GB2162181A - Process for producing pyrrolidine derivatives - Google Patents
Process for producing pyrrolidine derivatives Download PDFInfo
- Publication number
- GB2162181A GB2162181A GB08518550A GB8518550A GB2162181A GB 2162181 A GB2162181 A GB 2162181A GB 08518550 A GB08518550 A GB 08518550A GB 8518550 A GB8518550 A GB 8518550A GB 2162181 A GB2162181 A GB 2162181A
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- GB
- United Kingdom
- Prior art keywords
- compound
- formula
- following formula
- reacted
- bromo
- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The present invention relates to a novel process for preparing pyrrolidine derivatives of the formula (i): <IMAGE> characterized in that the compound of the following formula (II): <IMAGE> (wherein X is bromo or chloro) is reacted with the compound of the following formula: Cl-CO-R' (wherein R' is methoxy, ethoxy or t-butoxy) to obtain the acid anhydride of the following formula (III): <IMAGE> and the compound of formula (III) is acylated with the compound of the following formula (IV): <IMAGE> to obtain the compound of the following formula (V): <IMAGE> and the compound of formula (V) is reacted with thiourea to obtain the compound of the following formula (VI): <IMAGE> which is claimed per se, and, finally, the compound of formula (VI) is hydrolyzed to obtain the pyrrolidine derivatives of the formula (I).
Description
SPECIFICATION
Process for producing pyrrolidine derivatives
The present invention relates to a new process for producing pyrrolidine derivatives of the following formula (I) which are useful for lowering blood pressure and preventing hypertension.
A process for the production of pyrrolidine derivatives is described in Japanese Laid-Open Patent Application No. 52-116457. In this process, as starting materials, methacrylic acid and thioacetic acid are reacted to produce 3-acetylthio- 2-methylpropionic acid.
Meanwhile, the L-proline t-butyl ester which is produced via the three-step process from L-proline, is acylated with 3-acetylthio-2-methylpropionic acid followed by formation of the dicyclohexylamine salt, and then the acetyl group is removed to obtain the desired compound.
Alternative methods are also described which utilize the Schotten-Baumann reaction; that is, 3-acetylthio-2-methylpropionyl chloride which is produced using thionyl chloride, is reacted with L-proline and subsequently the acetyl group is removed by hydrolysis to give the desired compound.
As to the prior art regarding this invention, Japanese Laid-open Patent Application No. 56-100760 describes a process for the production of pyrrolidine derivatives wherein metacrylic acid and hydrogen bromide are reacted to produce 3-bromo-2-methylpropionic acid, which is in turn reacted with thionyl chloride to give the corresponding acid chloride. Then, utilizing the Schotten-Baumann reaction, the acid chloride is reacted with L-proline to produce the 1-[3-bromo- (2S)-methylpropionyl]-pyrrolidine-(2S)-carboxylic acid which is then subjected to a reaction with sodium thiosulfate to give Bunte salts. Then the
Bunte salts are hydrolyzed with HCI to obtain the 1-[3-mercapto-(2S)-methylpropionyl]-pyrrolidine -(2S)carboxylic acid as a final product.
However, these known methods have disadvantages in that they utilize thionyl chloride which requires anti-pollution facilities. Also these known processes produce low yields and are economically expensive.
The present invention provides a process for the production of pyrrolidine derivatives which does not require anti-pollution facilities. Furthermore, present invention provides increased yield through a simplified process using 3-halo-2-methyl propionic acid as the starting material. The compound of general formula (I) of the present invention is produced according to the following steps:
(i) The compound of the following formula (II) was dissolved in methylene chloride, chloroform, carbon tetrachloride, benzene, ethyl acetate, nitromethane or dichloroethane, and reacted with a compound of the formula[CICOR'] in the presence of an organic base, at a temperature of about 5 to-300c to obtain the acid anhydride of the following formula (III):
wherein X is chloro or bromo;R' is methoxy, ethoxy, or t-butoxy.
In the above reaction, pyridine, triethyl-amine, diethyl-amine, or dimethyl-aniline can be used as the organic base.
(ii) The compound of general formula(lil) obtained from the step (i) is acylated with the compound of the general formula (VI) at a temperature between 10"C and 30"C.
