-ジケトン、又はβ-ケトアミド：１．２４ｍｍｏｌ）、尿素（又はチオ尿素：１．２４ｍｍｏｌ）及び乾燥アセトニトリル（５ｍｌ）を加え、窒素気流下、アセトニトリル還流下で表３に示す各々の時間反応させた。
ＴＬＣにより反応の終了を確認した後、溶媒を濃縮して、蒸留水を加えて結晶を析出させた。結晶を炉別して、蒸留水、エーテルで結晶を洗った。これを少量のメタノールに溶かし、シリカゲルカラム（溶出溶媒：ＣＨＣｌ_３：ＭｅＯＨ＝１９：１）により精製して乾燥させると結晶としてジヒドロピリミジン−２−オン（又は、チオン）誘導体のジヒドロキシボリル誘導体である、ジヒドロキシボリル基含有ジヒドロピリミジン−２−オン（又はチオン）誘導体１−１を得た。得られた生成物は、ＩＲ、ＮＭＲ、融点により化学構造を特定した。得られた結果を表３（３−１〜３−４）に示す。収率はホルミルフェニルホウ酸誘導体に対する単離収率（％）である。

Any one of the formylphenylboric acid derivatives (4-1, 4-2 or 4-3; 1 mmol each), β-ketoester (or β-diketone, or β-ketoamide: 1.24 mmol), urea (or Thiourea: 1.24 mmol) and dry acetonitrile (5 ml) were added, and the reaction was carried out for each time shown in Table 3 under reflux of acetonitrile under a nitrogen stream.
After confirming the completion of the reaction by TLC, the solvent was concentrated, and distilled water was added to precipitate crystals. The crystals were separated in a furnace and washed with distilled water and ether. When this is dissolved in a small amount of methanol and purified by a silica gel column (elution solvent: CHCl ₃ : MeOH = 19: 1) and dried, it is a dihydropyrimidin-2-one (or thione) derivative dihydroxyboryl derivative as a crystal. Dihydroxyboryl group-containing dihydropyrimidin-2-one (or thione) derivative 1-1 was obtained. The resulting product was identified for its chemical structure by IR, NMR, and melting point. The obtained results are shown in Table 3 (3-1 to 3-4). The yield is the isolated yield (%) based on the formylphenylboric acid derivative.

1c: 表３−１、No. 3 (74 % yield) ; 白色結晶 ; mp 201.2 ℃.
Rf = 0.38.
¹H (400 MHz, DMSO) : 2.23 (s, 3H, CH₃), 3.51 (s, 3H,OCH₃), 5.13 (d, 1H, J =3.17 Hz, CH), 7.176 (d, 2H, J =8.05 Hz, Ph), 7.65-7.74 (m, 3H, Ph and NH), 8.02 (br s, 2H, B(OH)₂), 9.18 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 17.9, 50.9, 53.9, 99.0, 125.3 (2×C), 133.2, 134.4 (2×C), 144.9, 145.3, 165.6, 174.3.
IR (KBr) : 3273, 2954, 2360, 1694, 1434, 1340, 1237, 1098.
Compound analysis data (1): Dihydroxyboryl group-containing dihydropyrimidin-2-one (or thione) derivative

1c: Table 3-1, No. 3 (74% yield); white crystals; mp 201.2 ° C.
Rf = 0.38.
¹ H (400 MHz, DMSO): 2.23 (s, 3H, CH ₃ ), 3.51 (s, 3H, OCH ₃ ), 5.13 (d, 1H, J = 3.17 Hz, CH), 7.176 (d, 2H, J = 8.05 Hz, Ph), 7.65-7.74 (m, 3H, Ph and NH), 8.02 (br s, 2H, B (OH) ₂ ), 9.18 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 17.9, 50.9, 53.9, 99.0, 125.3 (2 × C), 133.2, 134.4 (2 × C), 144.9, 145.3, 165.6, 174.3.
IR (KBr): 3273, 2954, 2360, 1694, 1434, 1340, 1237, 1098.

1d: 表３−１、No. 4 (64 % yield) ; 白色結晶 ; mp 198.6 ℃.
Rf = 0.59.
¹H (400 MHz, DMSO) : 2.24 (s, 3H, CH₃), 3.50 (s, 3H, OCH₃), 5.13 (br s, 1H, CH), 7.16-7.35 (m, 2H, Ph), 7.58-7.80 (m, 3H, Ph and NH), 8.02 (br s, 2H, B(OH)₂), 9.16 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 17.9, 50.8, 54.2, 99.1, 126.2, 127.5, 128.2, 132.2, 133.1, 143.7, 148.5, 152.1, 165.9.

1d: Table 3-1, No. 4 (64% yield); white crystals; mp 198.6 ° C.
Rf = 0.59.
¹ H (400 MHz, DMSO): 2.24 (s, 3H, CH ₃ ), 3.50 (s, 3H, OCH ₃ ), 5.13 (br s, 1H, CH), 7.16-7.35 (m, 2H, Ph), 7.58-7.80 (m, 3H, Ph and NH), 8.02 (br s, 2H, B (OH) ₂ ), 9.16 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 17.9, 50.8, 54.2, 99.1, 126.2, 127.5, 128.2, 132.2, 133.1, 143.7, 148.5, 152.1, 165.9.

1e: 表３−１、No. 5 (48 % yield) ; 白色結晶 ; mp 192.4 ℃.
Rf = 0.38.
¹H (400 MHz, DMSO) : 2.27 (s, 3H, CH₃), 3.43 (s, 3H, CH₃), 5.44 (br s, 1H, CH), 7.09 (br s, 1H, NH), 7.14-7.48 (m, 4H, Ph), 8.21 (br s, 2H, B(OH)₂), 9.25 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 17.8, 50.8, 53.8, 99.4, 125.7, 126.5, 129.7, 133.1, 135.5, 148.3, 148.5, 151.5, 165.8.

1e: Table 3-1, No. 5 (48% yield); white crystals; mp 192.4 ° C.
Rf = 0.38.
¹ H (400 MHz, DMSO): 2.27 (s, 3H, CH ₃ ), 3.43 (s, 3H, CH ₃ ), 5.44 (br s, 1H, CH), 7.09 (br s, 1H, NH), 7.14 -7.48 (m, 4H, Ph), 8.21 (br s, 2H, B (OH) ₂ ), 9.25 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 17.8, 50.8, 53.8, 99.4, 125.7, 126.5, 129.7, 133.1, 135.5, 148.3, 148.5, 151.5, 165.8.

1f: 表３−１、No. 6 (80 % yield) ; 淡黄結晶 ; mp 205.4 ℃.
Rf = 0.39.
¹H (400 MHz, DMSO) : 2.09 (s, 3H, CH₃), 2.27 (s, 3H, CH₃), 5.25 (s, 1H, CH), 7.19 (d, 2H, J =7.56 Hz, Ph), 7.71 (d, 2H, J =7.56 Hz, Ph), 7.80 (br s, 1H, NH), 8.00 (br s, 2H, B(OH)₂), 9.16 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 19.0, 30.3, 53.9, 109.6, 125.5 (2×C), 133.3, 134.4 (2×C), 145.9, 148.1, 152.1, 194.3.
IR (KBr) : 3275, 2938, 2410, 1695, 1608, 1563, 1412, 1348, 1243.

1f: Table 3-1, No. 6 (80% yield); pale yellow crystal; mp 205.4 ° C.
Rf = 0.39.
¹ H (400 MHz, DMSO): 2.09 (s, 3H, CH ₃ ), 2.27 (s, 3H, CH ₃ ), 5.25 (s, 1H, CH), 7.19 (d, 2H, J = 7.56 Hz, Ph ), 7.71 (d, 2H, J = 7.56 Hz, Ph), 7.80 (br s, 1H, NH), 8.00 (br s, 2H, B (OH) ₂ ), 9.16 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 19.0, 30.3, 53.9, 109.6, 125.5 (2 × C), 133.3, 134.4 (2 × C), 145.9, 148.1, 152.1, 194.3.
IR (KBr): 3275, 2938, 2410, 1695, 1608, 1563, 1412, 1348, 1243.

