KR820001832B1 - Process for preparing halogen substituted mercaptoacylamino acids - Google Patents

Abstract

Title compds. (I; R = H, lower alkanoyl; m = 1; 2; n = 0, 1; R1 = H, lower alkanoyl; R2, R2' = H, halogenl R3 = H, lower alkyl, CF3; R4 = H, lower alkyl, CF3; R6 = H), useful as hypotensive agents due to their ability to inhibit angloten-sin-converting enzyme, were prepd. by coupling of II and III. Thus, H-Pro-OCMe3 was condensed with AcSCH2CH(CF3)CO2H by dicyclohexylcarbodiimide in CH2Cl2 to give AcSCH2CH(CF3)CO-Pro-OCMe3, which was de-tert-butylated with CF3CO2H and deacetylated with aq. NH3 to give HSCH2CH(CF3)CO-Pro-OH.

Description

Manufacturing method of halogen substituted mercaptoacylamino acids

The present invention relates to a method for producing a halogen-substituted mercaptoacylamino acid represented by the following general formula (I) and a basic salt thereof.

Where

R is a hydrogen atom or a lower alkaoyl group,

m is 1 or 2,

n is 0 or 1,

R ₁ is a hydrogen atom or a lower alkyl group,

R ₂ and R ₂ ′ are each a hydrogen atom or a halogen atom,

R ₃ is a hydrogen atom, a lower alkyl group or a trifluoro methyl group, and when n is 1, it is a halogen atom,

R ₄ is a hydrogen atom, a lower alkyl group or a trifluoromethyl group,

R ₆ is a hydrogen atom, when m is 1 it is a halogen atom,

At least one of R ₂ , R ₂ ′, R ₃ , R ₄ and R ₆ is a halogen atom or a trifluoromethyl (CF ₃ ) group as indicated by symbols, and R ₂ and R ₂ ′ are both halogen atoms at the same time ,

Asterisk (*) represents an absent carbon atom.

The present invention broadly relates to halogen derivatives of dercaptoacylproline and mercaptoacylpipecolic acid represented by the general formula (I).

In proline (when m is 1), the compound represented by the following general formula (II) and (III) and the basic salt of these compounds are also contained in the compound represented by general formula (I).

Where

R is a hydrogen atom or a lower alkanoyl group,

R ₁ is a hydrogen atom or a lower alkyl group,

R ₂ and R ₅ are each a hydrogen atom or a fluoro atom,

R ₃ and R ₄ are each a hydrogen atom or a trifluoromethyl group, one of which is a hydrogen atom, the other is a trifluoro methyl group,

n is 0 or 1;

Where

R and R ₁ are as defined in the general formula (II),

R ₂ and R ₅ are each a hydrogen atom or a halogen atom,

R ₃ is a hydrogen atom, a halogen atom, or a lower alkyl group. When both R ₂ and R ₅ are hydrogen atoms, R ₃ is a halogen atom. When R ₂ or R ₅ is a halogen atom, R ₃ is other than a halogen atom. Is the flag of,

R ₄ is a hydrogen atom,

n is 0 or 1;

Therefore, in the case of General formula (II), when n is 0 and R <_2> and R <_5> are both hydrogen atoms, R <_3> is a trifluoro methyl group.

When n is 1, either R ₃ or R ₄ is a trifluoromethyl group and the other is a hydrogen atom. That is, there is one trifluoromethyl group in the acyl side chain of the molecule.

탄소 상에 위치하며, n이 1일 때에는 카르보닐기(R₃=CF₃, R₄=H)의

탄소 또는 카르보닐기(R₃=H, R₄=CF₃)의 β탄소상에 위치하는데, 이 때 R₃, R₄와 짝을 이루는 다른 치환체는 수소 원자로 된다. R₃또는 R₄중 어느 하하가 트리플루오로메틸기일 때에는 R₂와 R₅는 각각 수소 원자 또는 할로겐 원자이다.The trifluoromethyl group of the carbonyl group (R ₃ = CF ₃ ) when n is 0

Is located on carbon, and when n is 1, the carbonyl group (R ₃ = CF ₃ , R ₄ = H)

It is located on the β carbon of a carbon or carbonyl group (R ₃ = H, R ₄ = CF ₃ ), wherein the other substituents paired with R ₃ and R ₄ become hydrogen atoms. When either of R <_3> or R <_4> is a trifluoromethyl group, R <_2> and R <_5> is a hydrogen atom or a halogen atom, respectively.

In the case of Formula (III), one or both of R ₂ and R ₅ are halogen atoms, R ₃ and R ₄ are each a hydrogen atom, a lower alkyl group, or both R ₂ and R ₅ are hydrogen atoms , R ₃ is halogen, preferably a chlorine atom or a bromine atom and R ₄ is preferably a hydrogen atom.

