JPS6261032B2 - - Google Patents
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- Publication number
- JPS6261032B2 JPS6261032B2 JP1119581A JP1119581A JPS6261032B2 JP S6261032 B2 JPS6261032 B2 JP S6261032B2 JP 1119581 A JP1119581 A JP 1119581A JP 1119581 A JP1119581 A JP 1119581A JP S6261032 B2 JPS6261032 B2 JP S6261032B2
- Authority
- JP
- Japan
- Prior art keywords
- hydroxy
- pyrone
- dihydro
- methyl
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- AOJLDZLRTUWFFY-UHFFFAOYSA-N 6-methyl-4-oxo-1h-pyridine-3-carboxylic acid Chemical compound CC1=CC(=O)C(C(O)=O)=CN1 AOJLDZLRTUWFFY-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical class O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 238000000034 method Methods 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- NSYSSMYQPLSPOD-UHFFFAOYSA-N triacetate lactone Chemical compound CC1=CC(O)=CC(=O)O1 NSYSSMYQPLSPOD-UHFFFAOYSA-N 0.000 description 6
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- -1 amine compound Chemical class 0.000 description 3
- VEFDLKXOSOFUIN-UHFFFAOYSA-N 5-hydroxy-4-pentenoic acid d-lactone Chemical class O=C1CCC=CO1 VEFDLKXOSOFUIN-UHFFFAOYSA-N 0.000 description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 2
- CZVTYGFISHLVHK-UHFFFAOYSA-N 4h-pyran-2,3-dione Chemical compound O=C1CC=COC1=O CZVTYGFISHLVHK-UHFFFAOYSA-N 0.000 description 1
- XRIHTJYXIHOBDQ-UHFFFAOYSA-N 6-methyl-2-oxo-1h-pyridine-3-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)C(=O)N1 XRIHTJYXIHOBDQ-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Description
【発明の詳細な説明】
本発明は、ニコチン酸誘導体さらに詳しくは４
−ヒドロキシ−６−メチルニコチン酸の製造方法
に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to nicotinic acid derivatives, more specifically 4
The present invention relates to a method for producing -hydroxy-6-methylnicotinic acid.
４−ヒドロキシ−６−メチルニコチン酸は、セ
フアロスポリン誘導体等の医薬品の中間体原料と
して有用な化合物であり、従来この化合物の製造
方法として以下に示すような方法が知られてい
る。 4-Hydroxy-6-methylnicotinic acid is a compound useful as an intermediate raw material for pharmaceuticals such as cephalosporin derivatives, and the following methods are conventionally known as methods for producing this compound.
(1) ４−ヒドロキシ−６−メチル−２−ピロンと
Ｎ，Ｎ−ジメチルホルムアミドジメチルアセタ
ールとを反応させて３−ジメチルアミノメチレ
ン−６−メチル−４−オキソ−３，４−ジヒド
ロ−２−ピロンを得、次いでアンモニアまたは
第一級アミンを反応させる方法。（J.Org.
Chem.37、1145〜1148（1972））
(2) ３−置換アニリノメチレン−６−メチル−４
−オキソ−３，４−ジヒドロ−２−ピロンをア
ルカリ性条件下で加水分解して４−ヒドロキシ
−６−メチル−２−ピロン−３−カルボアルデ
ヒドを得、次いでアンモニアの存在下アミン化
合物と反応させる方法。（特開昭54−125678
号）
しかしながら、(1)の方法では原料となるＮ，Ｎ
−ジメチルホルムアミドジメチルアセタールは湿
気の影響を受け分解しやすく、かつ非常に高価で
ある点、(2)の方法は原料となる３−置換アニリノ
メチレン−６−メチル−４−オキソ−３，４−ジ
ヒドロ−２−ピロンを得るために、ニトロ基、ア
ルコキシ基またはハロゲン基で置換されたアニリ
ンを必要とするため、原料が工業的に割高となる
点で、４−ヒドロキシ−６−メチルニコチン酸の
工業的製造方法として満足のゆくものではなかつ
た。(1) 4-hydroxy-6-methyl-2-pyrone and N,N-dimethylformamide dimethyl acetal are reacted to produce 3-dimethylaminomethylene-6-methyl-4-oxo-3,4-dihydro-2- A method of obtaining pyrone and then reacting with ammonia or a primary amine. (J.Org.