After the acylation reaction, water is added to remove the silylic compound, Thereafter, the reaction mixture is adjusted to pH between 4.0 and 6.0 with sodium hydroxide, sodium carbonate, potassium hydroxide, or potassium carbonate. The aqueous phases were separated and adjusted to pH 2.0 with hydrochloric acid, whereupon the compound of general formula (V) was obtained
wherein X is chloro or bromo.
The compound of formula (IV) used in the aforementioned reaction can be obtained by reacting the Lproline with trimethyl silylchloride, hexamethyldisilazane or trimethyl silylacetamide in an organic solvent such as methylene chloride, chloroform, carbon tetrachloride, benzene, ethyl acetate, nitromethane, or dichloroethane.
(iii) The compound of formula (V) obtained from the step(ii) was reacted with 1 to 2.5 mol equivalent of thiourea in a solvent such as water, methanol, ethanol, isopropanol or its aqueous solution at a temperature between about 60"e and 100"e to obtain the compound of formula (VI).
wherein X is chloro or bromo.
The compound of formula (VI) was subjected to the hydrolysis reaction by adding 1 to 2 mol equivalent of an alkali-metal hydroxide or alkali-metal carbonate.
According to the present invention, the reaction can be completed by adding hydrochloric acid to the solution to the extent that the pH value of the solution is in the range of 0.5 to 2.5, to obtain the compound of the formula (i).
Referring to accompanying drawings,
Figure 1 shows an nmr spectrum of the product of example 1 according to the invention,
Figure 2 shows an nmr spectrum of the product of example 5 according to the invention.
Nmr was measured using an NMR spectrometer Model EM-360, 60 MHz of the Varian Instrument Division.
The following examples are given by way of illustration of the present invention but are in no way intended to limit its scope.
Example I
(a) 1.039 of L-proline and 2.2ml of hexamethyl disilazane were added to 20ml of methylene chloride and heated to reflux. And then, the solution was cooled to room temperature.
(b) 1 .50g of 3-bromo-2-methylpropionic acid and 0.85g of methyl chloroformate were added to 15ml of methylene chloride and cooled to -15 c. While maintaing this temperature, 0.8ml of pyridine containing 5ml of methylene chloride was added dropwise over a period of 15 minutes and the mixture was stirred for a further 90 minutes at a temperature between -15'e and -20 c.
While maintaining this temperature, the clear solution obtained from(a) was added dropwise over a period of 30 minutes at a temperature between 75 c and -20 c. After the mixture was left to stand at room temperature for 60 minutes, 10ml of distilled water was added and the mixture was adjusted to pH 5.0 with 20% NaOH solution. Thereafter the aqueous phase was separated and adjusted to pH 5.0 with a concentrated hydrocholric acid and cooled to a temperature between O"e and 5 c and then stirred for 60 minutes.After the mixture was left to stand at a temperature of between 00c and 5"e overnight, the precipitate formed was filtered off, washed with cold water, and thereafter dried over phosphorus pentoxide under reduced pressure to obtain 1.039 of white crystalline 1-[3-bromo-(2S)-methylpropionyl]- pyrrolidine-(2S)-carboxylic acid.
Melting point: 113 c T.L.C.: Benzene: n-butanol: Acetic acid=25:3:3
Rf = 0.4 NMR (CdC13) : Refer to Figure 1.
Example 2
(a) 1.159 of L-proline was added to 10ml of methylene chloride and cooled to a temperature of between O"e and 55c. To this solution, 2.5ml of trimethylsilyl chloride was slowly added and then 1.6ml of pyridine was added dropwise over a period of 15 minutes. Then the mixture was stirred for 2 hours at 5"C.
(b) 1.67g of 3-bromo-2-methyl propionic acid was added to 10ml of methylene chloride and cooled to 15 c, and then, 1.1g of ethyl chloroformate was added. Next, 0.9ml of pyridine dissolved in 5ml of methylene chloride, was added dropwise over a period of 30 minutes and stirred for 90 minutes at a tempera ture between -15"c and -20 c.
(c) The reaction mixture obtained from (a) was added dropwise to the reaction mixture obtained from (b) over a period of 15 minutes at a temperature between -15 c and -20 c. The mixture was reacted for 60 minutes at a temperature between -15 c and -20 c and left to stand for 60 minutes at room temperature.
