JPH0730009B2 - Process for producing trans-4-guanidinomethylcyclohexanecarboxylic acid ester or addition salt thereof - Google Patents
Process for producing trans-4-guanidinomethylcyclohexanecarboxylic acid ester or addition salt thereofInfo
- Publication number
- JPH0730009B2 JPH0730009B2 JP17895285A JP17895285A JPH0730009B2 JP H0730009 B2 JPH0730009 B2 JP H0730009B2 JP 17895285 A JP17895285 A JP 17895285A JP 17895285 A JP17895285 A JP 17895285A JP H0730009 B2 JPH0730009 B2 JP H0730009B2
- Authority
- JP
- Japan
- Prior art keywords
- addition salt
- trans
- guanidinomethylcyclohexanecarboxylic
- guanidinomethylcyclohexanecarboxylic acid
- acid
- 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 - Lifetime
Links
- 150000003839 salts Chemical class 0.000 title claims description 11
- -1 trans-4-guanidinomethylcyclohexanecarboxylic acid ester Chemical class 0.000 title claims description 7
- 238000000034 method Methods 0.000 title description 8
- 239000002253 acid Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- JBRMEFWJFBHUKG-UHFFFAOYSA-N 4-[(diaminomethylideneamino)methyl]cyclohexane-1-carboxylic acid Chemical compound NC(N)=NCC1CCC(C(O)=O)CC1 JBRMEFWJFBHUKG-UHFFFAOYSA-N 0.000 claims description 8
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- GJYCVCVHRSWLNY-UHFFFAOYSA-N 2-butylphenol Chemical compound CCCCC1=CC=CC=C1O GJYCVCVHRSWLNY-UHFFFAOYSA-N 0.000 description 2
- RBXZATCLMSBPGG-SKKCDYJJSA-N Cl.C1=CC(C(C)(C)C)=CC=C1OC(=O)[C@@H]1CC[C@@H](CNC(N)=N)CC1 Chemical compound Cl.C1=CC(C(C)(C)C)=CC=C1OC(=O)[C@@H]1CC[C@@H](CNC(N)=N)CC1 RBXZATCLMSBPGG-SKKCDYJJSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- ZNMROZJFHALUOA-UHFFFAOYSA-N bis(4-tert-butylphenyl) sulfite Chemical compound C1=CC(C(C)(C)C)=CC=C1OS(=O)OC1=CC=C(C(C)(C)C)C=C1 ZNMROZJFHALUOA-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XSJVWZAETSBXKU-UHFFFAOYSA-N 2-ethoxypropane Chemical compound CCOC(C)C XSJVWZAETSBXKU-UHFFFAOYSA-N 0.000 description 1
- QCVUPSYRZFNUBN-UHFFFAOYSA-N 4-[(diaminomethylideneamino)methyl]cyclohexane-1-carboxylic acid;hydrochloride Chemical compound Cl.NC(N)=NCC1CCC(C(O)=O)CC1 QCVUPSYRZFNUBN-UHFFFAOYSA-N 0.000 description 1
- QHPQWRBYOIRBIT-UHFFFAOYSA-N 4-tert-butylphenol Chemical compound CC(C)(C)C1=CC=C(O)C=C1 QHPQWRBYOIRBIT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- JBRMEFWJFBHUKG-LJGSYFOKSA-N NC(=N)NC[C@H]1CC[C@H](C(O)=O)CC1 Chemical class NC(=N)NC[C@H]1CC[C@H](C(O)=O)CC1 JBRMEFWJFBHUKG-LJGSYFOKSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】 本発明は、トランス−４−グアニジノメチルシクロヘキ
サンカルボン酸エステル類、更に詳細には、、一般式
（Ｉ） で表わされるトランス−４−グアニジノメチルシクロヘ
キサンカルボン酸エステル又はその酸付加塩の製造方法
に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to trans-4-guanidinomethylcyclohexanecarboxylic acid esters, more specifically, compounds represented by general formula (I) Relates to a method for producing trans-4-guanidinomethylcyclohexanecarboxylic acid ester represented by or an acid addition salt thereof.