In particular, R is a hydrogen atom or a lower alkanoyl, especially hydrogen atom or acetyl group in the general formula (Ⅰ), R ₁ is a hydrogen atom or a lower alkyl group, especially a hydrogen atom, R ₂ and R ₅ are each a hydrogen atom Or a halogen atom, in particular a hydrogen atom or a fluorine atom, R ₃ and R ₄ are each a hydrogen atom, a trifluoromethyl group or a lower alkyl group, and when R ₂ , R ₅ and R ₆ are all hydrogen atoms, R ₃ or R ₄ One of them is a trifluoromethyl group, the other is a halogen atom, and a compound in which n is 0 or 1, in particular, a compound of 1 is preferred.

One or two halogen atoms may be present in a pyrrolidine ring, one halogen atom may be present on a third or fourth carbon atom, and two halogen atoms may be present on a fourth position. It is preferable that all of them are present in. Moreover, it is preferable that a fluorine atom exists in a pyrrolidine ring, Especially, it is preferable that 1 or 2 fluorine atoms exist on a fluorine atom of a 4th position.

For l cholic acid, and (m is 2 time), general formula (Ⅰ) compounds R is hydrogen or lower alkanoyl, especially hydrogen or acetyl group, R ₁ is a hydrogen or lower alkyl, especially hydrogen and R ₂ Preference is given to compounds in which R ₂ ′ is each hydrogen or halogen, in particular hydrogen or fluorine, one of R ₃ and R ₄ is CF ₃ , the other is hydrogen, and n is 0 or 1, in particular 1. R ₂ and R ₂ ′ can each be hydrogen or halogen, in particular fluorine, and when R ₃ or R ₄ is CF ₃ , both R ₂ and R ₂ ′ are hydrogen.

Proline or pipecolic acid is particularly preferably L-configuration. The term lower alkyl group refers to straight-chain and branched hydrocarbon groups from methyl to heptyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and isopentyl And the like. Among the alkyl groups of C ₁ -C ₄ , especially alkyl groups on C ₁ and C ₂ are preferred.

The term lower alkanoyl group means groups having an acyl group of a lower fatty acid (C ₂ -C ₇ ), for example, an acetyl group, propionyl group, butyryl group and the like. Likewise, lower alkanoyl groups of up to 4 carbon atoms, in particular acetyl groups, are preferred. As the halogen, all four common halogens are preferable, among which chlorine, bromine and fluorine, in particular fluorine, are preferable.

The compound of general formula (I) can be manufactured by various synthesis methods.

In general, these compounds can be synthesized by the coupling reaction of an acid of formula (IV) with an amino acid of formula (V) by a method that can be used to form amide bonds.

See, for example, "Methoden der Organischen Chemie" (Houben-Weyl), Part 1, pages 376 and below, Part 3, pages 1 and below (1974).

The acid of general formula (IV) can be obtained by adding thio acid (R-SH) to the acrylic acid suitably substituted when n is 1.

In order to temporarily protect the mercapto group in the compound of general formula (IV), R can be made into the p-methoxy-benzyl group. This group is removed using trifluoroacetic acid and mercury acetate.

The acid of general formula (IV) is obtained by substitution reaction using thio acid (R-SH) and 2-halo acid when n is zero.

According to a specific example, when n is 0, a mixed anhydride, a symmetric anhydride, an acid chloride, an active ester, or a Woodward reagent is formed before the acid represented by the following general formula (VI) is reacted with the acid of the general formula (V). (V) by a known method of activating acid (V) using Woodward reagent K, EEDQ (N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline), and the like. Preference is given to coupling the acid of with the haloalkanoic acid of formula (VI).

In the above formula, X is halogen, in particular chlorine or bromine.

The product by this reaction has the following general formula.

This product undergoes a substitution reaction with the anion of thio acid of the following general formula to give a compound of the following general formula.

R-CO-SH (Ⅷ)

In the above general formula, R ₇ is a lower alkyl group.

This product is converted into a compound of the following general formula by alkali hydrolysis or vulcanization which is a conventional method.

When R ₁ is an ester group (that is, obtained when R ₁ is a lower alkyl group or an ester of starting acid (V)), this ester group can be removed by a known method.

For example, when R ₁ is t-butoxy or t-amyloxy, treatment of the esters of formula (VII) or (X) with trifluoroacetic acid and anisol yields corresponding free acids. If other alkoxy groups are present, they are alkali hydrolyzed to give the equivalent acid.