1g: 表３−１、No. 7 (74 % yield) ; 淡黄結晶 ; mp 189.8 ℃.
Rf = 0.42.
¹H (400 MHz, DMSO) : 2.07 (s, 3H, CH₃), 2.28 (s, 3H, CH₃), 5.23 (d, 1H, J =3.17 Hz, CH), 7.20-7.36 (m, 2H, Ph), 7.62-7.74 (m, 2H, Ph), 7.79 (br s, 1H, NH), 8.25 (br s, 2H, B(OH)₂), 9.16 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 16.5, 55.2, 107.3, 119.7, 123.4, 125.4, 128.6, 134.4, 135.3, 139.0, 144.7, 165.0, 194.8.

1g: Table 3-1, No. 7 (74% yield); pale yellow crystal; mp 189.8 ° C.
Rf = 0.42.
¹ H (400 MHz, DMSO): 2.07 (s, 3H, CH ₃ ), 2.28 (s, 3H, CH ₃ ), 5.23 (d, 1H, J = 3.17 Hz, CH), 7.20-7.36 (m, 2H , Ph), 7.62-7.74 (m, 2H, Ph), 7.79 (br s, 1H, NH), 8.25 (br s, 2H, B (OH) ₂ ), 9.16 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 16.5, 55.2, 107.3, 119.7, 123.4, 125.4, 128.6, 134.4, 135.3, 139.0, 144.7, 165.0, 194.8.

1h: 表３−１、No. 8 (51 % yield) ; 黄色結晶 ; mp 199.8 ℃.
Rf = 0.45.
¹H (400 MHz, DMSO) : 2.01 (s, 3H, CH₃), 2.31 (s, 3H, CH₃), 5.53 (d, 1H, J =2.44 Hz, CH), 7.12 (br s, 1H, NH), 7.18 (d, 1H, J =7.80 Hz, Ph), 7.23 (t, 1H, J =7.32 Hz, Ph), 7.34 (t, 1H, J =7.56 Hz, Ph), 7.51 (d, 1H, J=7.32 Hz), 8.40 (br s, 2H, B(OH)₂), 9.23 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 18.9, 30.2, 54.3, 109.3, 125.7, 126.6, 129.9, 132.6, 133.8, 147.5, 148.3, 151.3, 194.8.

1h: Table 3-1, No. 8 (51% yield); yellow crystals; mp 199.8 ° C.
Rf = 0.45.
¹ H (400 MHz, DMSO): 2.01 (s, 3H, CH ₃ ), 2.31 (s, 3H, CH ₃ ), 5.53 (d, 1H, J = 2.44 Hz, CH), 7.12 (br s, 1H, NH), 7.18 (d, 1H, J = 7.80 Hz, Ph), 7.23 (t, 1H, J = 7.32 Hz, Ph), 7.34 (t, 1H, J = 7.56 Hz, Ph), 7.51 (d, 1H , J = 7.32 Hz), 8.40 (br s, 2H, B (OH) ₂ ), 9.23 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 18.9, 30.2, 54.3, 109.3, 125.7, 126.6, 129.9, 132.6, 133.8, 147.5, 148.3, 151.3, 194.8.

1i: 表３−１、No. 9 (53 % yield) ; 白色結晶 ; mp 214.3 ℃.
Rf = 0.27.
¹H (400 MHz, DMSO) : 2.02 (s, 3H, CH₃), 5.40 (d, 1H, J =2,20 Hz, CH), 6.98 (t, 1H, J =7.32 Hz, Ph), 7.16-7.28 (m, 4H, NH Ph), 7.46-7.60 (m, 3H, NH Ph), 7.71 (d, 2H, J =7.81 Hz, Ph), 7.97 (br s, 2H, B(OH)₂), 8.68 (br, s, 1H, NH), 9.54 (br, s, 1H, NH).
¹³C (136MHz, DMSO) : 17.0, 55.1, 105.4, 119.6, 123.1 (2×C), 125.2 (2×C), 128.5 (2×C), 131.7, 134.3 (2×C), 138.2, 139.2, 146.0, 152.6, 165.3.
IR (KBr) : 3306, 3141, 2926, 2361, 1695, 1631, 1372, 1329, 1247, 1112.

1i: Table 3-1, No. 9 (53% yield); white crystals; mp 214.3 ° C.
Rf = 0.27.
¹ H (400 MHz, DMSO): 2.02 (s, 3H, CH ₃ ), 5.40 (d, 1H, J = 2,20 Hz, CH), 6.98 (t, 1H, J = 7.32 Hz, Ph), 7.16 -7.28 (m, 4H, NH Ph), 7.46-7.60 (m, 3H, NH Ph), 7.71 (d, 2H, J = 7.81 Hz, Ph), 7.97 (br s, 2H, B (OH) ₂ ) , 8.68 (br, s, 1H, NH), 9.54 (br, s, 1H, NH).
¹³ C (136MHz, DMSO): 17.0, 55.1, 105.4, 119.6, 123.1 (2 × C), 125.2 (2 × C), 128.5 (2 × C), 131.7, 134.3 (2 × C), 138.2, 139.2, 146.0, 152.6, 165.3.
IR (KBr): 3306, 3141, 2926, 2361, 1695, 1631, 1372, 1329, 1247, 1112.

1j: 表３−１、No. 10 (70 % yield) ; 白色結晶 ; mp 216.6 ℃.
RF = 0.37.
¹H (400 MHz, DMSO) : 2.03 (s, 3H, CH₃), 5.39 (s, 1H, CH), 6.98 (t, 1H, J =7.07 Hz, Ph), 7.10-7.40 (m, 4H, Ph), 7.42-7.60 (m, 3H, Ph), 7.66 (d, 1H, J =6.34 Hz, Ph), 7.73 (br s, 1H, NH), 7.98 (br s, 2H, B(OH)₂), 8.67 (br s, 1H, NH), 9.50 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 17.1, 55.6, 105.6, 119.7 (2×C), 123.1, 127.4, 128.2 (2×C), 128.5, 132.4, 133.2, 134.8, 138.0, 139.2, 143.3, 152.5, 165.4.
Compound analysis data (2): Dihydroxyboryl group-containing dihydropyrimidin-2-one (or thione) derivative (2)

1j: Table 3-1, No. 10 (70% yield); white crystals; mp 216.6 ° C.
RF = 0.37.
¹ H (400 MHz, DMSO): 2.03 (s, 3H, CH ₃ ), 5.39 (s, 1H, CH), 6.98 (t, 1H, J = 7.07 Hz, Ph), 7.10-7.40 (m, 4H, Ph), 7.42-7.60 (m, 3H, Ph), 7.66 (d, 1H, J = 6.34 Hz, Ph), 7.73 (br s, 1H, NH), 7.98 (br s, 2H, B (OH) ₂ ), 8.67 (br s, 1H, NH), 9.50 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 17.1, 55.6, 105.6, 119.7 (2 × C), 123.1, 127.4, 128.2 (2 × C), 128.5, 132.4, 133.2, 134.8, 138.0, 139.2, 143.3, 152.5, 165.4.

1k: 表３−２、No. 11 (18 % yield) ; 白色結晶 ; mp165.5 ℃.
Rf = 0.43.
¹H (400 MHz, DMSO) : 2.12 (s, 3H, CH₃), 5.53 (d, 1H, J =2.44 Hz, CH), 6.90-7.02 (m, 2H, NH Ph), 7.10-7.30 (m, 4H, Ph), 7.37 (t, 1H, J =6.82 Hz, Ph), 7.46 (d, 3H, J=8.29 Hz, Ph and NH), 8.43 (br s, 2H, B(OH)₂), 8.77 (br s, 1H, NH), 9.47 (br , 1H, NH).
¹³C (136MHz, DMSO) : 17.4, 54.7, 105.0, 120.0 (2×C), 123.1, 126.5, 126.7, 128.4 (2×C), 128.5, 129.7, 133.7, 138.9, 139.5, 147.3, 151.6, 165.5.

1k: Table 3-2, No. 11 (18% yield); white crystals; mp165.5 ° C.
Rf = 0.43.
¹ H (400 MHz, DMSO): 2.12 (s, 3H, CH ₃ ), 5.53 (d, 1H, J = 2.44 Hz, CH), 6.90-7.02 (m, 2H, NH Ph), 7.10-7.30 (m , 4H, Ph), 7.37 (t, 1H, J = 6.82 Hz, Ph), 7.46 (d, 3H, J = 8.29 Hz, Ph and NH), 8.43 (br s, 2H, B (OH) ₂ ), 8.77 (br s, 1H, NH), 9.47 (br, 1H, NH).
¹³ C (136MHz, DMSO): 17.4, 54.7, 105.0, 120.0 (2 × C), 123.1, 126.5, 126.7, 128.4 (2 × C), 128.5, 129.7, 133.7, 138.9, 139.5, 147.3, 151.6, 165.5.