Chem. 37 , 1145-1148 (1972)) (2) 3-substituted anilinomethylene-6-methyl-4
- Hydrolysis of oxo-3,4-dihydro-2-pyrone under alkaline conditions to give 4-hydroxy-6-methyl-2-pyrone-3-carbaldehyde, which is then reacted with an amine compound in the presence of ammonia. Method. (Unexamined Japanese Patent Publication No. 54-125678
However, in method (1), the raw materials N,N
- Dimethylformamide dimethyl acetal is easily decomposed under the influence of moisture and is very expensive. In order to obtain -dihydro-2-pyrone, aniline substituted with a nitro group, an alkoxy group, or a halogen group is required, so the raw material is industrially expensive, and 4-hydroxy-6-methylnicotinic acid It was not satisfactory as an industrial manufacturing method.
本発明者らは、工業的に入手が容易な原料を用
い、かつ簡略な工数で製造可能な４−ヒドロキシ
−６−メチルニコチン酸の製造方法を見いだすべ
く鋭意研究し、本発明を完成するに至つた。 The present inventors have conducted extensive research to find a method for producing 4-hydroxy-6-methylnicotinic acid that can be produced using industrially easily available raw materials and with a simple number of steps, and have completed the present invention. I've reached it.
すなわち、本発明は一般式（）
（ただし式中、R1およびR2はそれぞれ水素原
子、炭素数１ないし３のアルキル基、アリール基
を表わし、R1とR2は互いに同一でも異つてもよ
い。ｎは２または３を表わす。）
で示される３，４−ジヒドロ−４−オキソ−２
−ピロン誘導体とアンモニアを反応させることを
特徴とする、４−ヒドロキシ−６−メチルニコチ
ン酸の製造方法に関するものである。 That is, the present invention is based on the general formula () (In the formula, R 1 and R 2 each represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an aryl group, and R 1 and R 2 may be the same or different from each other. n represents 2 or 3. ) 3,4-dihydro-4-oxo-2
- A method for producing 4-hydroxy-6-methylnicotinic acid, characterized by reacting a pyrone derivative with ammonia.
本発明方法における反応を化学式で表わすと、
以下のようになる。 The reaction in the method of the present invention is expressed as a chemical formula:
It will look like this:
本発明方法の一実施態様を以下に示す。まず、
一般式（）で表わされる３，４−ジヒドロ−２
−ピロン誘導体とアンモニアを溶媒とともにオー
トクレーブ中に加え、加熱撹拌し反応を行なう。
反応終了後、析出した結晶を取して水に加え溶
解する。ついで濃塩酸を加え、得られる結晶を
取し、水洗・乾燥を行なうと目的物の４−ヒドロ
キシ−６−メチルニコチン酸が得られる。 One embodiment of the method of the present invention is shown below. first,
3,4-dihydro-2 represented by general formula ()
- Add the pyrone derivative and ammonia together with a solvent into an autoclave, heat and stir to react.
After the reaction is completed, the precipitated crystals are collected and dissolved in water. Then, concentrated hydrochloric acid is added, and the resulting crystals are collected, washed with water, and dried to obtain the target product, 4-hydroxy-6-methylnicotinic acid.