When the acid of general formula (V) is used as a starting material or the final product is obtained in the form of a free carboxylic acid, the acid may be a diazoalkane such as diazomethane, 1-n-butyl-3-p-tollitriagen, or the like. It can be converted into esters by esterification with 1-alkyl-3-p-tolyl-triazene or a homogeneous compound thereof.

According to an alternative, esters of formula (V), preferably methyl esters or t-butyl esters, are dicyclohexylcarbodiimide, N, N'- in anhydrous media such as dichloromethane, tetrahydrofuran, dioxane, etc. Treatment with acylthioalkanoic acid of the following general formula (XI) in the temperature range of about 0 ° C to 10 ° C in the presence of carbonylbisimidazole, ethoxyacetylene, diphenylphosphoryl azide or similar coupling reagent.

At this time, the ester group is removed by, for example, trifluoroacetic acid and anisole treatment at a temperature of about room temperature, thereby generating free acid (R ₁ = H). As another method, when n is 1, R ₄ is CH ₃ and R ₃ is H, an acrylic acid derivative of the following general formula (XII) is reacted with thio acid of the general formula (VIII) instead of the compound of general formula (XIII). Then proceed as described above.

By the method of Example 14 mentioned later, it is obtained as a compound of general formula (XII) from 3-trifluoromethyl-acrylic acid and ester of general formula (V).

In general formula (I), the compound of general formula (I) whose R is hydrogen can be converted into the symmetric bis compound which R <_1> has a following general formula, for example by direct oxidation with iodine.

In the present invention, reference is made to the examples of preparation of this bis compound.

Halogenated compounds of formula (V) to be used as starting materials can be prepared by methods known in the art. See, for example, Biochemistry 4, 2509 (1965), Austrian Chemistry 20, 1493 (1967), US Chem. Som. 86, 4709 (1964), See J. Med Chem. 20, 1176 (1977).

Compounds of formula (I) have one or more asymmetric centers, the basic of which is indicated by an asterisk (*) in formula (I). Thus, these compounds exist in racemic stereoisomeric forms or racemic mixtures thereof. All these compounds are within the scope of the present invention. Synthesis as described above can utilize either racemate or enantiomer as starting material. When the starting material of the racemate is used in the synthesis process, the stereoisomer in the product can be separated by conventional chromatographic or fractional crystallization.

In general, L-isomers are preferred for asymmetric carbons. The compounds according to the invention form basic salts with various inorganic or organic or organic bases which fall within the scope of the invention. Among these salts are alkali metal salts such as ammonium salts, sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, dicyclohexylamine salts, organic bases such as benzatin, N-methyl-D-glucamine and hydrabamin salts. Salts, salts of amino acids such as arginine, lysine and the like. Other salts are also useful for isolating or purifying the product, but physiologically acceptable nontoxic salts are preferred.

These salts are formed by conventional methods in which the product in free acid form is reacted with at least one equivalent of a base which provides a salt ion in a solvent or medium or water in which the salt is insoluble and then freeze-dried to remove the water. The salt may also be neutralized with an insoluble acid such as a cation exchange resin in the form of hydrogen ions (e.g., a polystyrene sulphonic acid resin such as Dowex 50) or an aqueous acid solution and then extracted with an organic solvent such as ethyl acetate or dichloromethane. Can be obtained and, if necessary, another salt can be produced.

The compounds according to the invention can be used as antihypertensives, which inhibit the conversion of decapeptide angiotensin (I) to angiotensin (II) and thus are used to reduce or alleviate angiotensin associated with hypertension. do. When the renin enzyme acts on an angiotensinogen, a sudoglobulin in plasma, angiotensin (I) is produced and angiotensin converting enzyme (ACE) results in angiogiosinin (ACE). Converted to tensin (II). Angiotensin (II) is an active boosting substance that causes various types of hypertension in mammals such as mice and dogs.

(레닌)

앤지오텐신Ⅰ

(ACE)

앤지오텐신Ⅱ의 진행을 방해하는 작용이 있기 때문에 본 발명에 따른 일반식(Ⅰ)의 화합물 또는 생리적으로 무독한 이의 염의 1종 또는 이들을 병용한 약제를 포유동물에 투여함으로써 앤지오텐신에 의한 포유 동물의 고혈압을 경감시킬 수가 있다.The compounds according to the invention reduce or inhibit the production of angiotensin (II) boosters, thereby reducing angiotensinogen.

(Lenin)

Angiotensin I

(ACE)

Since there is an action that interferes with the progress of angiotensin II, the mammal may be treated with angiotensin by administering to the mammal a compound of the general formula (I) according to the present invention or a physiologically toxic salt thereof or a combination thereof. It can reduce the hypertension of animals.