1l: 表３−２、No. 12 (24 % yield) ; 橙色結晶 ; mp 193.7 ℃.
Rf = 0.46.
¹H (400 MHz, DMSO) : 1.97 (s, 3H, CH₃), 5.30 (d, 1H, J =2.93 Hz, CH), 7.15 (d, 2H, J =8.05 Hz, Ph), 7.36-7.54 (m, 5H, Ph), 7.69 (d, 2H, J =8.05 Hz), 7.77 (br s, 1H, NH), 7.99 (br s, 2H, B(OH)₂), 9.14 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 18.5, 55.3, 109.5, 125.2 (2×C), 127.8(2×C), 128.6 (2×C), 130.3, 131.5, 134.3 (2×C), 141.0, 145.2, 146.0, 152.3, 194.4.
IR (KBr) : 3275, 2938, 2410, 1695, 1608, 1563, 1412, 1348, 1243.

1l: Table 3-2, No. 12 (24% yield); orange crystals; mp 193.7 ° C.
Rf = 0.46.
¹ H (400 MHz, DMSO): 1.97 (s, 3H, CH ₃ ), 5.30 (d, 1H, J = 2.93 Hz, CH), 7.15 (d, 2H, J = 8.05 Hz, Ph), 7.36-7.54 (m, 5H, Ph), 7.69 (d, 2H, J = 8.05 Hz), 7.77 (br s, 1H, NH), 7.99 (br s, 2H, B (OH) ₂ ), 9.14 (br s, 1H , NH).
¹³ C (136MHz, DMSO): 18.5, 55.3, 109.5, 125.2 (2 × C), 127.8 (2 × C), 128.6 (2 × C), 130.3, 131.5, 134.3 (2 × C), 141.0, 145.2, 146.0, 152.3, 194.4.
IR (KBr): 3275, 2938, 2410, 1695, 1608, 1563, 1412, 1348, 1243.

1m: 表３−２、No. 13 (19 % yield) ; 橙色結晶 ; mp 187.1 ℃.
Rf = 0.46.
¹H (400 MHz, DMSO) : 1.65 (s, 3H, CH₃), 5.30 (d, 1H, J =2.93 Hz, CH), 7.18-7.29 (m, 2H, Ph), 7.36-7.54 (m, 5H, Ph), 7.60-7.68 (m, 2H, Ph), 7.73 (br s, 1H, NH), 8.02 (br s, 2H B(OH)₂), 9.11 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 18.5, 55.7, 109.6, 127.5, 127.8 (2×C), 128.2 , 128.6 (2×C), 131.51,
132.3, 133.2, 134,6, 141.1, 143.2, 144.8, 152.1, 194.4.

1m: Table 3-2, No. 13 (19% yield); orange crystals; mp 187.1 ° C.
Rf = 0.46.
¹ H (400 MHz, DMSO): 1.65 (s, 3H, CH ₃ ), 5.30 (d, 1H, J = 2.93 Hz, CH), 7.18-7.29 (m, 2H, Ph), 7.36-7.54 (m, 5H, Ph), 7.60-7.68 (m, 2H, Ph), 7.73 (br s, 1H, NH), 8.02 (br s, 2H B (OH) ₂ ), 9.11 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 18.5, 55.7, 109.6, 127.5, 127.8 (2 × C), 128.2, 128.6 (2 × C), 131.51,
132.3, 133.2, 134,6, 141.1, 143.2, 144.8, 152.1, 194.4.

1n: 表３−２、No. 14 (64 % yield) ; 白色結晶 ; mp 214.4 ℃.
Rf = 0.24.
¹H (400 MHz, DMSO) : 1.98 (s, 3H, CH₃), 2.50 (s, 3H, CH₃), 5.19 (s, 1H, CH), 7.13-7.30 (m, 2H, Ph), 7.34-7.48 (m, 2H, NH and Ph), 7.59-7.70 (m, 2H, NH and Ph), 7.96 (br s, 2H, B(OH)₂), 8.47 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 16.4, 25.8, 55.2, 105.1, 127.3, 128.2, 132.4, 133.0, 137.0, 140.7, 143.2, 152.7, 166.8.

1n: Table 3-2, No. 14 (64% yield); white crystals; mp 214.4 ° C.
Rf = 0.24.
¹ H (400 MHz, DMSO): 1.98 (s, 3H, CH ₃ ), 2.50 (s, 3H, CH ₃ ), 5.19 (s, 1H, CH), 7.13-7.30 (m, 2H, Ph), 7.34 -7.48 (m, 2H, NH and Ph), 7.59-7.70 (m, 2H, NH and Ph), 7.96 (br s, 2H, B (OH) ₂ ), 8.47 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 16.4, 25.8, 55.2, 105.1, 127.3, 128.2, 132.4, 133.0, 137.0, 140.7, 143.2, 152.7, 166.8.

1o: 表３−２、No. 15 (11 % yield) ; 白色結晶 ; mp 205.1 ℃.
Rf = 0.45.
¹H (400 MHz, DMSO) : 0.88 (s, 3H, CH₃), 0.99 (t, 6H, J =7.32 Hz, CH₃), 1.30 (s, 3H, CH₃), 2.58 (quintet, 1H, J =6.83 Hz, CH), 4.23 (s, 1H, CH), 5.39 (s, 1H, CH), 7.13 (d, 2H, J =7.56 Hz, Ph), 7.72 (d, 2H, J=7.32 Hz, Ph), 7.98 (br s, 1H, NH), 8.03 (br s, 2H, B(OH)₂), 11.25 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 18.7, 18.9, 22.1, 27.5, 36.8, 50.2, 61.6, 94.0, 126.7 (2×C), 133.9 (2×C), 134.5, 141.1, 150.9, 161.3, 205.6.
IR (KBr) : 3345 ; 2971, 2993, 2360, 1688, 1650, 1587, 1455, 1373, 1261.

1o: Table 3-2, No. 15 (11% yield); white crystals; mp 205.1 ° C.
Rf = 0.45.
¹ H (400 MHz, DMSO): 0.88 (s, 3H, CH ₃ ), 0.99 (t, 6H, J = 7.32 Hz, CH ₃ ), 1.30 (s, 3H, CH ₃ ), 2.58 (quintet, 1H, J = 6.83 Hz, CH), 4.23 (s, 1H, CH), 5.39 (s, 1H, CH), 7.13 (d, 2H, J = 7.56 Hz, Ph), 7.72 (d, 2H, J = 7.32 Hz , Ph), 7.98 (br s, 1H, NH), 8.03 (br s, 2H, B (OH) ₂ ), 11.25 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 18.7, 18.9, 22.1, 27.5, 36.8, 50.2, 61.6, 94.0, 126.7 (2 × C), 133.9 (2 × C), 134.5, 141.1, 150.9, 161.3, 205.6.
IR (KBr): 3345; 2971, 2993, 2360, 1688, 1650, 1587, 1455, 1373, 1261.

1r: 表３−２、No. 18 (19 % yield) ; 白色結晶 ; mp 186,5 ℃.
Rf = 0.46.
¹H (400 MHz, DMSO) : 1.09 (t, 3H, J =7.07 Hz, CH₂ CH ₃ ), 2.28 (s, 3H, CH₃), 4.00 (q, 2H, J =7.07 Hz, CH ₂ CH₃), 5.10-5.22 (m, 1H, CH), 7.16 (d, 2H, J =8.05 Hz, Ph), 7.72 (d, 2H, J =8.05 Hz, Ph), 8.05 (br s, 2H, B(OH)₂), 9.61 (br s, 1H, NH), 10.29 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 14.0, 17.2, 53.2, 59.6, 100.7, 125.4 (2×C), 134.3 (2×C), 136.9, 145.0, 145.1, 165.1, 174.3.