8ml of distilled water was added and the mixture was adjusted to pH4.8 with a 30% NaoH solution. The aqueous phase was separated, filtered, and adjusted to pH 2.0 with concentrated hydrochloric acid. The reactant was stirred for 120 minutes at 5"c, and left to stand overnight at 5"c. The precipitate was filtered, washed with cold water, and dried over phosphorous pentoxide under reduced pressure to obtain 1.16g of white crystalline 1-[3-bromo-(2S)-methylpropionyl]- pyrrolidine-(2S)-carboxylic acid.
Example 3
Following the procedure described in Example 1, by using ethylchloro-formate instead of methyl chlorformate, a similar yield to the 1-[3-bromo-(2S)-methylpropionyl]-pyrrolidine- (2S)-carboxylic acid was obtained.
Example 4
Following the procedure described in Example 1, by using pivaloyl chloride instead of methylchloroformate, a similar yield to 1-[3-bromo-(2S)-methylpropionyl]-pyrrolidine -(2S)-carboxylic acid was obtained.
Example 5
0.819 of thiourea and 1.419 of 1-[3-bromo-(2S)- methylpropionyl]-pyrrolidine-(2S)-carboxylic acid were dissolved in 15ml of ethanol and heated to reflux for 3 hours, and then, cooled to room temperature.
To this mixture was added 0.39g of sodium hydroxide dissolved in 5ml of distilled water, and further heated to reflux for 1 hour. Ethanol was distilled off under reduced pressure and cooled to room temperature, and then, the mixture was adjusted to pH 1.0 with hydrochloric acid. The reaction mixture was extracted three times with 20ml ethyl acetate each time, and the extract was washed with 10ml of saturated NaCI solution and dried over sodium sulfate, and then filtered. The purified residue obtained by concentration under reduced pressure was dissolved in 5ml of ethyl acetate, filtered, and crystallised from hexane.The crystalline residue was left to stand overnight at 5"e and separated by filteration and dried at 400c to obtain 0.859 of 1-[3-mercapto-(2S)- methylpropionyl]-pyrrolidine-(2S)-carboxylic acid as white crystals.
Melting Point : 103 c [aj2D: : -131.7" (C= 1.7, ethanol)
n m r (CDCI3): Refer to Fig 2
Example 6 1 .52g of thiourea and 2.82g of 1-[3-bromo-(2S)-methylpropionyl]- pyrrolidine-(2S)-carboxylic acid were dissolved in 20ml of distilled water and reacted for 5 hours at a temperature between 80 c and 85"c, and cooled to room temperature. To this mixture was added 0.8g of sodium hydroxide dissolved in distilled water and thereafter heated to reflux for 1 hour and cooled to room temperature. The resultant mixture was adjusted to pH1.0 with 2N HCI solution and then the mixture was extracted three times with 25ml of ethyl acetate each time, and then the extract was washed with 15ml of saturated NaCI solution and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 8ml of ethyl acetate, filtered, and then crystallised from hexane. The crystalline residue was left to stand overnight at 5"c, and then filtered and dried at 40 c to obtain 1.72g of 1-[3mercapto-(2S)-methylpropionyl]- pyrrolidine-(2S)-carboxylic acid as white crystals.
Claims (6)
1. A process for preparing the compound of the following formula(l):
characterized in that the compound of the following formula(ll):
(wherein X is bromo or chloro) is reacted with the compound of the following formula:
Cl-CO-R' (wherein R' is methoxy, ethoxy or t-butoxy) to obtain the acid anhydride of the following formula (Ill):
and the compound of formula (III) is acylated with the compound of the following formula (IV):
to obtain the compound of the following formula (V):
and the compound of formula (V) is reacted with thiourea to obtain the compound of the following formula (VI):
and, finally, the compound of formula (VI) is hydrolyzed to obtain the pyrrolidine derivatives of the formula (I).
2. A process according to claim 1, in which the compound (III) is obtained by reacting the compound (II) with methyl chloroformate, ethyl chloroformate, or pivaloyl chloride in the presence of an organic base.
3. A process according to claim 1, in which the hydrolysis of the compound (VI) is carried out in the presence of alkali metal hydroxide or carbonate and the final pH value is adjusted to 0.5 to 2.5.
4. A process for the preparation of the compound of formula (I) as shown in claim 1 which comprises hydrolysing a compound of formula (VI) as defined in claim 1.