In order to lower blood pressure, it is preferable that about 0.1 to 100 mg / kg body weight per day, preferably about 1 to 50 mg / kg body weight once per day, preferably 2 to 4 times daily SL Engel, T Schaffer and B. Rubin's Proc. Soc. Exp. Biol. Med. 143 (1973), animal experiments. The substance may be administered orally, but may also be administered as a parenteral route of administration such as subcutaneous, intramuscular, intravenous or intraperitoneal administration.

The compounds according to the invention can be used to lower blood pressure as tablets, capsules, elixirs or for parenteral administration as sterile liquids or suspensions for oral administration. A unit according to the pharmaceutical preparation method, in which the compound of formula (I) according to the present invention or one or more mixtures of physiologically toxic salts thereof is combined with physiologically toxic excipients, carriers, binders, preservatives, stabilizers, flavors and the like. Formulated in formulation.

The content of the active substance in these formulations is such that the appropriate dose as described above is obtained.

Examples of auxiliaries that may be used in combination with tablets, capsules, etc. include tragacand rubber, acacia rubber, caking agents such as corn starch or gelatin, excipients such as dicalcium phosphate or microcrystalline cellulose, disintegrants such as corn starch, potato starch, alginic acid and the like. , Lubricants such as magnesium stearate, sweeteners such as sucrose, lactose, saccharin, flavoring agents such as peppermint, green tea oil, and cherry oil.

When the unit dosage form is a capsule, a liquid carrier such as fatty oil may be blended in addition to the aforementioned adjuvant.

In addition, in the case of coating or other physical unit dosage form, other substances may be contained.

For example, tablets may be coated with shellac, sugar, or both, and in the case of syrups or elixirs, active compounds, sugars as sweeteners, methyl or propyl parabens as preservatives, dyes and flavors such as cherries or oranges You can.

Injectable sterilizers may be formulated by conventional pharmaceutical methods for dissolving or suspending the active substance in excipients such as water for injection, vegetable oils of natural origin (eg, sesame oil, palm oil, peanut oil, cottonseed oil).

Hereinafter, the present invention will be described in more detail as examples. The temperature in an Example all points to Celsius (degreeC) temperature.

Example 1

3-acetylthio-2-trifluoromethylpropanoic acid

The mixture of thiol acetic acid (50 g) and 2- (trifluoromethyl) acrylic acid (66 g) are heated in a steam bath for 1 hour and then left at room temperature for 18 hours. Vacuum distillation of the reaction mixture yields the desired compound.

Example 2

1- (3-acetylthio-2-trifluoromethylpropane oil) -L-proline-t-butylester

The solution of L-proline t-butyl ester (5.1 g) dissolved in dichloromethane (40 mg) is stirred and cooled in an ice bath. Next, a solution of dicyclohexyl carbodiimide (6.9 g) dissolved in dichloromethane (15 ml) was added, followed immediately by 3-acetylthio-2-trifluoromethylpropanoic acid (6.5 g in dichloromethane (5 ml). ) Is added to the solution. After stirring for 15 minutes in an ice bath and for 16 hours at room temperature, the resulting precipitate is filtered and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and then washed to neutrality. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to give the desired compound.

Example 3

1- (3-acetylthio-2-trifluoromethylpropanoyl) -L-proline

1- (3-acetylthio-2-trifluoromethylpropanol-L-proline t-butylester (8 g) was dissolved in a mixture of aniazole (55 ml) and acetic acid trifluoride (110 ml), and at room temperature for 1 hour. After standing to remove the solvent in vacuo, the residue is precipitated several times in ether / hexane to afford the desired compound.

Example 4

1- (3-mercapto-2-trifluoromethylpropane oil) -L-proline

1- (3-acetylthio-2-trifluoromethylpropane oil) -L-proline (4 g) was dissolved in a mixture of water (8 ml) and concentrated ammonia (8 ml) under a nitrogen atmosphere and stirred at room temperature for 25 minutes. The reaction mixture is cooled, acidified and extracted with ethyl acetate. The organic layer is concentrated in vacuo to give the desired compound.

Example 5

2-Bromo-3,3,3-trifluoropropanoic acid

A solution of 3,3,3-trifluoroaniline (88 g) dissolved in a mixture of potassium bromide (250 g) and 2.5 N sulfuric acid (1.24 ml) was cooled to 0 ° C. in an ice bath, followed by vigorous stirring with sodium nitrite (65.5 g) is added in small portions over an hour. The reaction mixture is again stirred in an ice bath for several hours and then extracted with ether. The organic layer is washed with water, dried over magnesium sulfate and concentrated to dryness in vacuo to afford the desired compound.