1r: Table 3-2, No. 18 (19% yield); white crystals; mp 186,5 ° C.
Rf = 0.46.
¹ H (400 MHz, DMSO): 1.09 (t, 3H, J = 7.07 Hz, CH ₂ CH ₃ ), 2.28 (s, 3H, CH ₃ ), 4.00 (q, 2H, J = 7.07 Hz, CH ₂ CH ₃ ), 5.10-5.22 (m, 1H, CH), 7.16 (d, 2H, J = 8.05 Hz, Ph), 7.72 (d, 2H, J = 8.05 Hz, Ph), 8.05 (br s, 2H, B (OH) ₂ ), 9.61 (br s, 1H, NH), 10.29 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 14.0, 17.2, 53.2, 59.6, 100.7, 125.4 (2 × C), 134.3 (2 × C), 136.9, 145.0, 145.1, 165.1, 174.3.

1s: 表３−３、No. 19 (13 % yield) ; 白色結晶 ; mp 170.3 ℃.
Rf = 0.72 （クロロホルム：メタノール＝４：１）.
¹H (400 MHz, DMSO) : 1.16 (t, 3H, J =7.07 Hz, CH₂ CH ₃ ), 2.36 (s, 3H, CH₃), 4.05 (q, 2H, J =6.83 Hz, CH ₂ CH₃), 5.19-5.26 (m, 1H, CH), 7.30 (d, 1H, J =7.56 Hz, Ph), 7.37 (t, 1H, J =7.32 Hz, Ph), 7.73 (br s, 1H, NH) 7.60 (d, 1H, J =7.07 Hz, Ph), 8.15 (br s, 2H, B(OH)₂), 9.67 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 14.1, 17.3, 54.6, 59.7, 100.9, 127.8, 128.5, 132.6, 133.6, 134.6, 142.6, 145.0, 165.3, 174.1.
IR (KBr) ; 3280, 2981, 2929, 2360, 1693, 1653, 1568, 1433, 1370, 1337, 1185.
Compound analysis data (3): Dihydroxyboryl group-containing dihydropyrimidin-2-one (or thione) derivative (3)

1s: Table 3-3, No. 19 (13% yield); white crystals; mp 170.3 ° C.
Rf = 0.72 (chloroform: methanol = 4: 1).
¹ H (400 MHz, DMSO): 1.16 (t, 3H, J = 7.07 Hz, CH ₂ CH ₃ ), 2.36 (s, 3H, CH ₃ ), 4.05 (q, 2H, J = 6.83 Hz, CH ₂ CH ₃ ), 5.19-5.26 (m, 1H, CH), 7.30 (d, 1H, J = 7.56 Hz, Ph), 7.37 (t, 1H, J = 7.32 Hz, Ph), 7.73 (br s, 1H, NH ) 7.60 (d, 1H, J = 7.07 Hz, Ph), 8.15 (br s, 2H, B (OH) ₂ ), 9.67 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 14.1, 17.3, 54.6, 59.7, 100.9, 127.8, 128.5, 132.6, 133.6, 134.6, 142.6, 145.0, 165.3, 174.1.
IR (KBr); 3280, 2981, 2929, 2360, 1693, 1653, 1568, 1433, 1370, 1337, 1185.

1t: 表３−３、No. 20 (2 % yield) ; 白色結晶 ; mp 181.1 ℃.
Rf = 0.65.
¹H (400 MHz, DMSO) : 1.00 (t, 3H, J =7.07 Hz, CH₂ CH ₃ ), 2.30 (s, 3H, CH₃), 3.80-4.25 (m, 2H, CH ₂ CH₃), 5.48 (s, 1H, CH), 7.18 (d, 1H, J =7.81 Hz, Ph), 7.23 (t, 1H, J =7.31 Hz, Ph), 7.36 (t, 1H, J =7.32 Hz, Ph), 7.47 (d, 1H, J =7.32 Hz, Ph), 8.32 (br s, 2H, B(OH)₂), 8.94 (br s, 1H, NH), 10.28 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 14.2, 17.3, 54.2, 59.8, 101.5, 126.3, 127.1, 130.1, 133.7, 135.0, 144.9, 147.1, 165.4, 173.6.

1t: Table 3-3, No. 20 (2% yield); white crystals; mp 181.1 ° C.
Rf = 0.65.
¹ H (400 MHz, DMSO): 1.00 (t, 3H, J = 7.07 Hz, CH ₂ CH ₃ ), 2.30 (s, 3H, CH ₃ ), 3.80-4.25 (m, 2H, CH ₂ CH ₃ ), 5.48 (s, 1H, CH), 7.18 (d, 1H, J = 7.81 Hz, Ph), 7.23 (t, 1H, J = 7.31 Hz, Ph), 7.36 (t, 1H, J = 7.32 Hz, Ph) , 7.47 (d, 1H, J = 7.32 Hz, Ph), 8.32 (br s, 2H, B (OH) ₂ ), 8.94 (br s, 1H, NH), 10.28 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 14.2, 17.3, 54.2, 59.8, 101.5, 126.3, 127.1, 130.1, 133.7, 135.0, 144.9, 147.1, 165.4, 173.6.

1u: 表３−３、No. 21 (22 % yield) ; 白色結晶 ; mp 181.7 ℃.
Rf = 0.56.
¹H (400 MHz, DMSO) : 2.28 (s, 3H, CH₃), 3.54 (s, 3H, CH₃), 5.59 (d, 1H, J =3.42 Hz, CH), 7.16 (d, 2H, J =7.32 Hz, Ph), 7.72 (d, 2H, J =7.32 Hz, Ph), 8.02 (br s, 2H, B(OH)₂), 9.65 (br s, 1H, NH), 10.33 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 17.2, 51.1, 100.4, 100.6, 125.4 (2×C), 134.4 (2×C) , 134.5, 144.9, 145.3, 165.1, 174.3.
IR (KBr) : 3323, 3008, 2952, 2360, 1696, 1670, 1570, 1433, 1342, 1180, 1115.

1u: Table 3-3, No. 21 (22% yield); white crystals; mp 181.7 ° C.
Rf = 0.56.
¹ H (400 MHz, DMSO): 2.28 (s, 3H, CH ₃ ), 3.54 (s, 3H, CH ₃ ), 5.59 (d, 1H, J = 3.42 Hz, CH), 7.16 (d, 2H, J = 7.32 Hz, Ph), 7.72 (d, 2H, J = 7.32 Hz, Ph), 8.02 (br s, 2H, B (OH) ₂ ), 9.65 (br s, 1H, NH), 10.33 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 17.2, 51.1, 100.4, 100.6, 125.4 (2 × C), 134.4 (2 × C), 134.5, 144.9, 145.3, 165.1, 174.3.
IR (KBr): 3323, 3008, 2952, 2360, 1696, 1670, 1570, 1433, 1342, 1180, 1115.

1v: 表３−３、No. 22 (25 % yield) ; 白色結晶 ; mp 197.8 ℃.
Rf = 0.52.
¹H (400 MHz, DMSO) : 2.30 (s, 3H, CH₃), 3.52 (s, 3H, CH₃), 5.15 (d, 1H, J =3.66 Hz, CH), 7.23 (d, 1H, J =7.81 Hz, Ph), 7.30 (t, 1H, J =7.32 Hz, Ph), 7.64 (br s, 1H, NH), 7.69 (d, 1H, J =7.32 Hz, Ph), 8.05 (br s, 2H, B(OH)₂), 9.63 (br s, 1H, NH), 10.30 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 17.3, 51.1, 54.3, 100.3, 127.6, 128.3, 132.3, 133.6, 134.6, 145.3, 165.7, 174.0.

1v: Table 3-3, No. 22 (25% yield); white crystals; mp 197.8 ° C.
Rf = 0.52.
¹ H (400 MHz, DMSO): 2.30 (s, 3H, CH ₃ ), 3.52 (s, 3H, CH ₃ ), 5.15 (d, 1H, J = 3.66 Hz, CH), 7.23 (d, 1H, J = 7.81 Hz, Ph), 7.30 (t, 1H, J = 7.32 Hz, Ph), 7.64 (br s, 1H, NH), 7.69 (d, 1H, J = 7.32 Hz, Ph), 8.05 (br s, 2H, B (OH) ₂ ), 9.63 (br s, 1H, NH), 10.30 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 17.3, 51.1, 54.3, 100.3, 127.6, 128.3, 132.3, 133.6, 134.6, 145.3, 165.7, 174.0.