本発明方法において原料として用いられる３，
４−ジヒドロ−２−ピロン誘導体は前記一般式
（）で示される化合物であり、その置換基R1お
よびR2としてはフエニール基、ナフチル基など
のアリール基、メチル基、エチル基、ｎ−プロピ
ル基などの炭素数１ないし３のアルキル基、およ
び水素原子などがあげられる。これら３，４−ジ
ヒドロ−２−ピロン誘導体のうち、好ましい具体
的な化合物としては、たとえばＮ，N′−ビス
（６−メチル−４−オキソ−３，４−ジヒドロ−
２−ピロン−３−イリデンメチルエチレンジアミ
ン、などがあげられる。 3, used as a raw material in the method of the present invention
The 4-dihydro-2-pyrone derivative is a compound represented by the above general formula (), and its substituents R 1 and R 2 include aryl groups such as phenyl group and naphthyl group, methyl group, ethyl group, and n-propyl group. Examples include alkyl groups having 1 to 3 carbon atoms, such as groups, and hydrogen atoms. Among these 3,4-dihydro-2-pyrone derivatives, preferred specific compounds include, for example, N,N'-bis(6-methyl-4-oxo-3,4-dihydro-
Examples include 2-pyron-3-ylidenemethylethylenediamine.
本発明方法におけるアンモニアと３，４−ジヒ
ドロ−２−ピロン誘導体の反応比率は、３，４−
ジヒドロ−２−ピロン誘導体１モルに対してアン
モニアを過剰、好ましくは２ないし４モル用い
る。 The reaction ratio of ammonia and 3,4-dihydro-2-pyrone derivative in the method of the present invention is 3,4-
Ammonia is used in excess, preferably 2 to 4 moles, per mole of dihydro-2-pyrone derivative.
本発明方法における反応は、封管もしくはオー
トクレーブ中で80ないし120℃に加熱することに
より行われる。反応に際して用いられる溶媒とし
ては、メタノール、エタノール、メトキシエタノ
ールおよび水などがあげられる。 The reaction in the method of the present invention is carried out by heating to 80 to 120°C in a sealed tube or autoclave. Examples of the solvent used in the reaction include methanol, ethanol, methoxyethanol, and water.
原料として用いられる３，４−ジヒドロ−２−
ピロン誘導体は、４−ヒドロキシ−６−メチル−
２−ピロンをオルトギ酸エチルおよび第一級また
は第二級アミンと反応させることにより容易に得
ることができる。（Monatsh.Chem、106、963−
971（1975）およびSynthesis、543〜544
（1976））
以上のように本発明方法は、Ｎ，Ｎ−ジメチル
ホルムアミドメチルアセタール等の高価な原料を
用いずにすみ、しかも反応が一段で完了するうえ
原料となる３，４−ジヒドロ−２−ピロン誘導体
は４−ヒドロキシ−６−メチル−２−ピロンに対
し0.5モル当量のエチレンジアミンを用いればよ
く工業的に有利な製造方法である。 3,4-dihydro-2- used as raw material
Pyrone derivatives are 4-hydroxy-6-methyl-
It can be easily obtained by reacting 2-pyrone with ethyl orthoformate and a primary or secondary amine. (Monatsh.Chem, 106 , 963−
971 (1975) and Synthesis, 543–544
(1976)) As described above, the method of the present invention does not require the use of expensive raw materials such as N,N-dimethylformamide methyl acetal, and the reaction is completed in one step. The -pyrone derivative can be produced by using 0.5 molar equivalent of ethylenediamine relative to 4-hydroxy-6-methyl-2-pyrone, which is an industrially advantageous manufacturing method.
以下実施例により本発明を詳細に説明する。 The present invention will be explained in detail below with reference to Examples.