Example 6

2-bromo-3,3,3-trifluoropropanoic acid chloride

The solution of 2-bromo-3,3,3-trifluoropropanoic acid (5 g) dissolved in thionyl chloride (5 ml) is heated while refluxing in a steam bath for 2 hours. Excess thionyl chloride is removed in vacuo and the residue is distilled off under reduced pressure to afford the desired compound.

[Example 7]

1- (2-acetylthio-3,3,3-trifluoropanoyl) -L-proline

A mixed solution formed by adding 2-bromo-3,3,3-trifluoropropanoic acid chloride (12 g) to a solution of L-proline (5.75 g) in 1 N sodium hydroxide (50 ml) cooled in an ice bath was added. Stir vigorously at room temperature for 3 hours. A solution of thiol acetic acid (4 ml) and potassium carbonate (4.8 g) in water (50 ml) was added to the reaction mixture, which was stirred for 16 hours at room temperature. The aqueous layer was then acidified with concentrated hydrochloric acid with ethyl acetate and extracted again with ethyl acetate. . The final organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo, and then the residue is chromatographed on silica gel column with benzene-acetic acid (7: 2) to afford the desired compound.

Example 8

1- (2-mercapto-3,3,3-trifluoropropane oil) -L-proline

Dissolve 1- (2-acetylthio-3,3,3-trifluoropropane oil) -L-proline (4 g) in a mixture of water (8 ml) and concentrated ammonia (8 ml) under nitrogen atmosphere and at room temperature for 30 minutes. After standing, the reaction mixture is acidified and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated to dryness in vacuo to afford the desired compound.

Example 9

1,1 '-[dithiobis- (2-trifluoromethyl-3-propaneyl)]-bis-L-proline

Dissolve 1- (3-mercapto-2-trifluoromethylpropane oil) -L-proline (1 g) in water adjusted to pH 7 with 1 N sodium hydroxide, and carefully add 1 N sodium hydroxide to pH 6 to Maintained at 7, dropwise add the ethanol solution of iodine. Once the stork is completely obtained, the addition of iodine is stopped and sodium thiosulfate is added to decolorize. Next, the reaction mixture is acidified and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated to dryness to afford the desired compound.

Example 10

1- (3-acetylthio-2-trifluoromethylpropaneoil) -L-proline sodium salt

1- (3-acetylthio-2-trifluoromethyl propanoyl) -L-proline (1 g) is suspended in water (10 ml), and the solution adjusted to pH 8 by adding 1N sodium hydroxide is lyophilized. Obtained.

Example 11

1- (3-acetylthio-2-trifluoromethylpropanoyl) -4,4-difluoro-L-proline

3-acetylthio-2-trifluoromethylpropanoic acid (in Example 6) in a solution of 4,4-difluoro-2-proline (7,5 g) dissolved in 1N sodium hydroxide (50 ml) cooled in an ice bath. According to the method (prepared from 3-acetylthio-2-trifluoromethylpropanoic acid and thionyl chloride) (12 g) is added and the mixture is vigorously stirred at room temperature for 2 hours. After acidification with concentrated hydrochloric acid, the mixture is extracted with ethyl acetate, and the organic layer is dried over magnesium sulfate and concentrated to dryness to obtain the target compound.

Example 12

1- (3-mercapto-2-trifluoromethylpropane oil) -4,4-difluoro-L-proline

Instead of 1- (3-acetylthio-2-trifluoromethylpropane oil) -L-proline in the method of Example 4, 1- (3-acetylthio-2-trifluoromethylpropane oil) -4, 4-difluoro-L-proline is used to obtain the desired compound.

Example 13

1,1 '-[dithiobis- (2-trifluoromethyl-3-propaneyl)]-bis-4,4-difluoro-L-proline

1- (3-mercapto-2-trifluoromethylpropaneyl) -4, instead of 1- (3-mercapto-2-trifluoromethylpropaneoyl-L-proline, in the method of Example 9 4-Difluoro-L-proline is used to obtain the desired compound.

Example 14

1- (4,4,4-trifluoro-2-butenyl oil) -L-proline

Ethyl 3-hydroxy-4,4,4-trifluorobutanoic acid ester (32.2 g, 0.173 mol) and boric anhydride (7.0 g, 0.1 mol) in 50 ml flasks with Dean-Stark trap ) (Melted with acid in a platinum crucible and ground under nitrogen atmosphere) is mixed and heated to 180 ° C. in a salt bath to dissolve all of the anhydride (takes about 6 hours).