上記一般式（Ｉ）で表わされるトランス−４−グアニジ
ノメチルシクロヘキサンカルボン酸エステル又はその酸
付加塩は本出願人が特開昭57−122059及び57−140713と
して出願している蛋白分解酵素阻害作用を有し、さらに
アレルギー疾患の予防および治療剤として有用な化合物
である。The trans-4-guanidinomethylcyclohexanecarboxylic acid ester represented by the above general formula (I) or an acid addition salt thereof has a proteolytic enzyme inhibitory action which is filed by the present applicant as JP-A-57-122059 and 57-140713. Further, it is a compound which is useful as a preventive and therapeutic agent for allergic diseases.
本発明方法によればトランス−４−グアニジノメチルシ
クロヘキサンカルボン酸又はその酸付加塩とジ（ｐ−ｔ
−ブチルフェニル）スルファイトを反応させることによ
り、上記一般式（Ｉ）で表わされるトランス−４−グア
ニジノメチルシクロヘキサンカルボン酸エステル又はそ
の酸付加塩が製造される。反応にジメチルホルムアミ
ド、ジメチルアセトアミドなど反応に関与しない溶媒
中、室温で10〜50時間撹はんすることにより容易に行な
われる。好ましくは、ピリジン、トリエチルアミンなど
の存在下に行なわれる。トランス−４−グアニジノメチ
ルシクロヘキサンカルボン酸の酸付加塩としては塩酸
塩、臭化水素酸塩、ｐ−トルエンスルホン酸、メシル酸
等があげられる。According to the method of the present invention, trans-4-guanidinomethylcyclohexanecarboxylic acid or its acid addition salt and di (pt)
By reacting -butylphenyl) sulfite, a trans-4-guanidinomethylcyclohexanecarboxylic acid ester represented by the above general formula (I) or an acid addition salt thereof is produced. It is easily carried out by stirring at room temperature for 10 to 50 hours in a solvent such as dimethylformamide or dimethylacetamide that does not participate in the reaction. Preferably, it is carried out in the presence of pyridine, triethylamine and the like. Examples of the acid addition salt of trans-4-guanidinomethylcyclohexanecarboxylic acid include hydrochloride, hydrobromide, p-toluenesulfonic acid, mesylic acid and the like.
上記により得られたトランス−４−グアニジノメチルシ
クロヘキサンカルボン酸 ４−ｔ−ブチルフェニルエス
テル塩酸塩は、エチルエーテル、酢酸エチル、水等を用
いて再結晶することで精製される。The trans-4-guanidinomethylcyclohexanecarboxylic acid 4-t-butylphenyl ester hydrochloride obtained above is purified by recrystallization using ethyl ether, ethyl acetate, water and the like.
本発明方法において用いられるジ（ｐ−ｔ−ブチルフェ
ニル）スルファイトはｐ−ｔ−ブチルフェノールにハロ
ゲン化チオニルを脱酸剤の存在下に反応させることによ
り容易に得られる。この反応においてもちいられる脱酸
剤は、反応の進行につれて副生するハロゲン化水素を捕
促、不活性化するものであり、トリエチルアミン、トリ
ブチルアミン、ジメチルアニリンなどの三級アミンが好
ましい。反応は、エーテル、ベンゼン、トルエン、キシ
レンなどの溶媒中、０℃〜室温で２〜20時間撹はんする
ことにより容易に行なわれる。The di (pt-butylphenyl) sulfite used in the method of the present invention can be easily obtained by reacting pt-butylphenol with thionyl halide in the presence of a deoxidizing agent. The deoxidizing agent used in this reaction captures and inactivates hydrogen halide produced as a by-product as the reaction proceeds, and tertiary amines such as triethylamine, tributylamine and dimethylaniline are preferable. The reaction is easily carried out by stirring in a solvent such as ether, benzene, toluene or xylene at 0 ° C. to room temperature for 2 to 20 hours.
本発明方法を工業的に実施する場合、ｐ−ｔ−ブチルフ
ェノールからジ（ｐ−ｔ−ブチルフェニル）スルファイ
トを製造し、これを単離することなく、そのままトラン
ス−４−グアニジノメチルシクロヘキサンカルボン酸又
はその酸付加塩を反応させて一般式（Ｉ）で示される目
的化合物を製造することもできる。When the method of the present invention is carried out industrially, di-4- (tert-butylphenyl) sulfite is produced from pt-butylphenol, and trans-4-guanidinomethylcyclohexanecarboxylic acid is directly used without isolation. Alternatively, the acid addition salt thereof can be reacted to produce the target compound represented by the general formula (I).