実施例 １
(a) Ｎ，N′−ビス（６−メチル−４−オキソ−
３，４−ジヒドロ−２−ピロン−３−イリデン
メチル）エチレンジアミンの製造
４−ヒドロキシ−６−メチル−２−ピロン
50.4ｇ、エチレンジアミン12.0ｇ、オルトギ酸
エチル200mlおよびメトキシエタノール250mlの
混液を加熱還流し、約80mlのエタノールを留去
した。析出した結晶を冷却後取しエタノール
で洗浄し、風乾したところＮ，N′−ビス（６
−メチル−４−オキソ−３，４−ジヒドロ−２
−ピロン−３−イリデンメチル）エチレンジア
ミン50.4ｇ（収率76％）が得られた。Example 1 (a) N,N'-bis(6-methyl-4-oxo-
Production of 3,4-dihydro-2-pyrone-3-ylidenemethyl)ethylenediamine 4-hydroxy-6-methyl-2-pyrone
A mixture of 50.4 g of ethylenediamine, 12.0 g of ethylenediamine, 200 ml of ethyl orthoformate and 250 ml of methoxyethanol was heated to reflux, and about 80 ml of ethanol was distilled off. The precipitated crystals were collected after cooling, washed with ethanol, and air-dried to yield N,N'-bis(6
-Methyl-4-oxo-3,4-dihydro-2
50.4 g (yield: 76%) of -pyron-3-ylidenemethyl)ethylenediamine was obtained.
(b) ４−ヒドロキシ−６−メチルニコチン酸の製
造
(a)で得られた生成物50.4ｇをメトキシエタノ
ール120mlと液体アンモニア36mlとともにオー
トクレーブ中に入れて加熱し、110℃で２時間
加熱撹拌した。反応終了後、冷却し析出した結
晶を取し85mlの水を加えて溶解した。次いで
濃塩酸でPHを１に調整した後、析出する結晶を
取し、少量の水で洗い、風乾したところ４−
ヒドロキシ−６−メチルニコチン酸23.9ｇ（収
率52％）が得られた。(b) Production of 4-hydroxy-6-methylnicotinic acid 50.4 g of the product obtained in (a) was heated in an autoclave with 120 ml of methoxyethanol and 36 ml of liquid ammonia, and heated and stirred at 110°C for 2 hours. . After the reaction was completed, the mixture was cooled and the precipitated crystals were collected and dissolved in 85 ml of water. After adjusting the pH to 1 with concentrated hydrochloric acid, the precipitated crystals were collected, washed with a small amount of water, and air-dried.
23.9 g (yield 52%) of hydroxy-6-methylnicotinic acid was obtained.
Claims (1)
造するに際し、一般式（） 〔ただし式中、R1およびR2はそれぞれ水素原
子、炭素数１ないし３のアルキル基、アリール基
を表わし、R1とR2は互いに同一でも異つていて
もよく、ｎは２または３を表わす。〕 で示される３，４−ジヒドロ−４−オキソ−２−
ピロン誘導体とアンモニアとを反応させることを
特徴とする４−ヒドロキシ−６−メチルニコチン
酸の製造方法。[Claims] 1 When producing 4-hydroxy-6-methylnicotinic acid, general formula () [However, in the formula, R 1 and R 2 each represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an aryl group, R 1 and R 2 may be the same or different from each other, and n is 2 or 3. represents. ] 3,4-dihydro-4-oxo-2- represented by
A method for producing 4-hydroxy-6-methylnicotinic acid, which comprises reacting a pyrone derivative with ammonia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1119581A JPS57126478A (en) | 1981-01-27 | 1981-01-27 | Preparation of nicotinic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1119581A JPS57126478A (en) | 1981-01-27 | 1981-01-27 | Preparation of nicotinic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57126478A JPS57126478A (en) | 1982-08-06 |
| JPS6261032B2 true JPS6261032B2 (en) | 1987-12-18 |
Family
ID=11771264
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1119581A Granted JPS57126478A (en) | 1981-01-27 | 1981-01-27 | Preparation of nicotinic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57126478A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59161359A (en) * | 1983-03-07 | 1984-09-12 | Tokuyama Soda Co Ltd | Preparation of 3-hydroxypyridone compound |
-
1981
- 1981-01-27 JP JP1119581A patent/JPS57126478A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57126478A (en) | 1982-08-06 |
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