1w: 表３−３、No. 23 (22 % yield) ; 白色結晶 ; mp 196.4 ℃.
Rf = 0.52.
¹H (400 MHz, DMSO) : 2.30 (s, 3H, CH₃), 3.45 (s, 3H, OCH₃), 5.44 (s, 1H, CH), 7.20 (d , 1H, J =7.81 Hz, Ph), 7.24 (t, 1H, J =7.32, Ph), 7.37 (t, 1H, J =7.32 Hz, Ph), 7.43 (d, 1H, J =7.32 Hz), 8.25 (br s, 2H, B(OH)₂), 9.00 (br s, 1H, NH), 10.36 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 17.0, 51.0, 54.0, 101.1, 126.2, 126.8, 129.8, 133.0, 135.4, 144.8, 147.0, 165.5, 173.5.

1w: Table 3-3, No. 23 (22% yield); white crystals; mp 196.4 ° C.
Rf = 0.52.
¹ H (400 MHz, DMSO): 2.30 (s, 3H, CH ₃ ), 3.45 (s, 3H, OCH ₃ ), 5.44 (s, 1H, CH), 7.20 (d, 1H, J = 7.81 Hz, Ph ), 7.24 (t, 1H, J = 7.32, Ph), 7.37 (t, 1H, J = 7.32 Hz, Ph), 7.43 (d, 1H, J = 7.32 Hz), 8.25 (br s, 2H, B ( OH) ₂ ), 9.00 (br s, 1H, NH), 10.36 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 17.0, 51.0, 54.0, 101.1, 126.2, 126.8, 129.8, 133.0, 135.4, 144.8, 147.0, 165.5, 173.5.

1x: 表３−３、No. 24 (38 % yield) ; 黄色結晶 ; mp 212.6 ℃.
Rf = 0.49.
¹H (400 MHz, DMSO) : 2.14 (s, 3H, CH₃), 2.32 (s, 3H, CH₃), 5.28 (d, 1H, J =3.66 Hz, CH), 7.14 (d, 2H, J =7.81 Hz, Ph), 7.72 (d, 2H, J =7.56 Hz, Ph), 8.03 (br s, 2H, B(OH)₂), 9.71 (br s, 1H, NH), 10.24 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 18.3, 30.5, 53.9, 110.5, 125.7 (2×C), 126.6, 128.7, 134.5 (2×C), 144.6, 174.2, 195.0.
IR (KBr) : 3377, 2929, 2360, 1609, 1569, 1412, 1362, 1180.

1x: Table 3-3, No. 24 (38% yield); yellow crystals; mp 212.6 ° C.
Rf = 0.49.
¹ H (400 MHz, DMSO): 2.14 (s, 3H, CH ₃ ), 2.32 (s, 3H, CH ₃ ), 5.28 (d, 1H, J = 3.66 Hz, CH), 7.14 (d, 2H, J = 7.81 Hz, Ph), 7.72 (d, 2H, J = 7.56 Hz, Ph), 8.03 (br s, 2H, B (OH) ₂ ), 9.71 (br s, 1H, NH), 10.24 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 18.3, 30.5, 53.9, 110.5, 125.7 (2 × C), 126.6, 128.7, 134.5 (2 × C), 144.6, 174.2, 195.0.
IR (KBr): 3377, 2929, 2360, 1609, 1569, 1412, 1362, 1180.

1y: 表３−４、No. 25 (44 % yield) ; 黄色結晶 ; mp 188.7 ℃.
Rf = 0.64.
¹H (400 MHz, DMSO) : 2.11 (s, 3H, CH₃), 2.33 (s, 3H, CH₃), 5.26 (d, 1H, J =3.66 Hz, CH), 7.24-7.38 (m, 2H, Ph), 7.65 (br s, 1H, NH), 7.69 (d, 1H, J =7.32 Hz, Ph), 8.05 (br s, 2H, B(OH)₂), 9.71 (br s, 1H, NH), 10.22 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 18.2, 30.3, 54.3, 110.2, 127.7, 128.5, 131.1, 132.6, 133.5, 141.8, 144.4, 173.8, 194.8.
Compound analysis data (4): dihydroxyboryl group-containing dihydropyrimidin-2-one (or thione) derivative (4)

1y: Table 3-4, No. 25 (44% yield); yellow crystals; mp 188.7 ° C.
Rf = 0.64.
¹ H (400 MHz, DMSO): 2.11 (s, 3H, CH ₃ ), 2.33 (s, 3H, CH ₃ ), 5.26 (d, 1H, J = 3.66 Hz, CH), 7.24-7.38 (m, 2H , Ph), 7.65 (br s, 1H, NH), 7.69 (d, 1H, J = 7.32 Hz, Ph), 8.05 (br s, 2H, B (OH) ₂ ), 9.71 (br s, 1H, NH ), 10.22 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 18.2, 30.3, 54.3, 110.2, 127.7, 128.5, 131.1, 132.6, 133.5, 141.8, 144.4, 173.8, 194.8.

1z: 表３−４、No. 26 (21 % yield) ; 黄色結晶 ; mp 186.6 ℃.
Rf = 0.68.
¹H (400 MHz, DMSO) : 2.05 (s, 3H, CH₃), 2.34 (s, 3H, CH₃), 5.58 (d, 1H, J =3.17 Hz, CH), 7.15 (d, 1H, J =7.80 Hz, Ph), 7.25 (dt, 1H, J =0.98, 7.32 Hz, Ph), 7.37 (dt, 1H, J=1.46 , 7.56 Hz, Ph), 7.53 (dd, 1H, J=1.46, 7.32 Hz, Ph), 8.46 (br, s, 2H, B(OH)₂), 9.03 (br s, 1H, NH), 10.29 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 18.7, 30.4, 54.5, 102.3, 126.2, 126.9, 133.0, 133.5, 144.8, 147.0, 173.5, 194.6.

1z: Table 3-4, No. 26 (21% yield); yellow crystals; mp 186.6 ° C.
Rf = 0.68.
¹ H (400 MHz, DMSO): 2.05 (s, 3H, CH ₃ ), 2.34 (s, 3H, CH ₃ ), 5.58 (d, 1H, J = 3.17 Hz, CH), 7.15 (d, 1H, J = 7.80 Hz, Ph), 7.25 (dt, 1H, J = 0.98, 7.32 Hz, Ph), 7.37 (dt, 1H, J = 1.46, 7.56 Hz, Ph), 7.53 (dd, 1H, J = 1.46, 7.32 Hz, Ph), 8.46 (br, s, 2H, B (OH) ₂ ), 9.03 (br s, 1H, NH), 10.29 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 18.7, 30.4, 54.5, 102.3, 126.2, 126.9, 133.0, 133.5, 144.8, 147.0, 173.5, 194.6.

1aa: 表３−４、No. 27 (29 % yield) ; 薄緑結晶 ; mp 213.8 ℃.
Rf = 0.41.
¹H (400 MHz, DMSO) : 2.05 (s, 3H, CH₃), 5.39 (d, 1H, J =1.95 Hz), 7.01 (t, 1H, J =7.31 Hz, Ph), 7.12-7.30 (m, 4H, Ph), 7.53 (d, 2H, J =7.80 Hz, Ph), 7.73 (d, 2H, J =7.80 Hz, Ph), 8.04 (br s, 2H, B(OH)₂), 9.43 (br s, 1H, NH), 9.74 (br s, 1H, NH), 9.99 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 16.5, 55.2, 107.3, 119.7 (2×C), 123.4, 125.4 (2×C), 128.6 (2×C), 133.6, 134.4 (2×C), 135.3, 139.0, 144.7, 165.0, 174.2.

1aa: Table 3-4, No. 27 (29% yield); light green crystal; mp 213.8 ° C.
Rf = 0.41.
¹ H (400 MHz, DMSO): 2.05 (s, 3H, CH ₃ ), 5.39 (d, 1H, J = 1.95 Hz), 7.01 (t, 1H, J = 7.31 Hz, Ph), 7.12-7.30 (m , 4H, Ph), 7.53 (d, 2H, J = 7.80 Hz, Ph), 7.73 (d, 2H, J = 7.80 Hz, Ph), 8.04 (br s, 2H, B (OH) ₂ ), 9.43 ( br s, 1H, NH), 9.74 (br s, 1H, NH), 9.99 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 16.5, 55.2, 107.3, 119.7 (2 × C), 123.4, 125.4 (2 × C), 128.6 (2 × C), 133.6, 134.4 (2 × C), 135.3, 139.0, 144.7, 165.0, 174.2.