本発明方法で得られる一般式（Ｉ）で表わされる化合物
の酸付加塩としては、塩酸塩、臭化水素酸塩、ｐ−トル
エンスルホン酸塩、メシル酸塩等があげられる。Examples of the acid addition salt of the compound represented by formula (I) obtained by the method of the present invention include hydrochloride, hydrobromide, p-toluenesulfonate, mesylate and the like.
また、本発明方法は１モルのトランス−４−グアニジノ
メチルシクロヘキサンカルボン酸またはその酸付加塩と
１モルのジ（ｐ−ｔ−ブチルフェニル）スルファイトが
反応すれは、１モルのｐ−ｔ−ブチルフェノールが理論
的に副生するが、ｐ−ｔ−ブチルフェノールは容易に高
収率で回収できる。また、ｐ−ｔ−ブチルフェノールは
トランス−４−グアニジノメチルシクロヘキサンカルボ
ン酸に比べて極めて安価であり、工業的に実施する場
合、トランス−４−グアニジノメチルシクロヘキサンカ
ルボン酸に対する一般式（Ｉ）で表わされる化合物の収
率が、一般式（Ｉ）で表わされる化合物の価格に大きな
影響を与える。本発明方法はトランス−４−グアニジノ
メチルシクロヘキサンカルボン酸からの収率がきわめて
高く工業的に優れた方法である。In the method of the present invention, if 1 mol of trans-4-guanidinomethylcyclohexanecarboxylic acid or its acid addition salt and 1 mol of di (pt-butylphenyl) sulfite are reacted, 1 mol of pt- Although butylphenol is theoretically a by-product, pt-butylphenol can be easily recovered in high yield. Further, pt-butylphenol is extremely inexpensive as compared with trans-4-guanidinomethylcyclohexanecarboxylic acid, and when industrially carried out, it is represented by the general formula (I) for trans-4-guanidinomethylcyclohexanecarboxylic acid. The yield of the compound has a great influence on the price of the compound represented by the general formula (I). The method of the present invention is an industrially excellent method in which the yield from trans-4-guanidinomethylcyclohexanecarboxylic acid is extremely high.
次に実施例を挙げて本発明を詳細に説明する。Next, the present invention will be described in detail with reference to examples.
参考例 ジ（４−ｔ−ブチルフェニル）スルファイト： ４−ｔ−ブチルフェノール9gをエチルエーテル52mlに溶
かし、これにチオニルクロリド3.56gを加える。氷冷下
この溶液にトリエチルアミン6.06gを激しく撹はんしな
がら滴下する。滴下終了後室温で一夜撹はんする。不溶
物をろ別後エチルエーテル15mlで洗浄し、ろ液と合わせ
て溶媒留去して標記化合物9.77gを暗赤色油状物として
得る。1 H−NMR （CC14）δ:1.38（18H,s,CH3×６） 7.00〜7.44（8H,m,芳香族水素） 実施例 トランス−４−グアニジノメチルシクロヘキサ
ンカルボン酸 ４−ｔ−ブチルフェニルエステル塩酸
塩： トランス−４−グアニジノメチルシクロヘキサンカルボ
ン酸塩酸塩4.35gとDMF23g混合物中にジ（４−ｔ−ブチ
ルフェニル）スルファイト10.05gを加え、更にピリジン
8.66gを加え室温で一夜撹はんする。反応終了後水浴上
（50〜60℃）で溶媒を減圧留去して得られる残留物に酢
酸エチル50mlを加えふりまぜ室温で一夜放置する。析出
した結晶をろ取し酢酸エチル、エチルエーテルで洗浄し
風乾すると5.74gの白色結晶を得る。この粗結晶をイソ
プロパノール23gに加温（60℃）して溶かし不溶物をろ
別後結晶の析出がみられる直前まで濃縮する。このイソ
プロパノール溶液中に白濁しなくなるまで水を加え室温
で一夜放置する。析出した結晶をろ取し、水、酢酸エチ
ルで洗浄後風乾して白色結晶5.41gを得る。得られた結
晶をイソプロパノール24gに加温（60℃）して溶かし、
不溶物をろ別後エチルエーテル80mlを撹はんしながら加
え一夜放置する。析出した結晶は吸引ろ集後イソプロパ
ノール−エチルエーテル（1:3）の混液およびエチルエ
ーテルで洗浄後風乾し標記化合物4.7gを白色結晶として
得る。（収率70％） mp 204.5〜208.0℃Reference example Di (4-t-butylphenyl) sulfite: 9 g of 4-t-butylphenol is dissolved in 52 ml of ethyl ether, and 3.56 g of thionyl chloride is added thereto. To this solution under ice cooling, 6.06 g of triethylamine was added dropwise with vigorous stirring. After completion of dropping, stir overnight at room temperature. The insoluble material was filtered off, washed with 15 ml of ethyl ether, and the solvent was distilled off together with the filtrate to obtain 9.77 g of the title compound as a dark red oily substance. 1 H-NMR (CC1 4) δ: 1.38 (18H, s, CH 3 × 6) 7.00~7.44 (8H, m, aromatic hydrogens) Example trans-4-guanidinomethyl cyclohexane carboxylic acid 4-t-butylphenyl Ester hydrochloride: 4.35 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride and 23 g of DMF were added with 10.05 g of di (4-t-butylphenyl) sulfite and pyridine.