The temperature is raised to 350 ° C. to allow 23 ml of distillate to collect in the trap. The distillate is again introduced into the reaction flask and the heating is repeated. This process is repeated four times to ensure that the hydroxy ester is fully dehydrated. The distillate was dissolved in petroleum ether, dried over phosphorus pentoxide and distilled to give 10 g of 4,4,4-trifluoro-2-butenoic acid-ethyl ester (boiling point: 115-120 ° C.) and 4,4,4-tri 650 mg of fluoro-2-butene acid (boiling point: 150 DEG C, recrystallized from 53 to 55 DEG C in pentane) is obtained. The ester is mixed with a 10% aqueous sodium hydroxide solution (24 ml) and the mixture stirred at 25 ° C. for 6 hours is diluted with water and extracted with methylene chloride to remove unreacted material.

The aqueous layer is adjusted to pH 3 with concentrated hydrochloric acid, and the mixture is extracted three times using 50 ml each of methylene chloride. The organic layers are combined, dried over magnesium sulfate, and the concentrated residue is distilled to give crystalline 4,4,4-trifluoro-2-butenoic acid (boiling point: 145-153 ° C.). Next, 4.6 g of an acid having a melting point of 54 to 55 is obtained by recrystallization in pentane. 4,4,4-trifluoro-2-butenoic acid (4.91 g, 35 mmol), hydroxybenzotriazole (4.73 g, 35 mmol), L-proline-t-butyl ester (6.00 g, 35 mmol) And dicyclohexylcarbodiimide (7.22 g, 35 mmol) in methylene chloride (200 ml) are stirred at room temperature under a nitrogen atmosphere. The filtrate of the reaction mixture was washed twice with 50 ml each time with 5% sodium sulfite, 50 ml twice with saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated to give an oil. It is dissolved in ether and the solution is cooled to filter out the precipitate. Next, the filtrate is concentrated to obtain 8.7 g of a solid (non-gum: 95 to 100 ° C).

A mixture of 1- (4,4,4-trifluoro-2-butenyl) -L-proline-t-butylester (4,0 g, 13.6 mmol) obtained above was diluted with trifluoroacetic acid (60 ml) and It is mixed with anisol (13 ml) and stirred under nitrogen atmosphere for 1 hour. The solvent is then removed under vacuum and the residue dissolved in ether (10 ml) is added in pentane (500 ml). Repeat this precipitation method and leave the residue at 0 ° C for 72 hours to cause crystallization.

Next, recrystallization of 1- (4,4,4-trifluoro-2-butenoyl) -L-proline in ethyl acetate-hexane yields 2.48 g of the target compound (boiling point: 119 to 120 ° C).

Example 15

1- (3-mercapto-4,4,4-trifluorobutan oil) -L-proline

Thiol acetic acid (1.5 ml) and 1- (4,4,4-trifluoro-2-butenyl oil) -L-proline (720 mg, 3 mmol) are mixed under an argon atmosphere, and the mixed solution is stirred at room temperature overnight. . Remove excess thiol acetate in vacuo and mix remaining 1- (3-acetylthio-4,4,4-trifluorobutanyl) -L-proline with an aqueous ammonia solution (15 ml of concentrated ammonia and 15 ml of mole). Stir at room temperature for 2 hours. The mixture is then diluted with ice and acidified with concentrated hydrochloric acid, extracted three times with 50 ml each time with methylene chloride, the extract is dried over sodium sulfate and concentrated to give an oil. It is dissolved in water, treated with carbon and purified by filtration through a micropore filter. The solution is then freeze-dried to give 700 mg of the target compound as a colorless glass.

Example 16

3-acetylthio-4,4,4-trifluorobutanoic acid chloride

Instead of 2-trifluoromethyl acrylic acid in the method of Example 1, 3-acetylthio-4,4,4-trifluorobutanoic acid was used using 4,4,4-trifluoro-2-butenoic acid. After obtaining, the target compound is obtained by chlorination with thionyl chloride in the same manner as in Example 6.

Example 17

1- (3-mercapto-4,4,4-trifluorobutanoil) -4,4-difluoro-L-proline

The product obtained using the chloride 1- (3-acetylthio-4,4,4-trifluorobutanoic acid instead of 3-acetylthio-2-trifluoromethylpropanoic acid in the method of Example 11 was carried out. Treatment in the same manner as in Example 4 gives the target compound.

Example 18

1,1'-Dithiobis- (4,4,4-trifluoro-3-butanyl) -bis-L-proline

1- (3-mercapto-4,4,4-trifluorobutanyl) -L instead of 1- (3-mercapto-2-trifluoromethylpropaneoyl) -L-proline in the method of Example 11 Proline is used to obtain the desired compound.