1bb: 表３−４、No. 28 (36 % yield) ; 薄緑結晶 ; mp 216.8 ℃.
Rf = 0.51.
¹H (400 MHz, DMSO) : 2.06 (s, 3H, CH₃), 5.38 (d, 1H, J =3.62 Hz, CH), 7.00 (t, 1H, J =7.31 Hz, Ph), 7.12-7.40 (m, 4H, Ph), 7.51 (d, 1H, J =7.80 Hz, Ph), 7.60-7.80 (m, 2H, Ph), 8.00 (br s, 2H, B(OH)₂), 9.38 (br s, 1H, NH), 9.68 (br s, 1H, NH), 9.93 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 16.4, 55.6, 107.3, 119.7 (2×C), 123.3, 127.6, 128.3 (2×C), 128.5, 132.6, 133.4, 134.5, 135.2, 138.9, 142.0, 165.0, 173.9.

1bb: Table 3-4, No. 28 (36% yield); light green crystal; mp 216.8 ° C.
Rf = 0.51.
¹ H (400 MHz, DMSO): 2.06 (s, 3H, CH ₃ ), 5.38 (d, 1H, J = 3.62 Hz, CH), 7.00 (t, 1H, J = 7.31 Hz, Ph), 7.12-7.40 (m, 4H, Ph), 7.51 (d, 1H, J = 7.80 Hz, Ph), 7.60-7.80 (m, 2H, Ph), 8.00 (br s, 2H, B (OH) ₂ ), 9.38 (br s, 1H, NH), 9.68 (br s, 1H, NH), 9.93 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 16.4, 55.6, 107.3, 119.7 (2 × C), 123.3, 127.6, 128.3 (2 × C), 128.5, 132.6, 133.4, 134.5, 135.2, 138.9, 142.0, 165.0, 173.9.

1cc: 表３−４、No. 29 (20 % yield) ; 薄緑結晶 ; mp 217.6 ℃.
Rf = 0.50.
¹H (400 MHz, DMSO) : 2.14 (s, 3H, CH₃), 5.71 (br s, 1H, CH), 6.98 (t, 1H, J =7.31 Hz, Ph), 7.15-7.29 (m, 4H, Ph), 7.42 (d, 1H, J =3.90Hz, Ph), 7.44-7.53 (m, 4H, Ph), 8.49 (br s, 2H, B(OH)₂), 8.81 (br s, 1H, NH), 9.65 (br s, 1H, NH), 10.04(br s, 1H, NH).
¹³C (136MHz, DMSO) : 16.8, 54.8, 106.9, 119.6, 119.8 (2×C),123.4, 127.0, 128.6 (2×C), 130.0, 133.9, 135.1, 136.3, 138.8, 146.1, 165.0, 172.9.

1cc: Table 3-4, No. 29 (20% yield); light green crystal; mp 217.6 ° C.
Rf = 0.50.
¹ H (400 MHz, DMSO): 2.14 (s, 3H, CH ₃ ), 5.71 (br s, 1H, CH), 6.98 (t, 1H, J = 7.31 Hz, Ph), 7.15-7.29 (m, 4H , Ph), 7.42 (d, 1H, J = 3.90Hz, Ph), 7.44-7.53 (m, 4H, Ph), 8.49 (br s, 2H, B (OH) ₂ ), 8.81 (br s, 1H, NH), 9.65 (br s, 1H, NH), 10.04 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 16.8, 54.8, 106.9, 119.6, 119.8 (2 × C), 123.4, 127.0, 128.6 (2 × C), 130.0, 133.9, 135.1, 136.3, 138.8, 146.1, 165.0, 172.9.

に従って、ジヒドロキシボリル基含有１，４−ジヒドロピリジン誘導体７−１を以下の様にして合成した。
２５ｍｌの二口フラスコに、ホルミルフェニルホウ酸誘導体（４−１、４−２又は４−３；各１．１ｍｍｏｌ）、β-ケトエステル（０．９ｍｍｏｌ）、３−アミノクロトン酸メチル（１ｍｍｏｌ）、乾燥２−プロパノール（５ｍｌ）を加え、窒素気流下、２−プロパノール還流温度下で表４に示す各々の時間反応させた。
ＴＬＣにより反応の終了を確認した後、溶媒を濃縮して、蒸留水を加えて結晶を析出させた。結晶を炉別して、蒸留水及びエーテルで結晶を洗った。これを少量のメタノールに溶かし、シリカゲルカラム（溶出溶媒：ＣＨＣｌ_３：ＭｅＯＨ＝１９：１）により精製して乾燥させると結晶としてジヒドロキシボリル基含有１，４−ジヒドロピリジン誘導体７−１を得た。得られた生成物は、ＩＲ、ＮＭＲ、融点により化学構造を特定した。得られた結果を表４に示す。収率はホルミルフェニルホウ酸誘導体に対する単離収率（％）である。 Example 2
Reaction formula:

Thus, a 1,4-dihydropyridine derivative 7-1 containing a dihydroxyboryl group was synthesized as follows.
In a 25 ml two-necked flask, formylphenylboric acid derivative (4-1, 4-2 or 4-3; 1.1 mmol each), β-ketoester (0.9 mmol), methyl 3-aminocrotonate (1 mmol), Dry 2-propanol (5 ml) was added and allowed to react for each time shown in Table 4 under a nitrogen stream under 2-propanol reflux temperature.
After confirming the completion of the reaction by TLC, the solvent was concentrated, and distilled water was added to precipitate crystals. The crystals were separated by furnace and washed with distilled water and ether. This was dissolved in a small amount of methanol, purified by a silica gel column (elution solvent: CHCl ₃ : MeOH = 19: 1) and dried to obtain dihydroxyboryl group-containing 1,4-dihydropyridine derivative 7-1 as crystals. The resulting product was identified for its chemical structure by IR, NMR, and melting point. Table 4 shows the obtained results. The yield is the isolated yield (%) based on the formylphenylboric acid derivative.

7a: 表４、No. 1 (75 % yield) ; 白色結晶 ; mp 168.3 ℃.
Rf = 0.40.
¹H (400 MHz, DMSO) : 2.24 (s, 6H, CH₃), 3.52 (s, 6H, OCH₃), 4.86 (s, 1H, CH), 7.07 (d, 2H, J =8.05 Hz, Ph), 7.59 (d, 2H, J =8.05 Hz, Ph), 7.89 (br s, 2H, B(OH)₂), 8.85 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 18.2 (2×C), 38.6, 50.7 (2×C), 101.5, 126.1 (2×C), 133.9, 134.0 (2×C), 145.7 (2×C), 149.60 (2×C), 167.4 (2×C).
Compound analysis data: 1,4-dihydropyridine derivative containing dihydroxyboryl group

7a: Table 4, No. 1 (75% yield); white crystals; mp 168.3 ° C.
Rf = 0.40.
¹ H (400 MHz, DMSO): 2.24 (s, 6H, CH ₃ ), 3.52 (s, 6H, OCH ₃ ), 4.86 (s, 1H, CH), 7.07 (d, 2H, J = 8.05 Hz, Ph ), 7.59 (d, 2H, J = 8.05 Hz, Ph), 7.89 (br s, 2H, B (OH) ₂ ), 8.85 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 18.2 (2 × C), 38.6, 50.7 (2 × C), 101.5, 126.1 (2 × C), 133.9, 134.0 (2 × C), 145.7 (2 × C), 149.60 (2 × C), 167.4 (2 × C).

7b: 表４、No. 2 (69 % yield) ; 薄緑結晶 ; mp 175.4 ℃.
Rf = 0.40.
¹H (400 MHz, DMSO) : 1.11 and 1.12 (each t, total 3H, J =7.07 Hz, CH₂ CH ₃ ), 2.23 and 2.24 (each s, total 6H, CH₃),3.51 and 3.52 (each s, total 6H, OCH₃), 3.94-4.02 (m, 2H, CH ₂ CH₃), 4.81-4.89 (m, 1H, CH), 7.05-7.12 (m, 2H, Ph),7.59 (d, 2H, J =8.05 Hz, Ph), 7.89 (br, s, 2H, B(OH)₂), 8.81 and 8,86(each br s, total 1H, NH)
¹³C (136MHz, DMSO) : 14.3, 18.3, 18.3, 50.7, 50.7, 59.1, 101.5, 126.2, 126.4 (2×C), 133.9 (2×C), 134.0, 145.4, 145.8, 149.7, 167.0, 167.5.
IR (KBr) : 3322, 3106, 2981, 2950, 2567, 1705, 1662, 1492, 1368, 1218, 1119.