5. A process according to claim 4 in which the compound of formula (VI) is prepared by reaction of a compound of formula (V) as defined in claim 1 with thiourea.
6. A compound of formula (Vl) as defined in claim 1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019840004361A KR860001391B1 (en) | 1984-07-23 | 1984-07-23 | Process for the preparation of pyrolidines |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8518550D0 GB8518550D0 (en) | 1985-08-29 |
| GB2162181A true GB2162181A (en) | 1986-01-29 |
| GB2162181B GB2162181B (en) | 1988-04-20 |
Family
ID=19234716
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08518550A Expired GB2162181B (en) | 1984-07-23 | 1985-07-23 | Process for producing pyrrolidine derivatives |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS6193157A (en) |
| KR (1) | KR860001391B1 (en) |
| DE (1) | DE3526023A1 (en) |
| ES (1) | ES8603819A1 (en) |
| FR (1) | FR2567881B1 (en) |
| GB (1) | GB2162181B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2667065A1 (en) * | 1990-09-21 | 1992-03-27 | Egyt Gyogyszervegyeszeti Gyar | PROCESS FOR PREPARING 1 - [(2S) -3-MERCAPTO-2-METHYL-1-OXOPROPYL] -L-PROLINE |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT395012B (en) * | 1986-06-27 | 1992-08-25 | Richter Gedeon Vegyeszet | METHOD FOR PRODUCING N- (1 (S) | THOXYCARBONYL-3-PHENYL-PROPYL) - (S) -ALANYL- (S) PROLIN AND ITS ACID ADDITION SALTS |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU509899B2 (en) * | 1976-02-13 | 1980-05-29 | E.R. Squibb & Sons, Inc. | Proline derivatives and related compounds |
| US4192945A (en) * | 1978-12-07 | 1980-03-11 | E. R. Squibb & Sons, Inc. | Process for preparing proline and homoproline derivatives |
| GB2065643B (en) * | 1979-12-13 | 1983-08-24 | Kanegafuchi Chemical Ind | Optically active n-mercaptoalkanoylamino acids |
| HU184082B (en) * | 1979-12-29 | 1984-06-28 | Egyt Gyogyszervegyeszeti Gyar | Process for preparing 1-3-/3mercapto-/2s/-methyl-propinyl/-pyrrolidine-/2s/-carboxylic acid |
| JPS58124764A (en) * | 1982-01-20 | 1983-07-25 | Kanegafuchi Chem Ind Co Ltd | Production of optically active thiol |
-
1984
- 1984-07-23 KR KR1019840004361A patent/KR860001391B1/en not_active IP Right Cessation
-
1985
- 1985-07-20 DE DE19853526023 patent/DE3526023A1/en active Granted
- 1985-07-22 JP JP60160393A patent/JPS6193157A/en active Granted
- 1985-07-22 ES ES545451A patent/ES8603819A1/en not_active Expired
- 1985-07-22 FR FR8511194A patent/FR2567881B1/en not_active Expired
- 1985-07-23 GB GB08518550A patent/GB2162181B/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2667065A1 (en) * | 1990-09-21 | 1992-03-27 | Egyt Gyogyszervegyeszeti Gyar | PROCESS FOR PREPARING 1 - [(2S) -3-MERCAPTO-2-METHYL-1-OXOPROPYL] -L-PROLINE |
| GR910100391A (en) * | 1990-09-21 | 1992-09-11 | Egyt Gyogyszervegyeszeti Gyar | Method for the preparation of 1-[(25)-3-mercapto-methyl-1-oxopropyl]-1-prolin |
Also Published As
| Publication number | Publication date |
|---|---|
| KR860001391B1 (en) | 1986-09-22 |
| KR860001066A (en) | 1986-02-22 |
| GB2162181B (en) | 1988-04-20 |
| DE3526023C2 (en) | 1988-10-20 |
| FR2567881B1 (en) | 1987-12-24 |
| ES545451A0 (en) | 1986-01-01 |
| JPS6137263B2 (en) | 1986-08-22 |
| ES8603819A1 (en) | 1986-01-01 |
| DE3526023A1 (en) | 1986-01-23 |
| JPS6193157A (en) | 1986-05-12 |
| GB8518550D0 (en) | 1985-08-29 |
| FR2567881A1 (en) | 1986-01-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19970723 |