Example 19

Cis-4-fluoro-L-proline, bromate

A) N-carbobenzyloxy-4-hydroxy-L-proline, methyl ester:

N-carbobenzyloxy-4-hydroxy-L-proline (12.4 g, 0.047 mol) is esterified with diazomethane in dioxane-ether. To prevent freezing of the dioxane, the diazomethane solution is added at 10 ° C, and the addition is stopped when the temperature reaches 0 ° C to 2 ° C. 14.6 g (yield: 100%) of an almost colorless viscous oily product are obtained.

B) N-carbenzyloxy-4-tosyloxy) -L-proline, methyl ester

N-carbobenzyloxy-4-hydroxy-L-proline and 14.5 g (0.052 mol) of methyl ester were dissolved in 30 ml of pyridine and the stirred solution was mixed with -5 ° with a mixture of 15 ml of pyridine and 11 g (0.058 mol) of tosyl chloride. Dropwise to -8 ° C. The resulting pale yellow solution was left to cool for 3 days, and then 300 ml of ice-cooled 2N hydrochloric acid was added with stirring. The rubbery precipitate was extracted with 200 ml of chloroform, the aqueous layer was extracted three times with 100 ml of chloroform once, and the solvent was evaporated to yield a pale yellow viscous oil. It is dissolved in 100 ml of methanol and diluted to 400 ml with water to precipitate an oily substance. This material is gradually determined by inoculation, friction and cooling (17.4 g, (77%), melting point: 62-65 ° C). Crystallization in 85 ml of isopropanol yields 15.9 g, (70%) of colorless crystalline target compound. It obtains (melting point: 67-69 degreeC).

C) cis-N-carbenzyloxy-4-fluoro-L-proline, methyl ester:

N-carbobenzyloxy-4-tosyloxy-L-proline and 19.1 g (0.044 mol) of methyl esters were stirred and suspended in 100 ml of distilled diethylene glycol, and it was anhydrous potassium fluoride at 42 degreeC under argon atmosphere. The solution treated with 19.1 g (0.33 mol) is heated at 81 ° -84 ° C. for 20 hours. Next, when the pale yellow solution produced by cooling is treated, 18.6 g of the target compound is obtained (pale yellow oily substance).

D) cis-N-carbenzyloxy-4-fluoro-L-proline:

Cis-N-carbenzyloxy-4-fluoro-L-proline, methyl ester (18.4 g, about 0.044 moles) was dissolved in 140 ml of methanol and -1 ° to -1 using 33 ml (0.066 moles) of 2N sodium hydroxide. After dropwise treating at 4 ° C, the mixture is left to stand at 0 ° C for 1 hour at room temperature. After removing about half of the solvent in a rotary evaporator, the solution was diluted with 300 ml of water and washed with ether (disposal of the wash), acidified to pH 2 with 12.5 ml of hydrochloric acid (1: 1) and ethyl acetate 1 Extract 4 times using 150ml each time. The extract was mixed, washed with 100 ml of saturated sodium chloride solution, dried (MgSO ₄ ), and the solvent was evaporated to yield 13.8 g of a pale yellow viscous oil.

The viscous oil obtained is dissolved in 60 ml of ethanol and treated with a solution of 5.1 g of cyclohexylamine in ethanol (10 ml) and diluted to 900 ml with ether. When a seed is added and the container wall is rubbed, the cyclohexylamine salt crystals of the target compound are separated. After cooling overnight, the weight is 11.0 g (melting point; 180-183 ° C), which is then crystallized in 70 ml of ethanol to give 7.6 g of a colorless solid (melting point: 185-187 ° C).

〕

= -40

(c=1, 메탄올).[

]

= -40

(c = 1, methanol).

The cyclhexylamine salt is suspended in 75 ml of ethyl acetate, stirred and treated with 45 ml of hydrochloric acid to separate the layers. The aqueous layer was extracted twice using 75 ml of ethyl acetate each time, and then the organic layers were combined, dried (MgSO ₄ ), and the solvent was evaporated. Final drying of the target compound, which is the remaining free acid, at 0.2 mm and 45 ° C. yielded 5.7 g (49%) of crystals (melting point; 116-118 ° C.).