7b: Table 4, No. 2 (69% yield); light green crystal; mp 175.4 ° C.
Rf = 0.40.
¹ H (400 MHz, DMSO): 1.11 and 1.12 (each t, total 3H, J = 7.07 Hz, CH ₂ CH ₃ ), 2.23 and 2.24 (each s, total 6H, CH ₃ ), 3.51 and 3.52 (each s , total 6H, OCH ₃ ), 3.94-4.02 (m, 2H, CH ₂ CH ₃ ), 4.81-4.89 (m, 1H, CH), 7.05-7.12 (m, 2H, Ph), 7.59 (d, 2H, J = 8.05 Hz, Ph), 7.89 (br, s, 2H, B (OH) ₂ ), 8.81 and 8,86 (each br s, total 1H, NH)
¹³ C (136MHz, DMSO): 14.3, 18.3, 18.3, 50.7, 50.7, 59.1, 101.5, 126.2, 126.4 (2 × C), 133.9 (2 × C), 134.0, 145.4, 145.8, 149.7, 167.0, 167.5.
IR (KBr): 3322, 3106, 2981, 2950, 2567, 1705, 1662, 1492, 1368, 1218, 1119.

7c: 表４、No. 3(80 % yield) ; 白色結晶 ; mp 168.0 ℃.
Rf = 0.30.
¹H (400 MHz, DMSO) : 2.24 (s, 6H, CH₃), 3.52 (s, 6H, OCH₃), 4.87 (s, 1H, CH), 7.08-7.20 (m, 2H, Ph), 7.52 (t, 1H, J=3.90 Hz, Ph), 7.56 (s, 1H, Ph), 7.92 (br s, 2H, B(OH)₂), 8.84 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 18.3 (2×C), 38.6, 50.7 (2×C), 101.7, 127.0, 129.0, 131.8, 133.0, 133.8, 145.6 (2×C), 146.8 (2×C), 167.5 (2×C).

7c: Table 4, No. 3 (80% yield); white crystals; mp 168.0 ° C.
Rf = 0.30.
¹ H (400 MHz, DMSO): 2.24 (s, 6H, CH ₃ ), 3.52 (s, 6H, OCH ₃ ), 4.87 (s, 1H, CH), 7.08-7.20 (m, 2H, Ph), 7.52 (t, 1H, J = 3.90 Hz, Ph), 7.56 (s, 1H, Ph), 7.92 (br s, 2H, B (OH) ₂ ), 8.84 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 18.3 (2 × C), 38.6, 50.7 (2 × C), 101.7, 127.0, 129.0, 131.8, 133.0, 133.8, 145.6 (2 × C), 146.8 (2 × C), 167.5 (2 × C).

7d: 表４、No. 4 (53 % yield) ; 薄緑結晶 ; mp 180.4 ℃.
Rf = 0.35.
¹H (400 MHz, DMSO) : 0.89-1.20 (m, 3H, CH₂ CH ₃ ), 2.00-2.32 (m, 6H, CH₃), 3.50 and 3.52 (each s, total 3H, OMe), 3.73-4.20 (m, 2H, CH ₂ CH₃), 4.75-4.83 (m, 1H, CH), 7.14 (d, 2H, J =5.12 Hz, Ph), 7.52 (t, 1H, J=4.15 Hz, Ph), 7.57 (d, 1H, J=9.51 Hz, Ph), 7.80-8.02 (m, 2H, B(OH)₂), 8.70-8.90 (m, 1H, NH).
¹³C (136MHz, DMSO) : 14.2 (2×C), 18.3 (2×C), 50.6, 59.0, 101.6, 126.9, 129.2, 131.8, 133.0, 133.2, 133.3, 145.6 (2×C), 147.0, 167.0, 167.5.

7d: Table 4, No. 4 (53% yield); light green crystal; mp 180.4 ° C.
Rf = 0.35.
¹ H (400 MHz, DMSO): 0.89-1.20 (m, 3H, CH ₂ CH ₃ ), 2.00-2.32 (m, 6H, CH ₃ ), 3.50 and 3.52 (each s, total 3H, OMe), 3.73- 4.20 (m, 2H, CH ₂ CH ₃ ), 4.75-4.83 (m, 1H, CH), 7.14 (d, 2H, J = 5.12 Hz, Ph), 7.52 (t, 1H, J = 4.15 Hz, Ph) , 7.57 (d, 1H, J = 9.51 Hz, Ph), 7.80-8.02 (m, 2H, B (OH) ₂ ), 8.70-8.90 (m, 1H, NH).
¹³ C (136MHz, DMSO): 14.2 (2 × C), 18.3 (2 × C), 50.6, 59.0, 101.6, 126.9, 129.2, 131.8, 133.0, 133.2, 133.3, 145.6 (2 × C), 147.0, 167.0 , 167.5.

7e: 表４、No. 5 (30 % yield) ; 白色結晶 ; mp 186.2 ℃.
Rf = 0.31.
¹H (400 MHz, DMSO) : 2.24 (s, 6H, CH₃), 3.53 (s, 6H, CH₃), 5.00 (s, 1H, CH), 6.99-7.10 (m, 1H, Ph), 7.23 (d, 2H, J =3.90 Hz, Ph), 7.28 (d, 1H, J =7.32 Hz, Ph), 8.15 (br s, 2H, B(OH)₂), 8.89 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 18.6 (2×C), 38.1, 51.1 (2×C), 103.1, 125.2, 128.1, 129.6, 132.1, 134.8, 145.8 (2×C), 152.4 (2×C), 168.6 (2×C).
IR (KBr) : 3459, 3323, 1658, 1488, 1437, 1348, 1224, 1124.

7e: Table 4, No. 5 (30% yield); white crystals; mp 186.2 ° C.
Rf = 0.31.
¹ H (400 MHz, DMSO): 2.24 (s, 6H, CH ₃ ), 3.53 (s, 6H, CH ₃ ), 5.00 (s, 1H, CH), 6.99-7.10 (m, 1H, Ph), 7.23 (d, 2H, J = 3.90 Hz, Ph), 7.28 (d, 1H, J = 7.32 Hz, Ph), 8.15 (br s, 2H, B (OH) ₂ ), 8.89 (br s, 1H, NH) .
¹³ C (136MHz, DMSO): 18.6 (2 × C), 38.1, 51.1 (2 × C), 103.1, 125.2, 128.1, 129.6, 132.1, 134.8, 145.8 (2 × C), 152.4 (2 × C), 168.6 (2 × C).
IR (KBr): 3459, 3323, 1658, 1488, 1437, 1348, 1224, 1124.

7f: 表４、No. 6 (23 % yield) ; 薄緑結晶 ; mp 189.7 ℃.
Rf = 0.35.
¹H (400 MHz, DMSO) : 1.14 and 1.15 (each t, total 3H, J =7.07 Hz, CH₂CH₃), 2.23 and 2.25 and, 2.27 (each s, total 6H, CH₃), 3.51 and 3.53 (each s, total 3H, OCH₃), 3.96-4.06 (m, 2H, CH₂CH₃), 5.01 (s, 1H, CH), 6.96-7.10 (m, 1H, Ph), 7.15-7.35 (m, 3H, Ph), 8.10-8.26 (m, 2H, B(OH)₂), 8.82-8.94 (m, 1H, NH).
¹³C (136MHz, DMSO) : 14.1, 18.4, 18.6, 50.9, 51.1, 59.7, 103.1, 125.1, 128.1, 129.6, 132.2, 145.4, 145.5, 145.7, 152.5, 168.0, 168.2, 168.6.

7f: Table 4, No. 6 (23% yield); light green crystal; mp 189.7 ° C.
Rf = 0.35.
¹ H (400 MHz, DMSO): 1.14 and 1.15 (each t, total 3H, J = 7.07 Hz, CH ₂ CH ₃ ), 2.23 and 2.25 and, 2.27 (each s, total 6H, CH ₃ ), 3.51 and 3.53 (each s, total 3H, OCH ₃ ), 3.96-4.06 (m, 2H, CH ₂ CH ₃ ), 5.01 (s, 1H, CH), 6.96-7.10 (m, 1H, Ph), 7.15-7.35 (m , 3H, Ph), 8.10-8.26 (m, 2H, B (OH) ₂ ), 8.82-8.94 (m, 1H, NH).
¹³ C (136MHz, DMSO): 14.1, 18.4, 18.6, 50.9, 51.1, 59.7, 103.1, 125.1, 128.1, 129.6, 132.2, 145.4, 145.5, 145.7, 152.5, 168.0, 168.2, 168.6.