Add 8.66g and stir overnight at room temperature. After completion of the reaction, the solvent is distilled off under reduced pressure on a water bath (50-60 ° C), 50 ml of ethyl acetate is added to the resulting residue, and the mixture is left to stir overnight at room temperature. The precipitated crystals are collected by filtration, washed with ethyl acetate and ethyl ether, and air-dried to give 5.74 g of white crystals. The crude crystals are dissolved in 23 g of isopropanol by heating (60 ° C.), and the insoluble matter is filtered off and concentrated until just before the precipitation of crystals is observed. Water is added to this isopropanol solution until it does not become cloudy, and the mixture is left at room temperature overnight. The precipitated crystals are collected by filtration, washed with water and ethyl acetate, and air-dried to obtain 5.41 g of white crystals. The crystals obtained are dissolved in 24 g of isopropanol by heating (60 ° C),
The insoluble matter is filtered off, 80 ml of ethyl ether is added with stirring, and the mixture is left standing overnight. The precipitated crystals were collected by suction filtration, washed with a mixed solution of isopropanol-ethyl ether (1: 3), washed with ethyl ether and air-dried to obtain 4.7 g of the title compound as white crystals. (Yield 70%) mp 204.5-208.0 ℃
Claims (1)
キサンカルボン酸又はその付加塩と、ジ（ｐ−ｔ−ブチ
ルフェニル）スルファイトを反応させることを特徴とす
る、一般式（Ｉ） で表わされるトランス−４−グアニジノメチルシクロヘ
キサンカルボン酸エステル又はその酸付加塩の製造方
法。1. A compound represented by the general formula (I), which comprises reacting trans-4-guanidinomethylcyclohexanecarboxylic acid or an addition salt thereof with di (pt-butylphenyl) sulfite. A method for producing a trans-4-guanidinomethylcyclohexanecarboxylic acid ester represented by or an acid addition salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17895285A JPH0730009B2 (en) | 1985-08-14 | 1985-08-14 | Process for producing trans-4-guanidinomethylcyclohexanecarboxylic acid ester or addition salt thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17895285A JPH0730009B2 (en) | 1985-08-14 | 1985-08-14 | Process for producing trans-4-guanidinomethylcyclohexanecarboxylic acid ester or addition salt thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6239561A JPS6239561A (en) | 1987-02-20 |
| JPH0730009B2 true JPH0730009B2 (en) | 1995-04-05 |
Family
ID=16057525
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17895285A Expired - Lifetime JPH0730009B2 (en) | 1985-08-14 | 1985-08-14 | Process for producing trans-4-guanidinomethylcyclohexanecarboxylic acid ester or addition salt thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0730009B2 (en) |
-
1985
- 1985-08-14 JP JP17895285A patent/JPH0730009B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6239561A (en) | 1987-02-20 |
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