に従って、ジヒドロキシボリル基含有ジヒドロピラノ[２，３−ｃ]ピラゾール化合物１０ａを以下の様にして合成した。
２５ｍｌの二口フラスコに、４−ホルミルフェニルホウ酸誘導体（４−３；１ｍｍｏｌ、０．１４９ｇ）、９５％ヒドラジン (１.１ｍｍｏｌ、０．０５４ｍｌ）、アセト酢酸エチル (１．１ｍｍｏｌ、０．１４３ｇ)、マロノニトリル（１ｍｍｏｌ、０．６６ｇ）、トリエチルアミン（１．１ｍｍｏｌ、０．０２８ｍｌ）、エタノール（４ｍｌ）を加え、還流下で１時間 反応させた。TLCより反応の終了を確認した後、溶媒を濃縮して、蒸留水を加えて結晶を析出させる。結晶を炉別して、蒸留水、エーテルで結晶を洗い、黄色結晶としてホウ素含有６−アミノ２，４−ジヒドロピラノ-[２，３−ｃ]ピラゾール−５−カルボニトリル（１０ａ）を収率５６％で得た。収率はホルミルフェニルホウ酸誘導体に対する単離収率（％）である。
得られた生成物１０ａの、ＩＲ、ＮＭＲ及び融点のデータを以下に示す。

mp 232-235 (decomp.) ; Rf = 0.51.
¹H (400 MHz, DMSO) : 1.76 (s, 3H, CH₃), 4.57 (s, 1H, CH), 6.88 (br s, 2H, B(OH)₂), 7.12 (d, 2H, J =8.05 Hz, Ph), 7.72 (d, 2H, J =8.05 Hz, Ph), 8.00 (br s, 2H, B(OH)₂), 12.09 (br s, 1H, NH).
¹³C (136MHz, DMSO) : 9.8, 36.3, 57.0, 97.6, 120.9, 126.6 (2×C), 134.4 (2×C), 134.6, 135.7, 146.3, 154.8, 160.9.
IR (KBr) : 3220, 2978, 2868, 2195, 1638, 1600, 1490, 1393, 1175, 1067, 978.
Example 3
Reaction formula:

Thus, a dihydroxyboryl group-containing dihydropyrano [2,3-c] pyrazole compound 10a was synthesized as follows.
In a 25 ml two-necked flask, 4-formylphenylboric acid derivative (4-3; 1 mmol, 0.149 g), 95% hydrazine (1.1 mmol, 0.054 ml), ethyl acetoacetate (1.1 mmol, 0.143 g) ), Malononitrile (1 mmol, 0.66 g), triethylamine (1.1 mmol, 0.028 ml) and ethanol (4 ml) were added and reacted for 1 hour under reflux. After confirming the completion of the reaction by TLC, the solvent is concentrated, and distilled water is added to precipitate crystals. The crystals were separated by furnace, washed with distilled water and ether, and boron-containing 6-amino-2,4-dihydropyrano- [2,3-c] pyrazole-5-carbonitrile (10a) as a yellow crystal in a yield of 56%. Obtained. The yield is the isolated yield (%) based on the formylphenylboric acid derivative.
The IR, NMR and melting point data of the resulting product 10a are shown below.

mp 232-235 (decomp.); Rf = 0.51.
¹ H (400 MHz, DMSO): 1.76 (s, 3H, CH ₃ ), 4.57 (s, 1H, CH), 6.88 (br s, 2H, B (OH) ₂ ), 7.12 (d, 2H, J = 8.05 Hz, Ph), 7.72 (d, 2H, J = 8.05 Hz, Ph), 8.00 (br s, 2H, B (OH) ₂ ), 12.09 (br s, 1H, NH).
¹³ C (136MHz, DMSO): 9.8, 36.3, 57.0, 97.6, 120.9, 126.6 (2 × C), 134.4 (2 × C), 134.6, 135.7, 146.3, 154.8, 160.9.
IR (KBr): 3220, 2978, 2868, 2195, 1638, 1600, 1490, 1393, 1175, 1067, 978.

Example 4
The human cervical cancer cell HeLa.S3 cell line was used to assay the cell growth inhibitory activity of dihydroquinoxaline derivatives. The obtained results are shown in Tables 5-1 to 5-6.
In the table, IC50 indicates the substrate concentration that leads to 50% growth inhibition, and T / C (%) indicates the ratio (%) of the average diameter of treated cancer cells to the average diameter of control cancer cells at 30 μM administration.

  The dihydroxyboryl group-containing nitrogen-containing heterocyclic derivative according to the present invention is used as a pharmaceutical (for example, a cancer therapeutic agent), an agricultural chemical or a functional material, or an intermediate thereof or a material for Suzuki-Miyaura cross-coupling reaction. Can do. Moreover, the manufacturing method of this invention can be utilized as a simple manufacturing method of the dihydroxyboryl group containing nitrogen-containing heterocyclic derivative by the one pot reaction between many components.

Claims (7)

A nitrogen-containing heterocyclic compound containing a dihydroxyboryl group,
The compound has the formula:

,formula:

Or the formula:

[Wherein, R ¹ represents an alkyl group having 1 to 10 carbon atoms which may have a halogen atom, an alkyloxy group or an alkylamino group, an aryl group having 6 to 16 carbon atoms which may have a halogen atom, or represents a halogen ^atom, R 2, ^{R 4} and ^{R 5} each independently represent an alkyl group or an aryl group having a carbon number of 6 to 16 1 to 10 or carbon atoms have a halogen atom, ^{R 3} is halogen An alkyl group having 1 to 10 carbon atoms which may have an atom, an alkyloxy group having 1 to 10 carbon atoms (however, when X is an oxygen atom, it is not an ethoxy group), and has a halogen atom A good alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 16 carbon atoms which may have a halogen atom, X represents an oxygen or sulfur atom, n is 0, or an integer of 1 to 4 The To express. Or a dihydroxyboryl group-containing nitrogen-containing heterocyclic compound. Compound 1 has the formula 1w:

The dihydroxyboryl group-containing nitrogen-containing heterocyclic compound according to claim 1, which is a compound 1w represented by:   A pharmaceutical comprising the dihydroxyboryl group-containing nitrogen-containing heterocyclic compound according to claim 1 or 2 as an active ingredient. A method for producing a dihydroxyboryl group-containing nitrogen-containing heterocyclic compound 1 or 1w according to claim 1 or 2, comprising three components comprising formylphenylboronic acid derivative 4, β-diketone derivative 3 and (thio) urea 2. ,
Reaction formula (1):

[Wherein R ¹ , R ² , R ³ , X and n are as defined above]. ],
A method for producing a dihydroxyboryl group-containing nitrogen-containing heterocyclic compound 1 comprising the step of carrying out a one-pot reaction according to 1. Reaction formula (1) is represented by reaction formula (1-1):

The production method according to claim 4, wherein the product 1 obtained is 1 w. It is a manufacturing method of the dihydroxyboryl group containing nitrogen-containing heterocyclic compound 7 of Claim 1, Comprising: Three components which consist of the formyl phenyl boronic acid derivative 4, 3-aminocrotonic acid ester 5, and the beta-ketoester derivative 6,
Reaction formula (2):

[Wherein, R ¹ , R ⁴ , R ⁵ and n are as defined above. ],
A method for producing a dihydroxyboryl group-containing nitrogen-containing heterocyclic compound 7 comprising the step of carrying out a one-pot reaction according to FIG. A method for producing a dihydroxyboryl group-containing nitrogen-containing heterocyclic compound 10 according to claim 1, comprising four components comprising formylphenylboronic acid derivative 4, β-ketoester derivative 6, malononitrile 8 and hydrazine 9.
Reaction formula (3):

[Wherein, R ¹ , R ⁴ , R ⁵ and n are as defined above. ],
A method for producing a dihydroxyboryl group-containing nitrogen-containing heterocyclic compound 10 comprising the step of carrying out a one-pot reaction according to the above.