E) cis-4-fluoro-L-proline, borate:

Cis-N-carbenzyloxy-4-fluoro-L-proline (5.5 g, 0.021 mol) is treated with 28 ml of hydrogen bromide in acetic acid (30-32%) and the stopper is loosened and stirred for 1 hour. Ether (300 ml) is added to the yellow mixture and the ethereal solution is decanted once the crystalline product has settled and washed with 300 ml of fresh ether. The product was finally heated with 70 ml of methyl ethyl ketone in a steam bath, cooled for 2 hours and then washed with cooled methyl ethyl ketone, then washed with ether and dried in vacuo to give 3.8 g of an almost colorless target compound (WEED, 86 %) Is obtained. Melting point 189-191 ° C (decomposition),

〕

=-19

(c=1, 메탄올).[

]

= -19

(c = 1, methanol).

Part of the crude crude bromate obtained is passed through a column of ion exchange resin to convert it into free acid.

Example 20

Cis-1- [D-3- (acetylthio) -2-methyljapanpanoil] -4-fluoro-L-proline

Cis-4-fluoro-L-proline, hydrobromide (4.5 g, 0.021 mol) and 4.2 g (0.023 mol) of D-3-acetylthio-2-methylpropanoic acid chloride were reacted in 50 ml of water in the presence of sodium carbonate, During the acylation (approximately 20 minutes), stabilize to pH 8.0-8.2. The mixture was left to stand for 1 hour, washed with ethyl acetate (50 ml × 2 times), and the layers were separated using ethyl acetate, acidified to pH 2 with hydrochloric acid, saturated with sodium chloride, and then separated. The aqueous layer is extracted again with ethyl acetate and the organic layers are mixed, dried and evaporated. After evaporation of ethyl acetate, the remaining solids are contacted under ether and evaporated again to yield a colorless material having a melting point of 146-148 ° (sintering temperature, 133).

〕

= -132

(c=1,메탄올).[

]

= -132

(c = 1, methanol).

The dicyclohexylamine salt is obtained by adding dicyclohexylamine to cis-1- [D-3- (acetylthio) -2-methylpropane oil] -4-fluoro-L-proline in 70 ml of ethyl acetate. 8.1 g of -204 ° (sintering temperature, 187) is crystallized.

〕

= -72

(c=1, 메탄올). 또,[

]

= -72

(c = 1, methanol). In addition,

Crystallization in 90 ml of isopropanol yields 7.0 g having a melting point of 205-207 ° (sintering temperature, 190 °). As a result of recrystallization in ethanol, the melting point change of specific light no longer appeared.

Dicyclohexylamine salt (16.9 g) is converted back to the free acid by partitioning between 10% potassium sulfite and ethyl acetate (60 ml of 10% KHSO ₄ , 4 × 50 ml ethyl acetate extract). When the organic layers were combined and evaporated to dryness, 4.1 g (yield 71%) of colorless free acid having a melting point of 154-156 ° (sintering temperature, 140) was obtained.

〕

= -142

(c=1, 메탄올).[

]

= -142

(c = 1, methanol).

Example 21

Cis-4-fluoro-1- (D-3-mercapto-2-methylpropaneoil) -L-proline

Cis-1- [D-3- (acetylthio) -2-methylpropaneoil] -4-fluoro-L-proline (3.9 g, 0.014 mol) was hydrolyzed in 22 ml of water containing 9 ml of ammonium hydroxide The reaction mixture is acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated to dryness to yield 3.3 g of glassy products, which were slowly crystallized when dried at 50 ° C. under 0.2 mm pressure. 20 ml of ethyl acetate is added to this material (at this time, slightly heated in argon atmosphere), diluted with 25 ml of hexane, mixed, and cooled overnight under argon atmosphere. After filtration under an argon milk powder, washing with hexane and vacuum drying yielded 2.8 g of a colorless solid target compound having a melting point of 135-137 ° (sintering temperature, 129).

〕

= -116

(c=1, 메탄올).[

]

= -116

(c = 1, methanol).

Example 22

1- [3- (acetylthio) -2-chloropropane oil] -L-proline (isomer A)

L-proline (1.44 g) and sodium carbonate (667 mg) were dissolved in 17 ml of water, stirred in an ice bath, and a solution of sodium carbonate (2 g) dissolved in 8.5 mg of water was added thereto, followed by 3-acetylthio-2- Chloropropanoic chloride (2.5 g) is added. Next, the ice bath was removed, and after 30 minutes, 17 ml of water was added to the resulting precipitate and dissolved. After a total of 1.5 hours the reaction mixture is extracted twice with ethyl acetate. The aqueous layer was cooled, acidified with concentrated hydrochloric acid, saturated with sodium chloride, extracted with ethyl acetate, concentrated to dryness in vacuo, and 100 g of crude oil was obtained. This material was added to a column of 100 g silica gel and eluted with benzene-acetic acid (7: 1) to give 2 g of product. Crystallization in water gave 450 mg of the target compound having a melting point of 11-113 °.

〕_D= -17

(c=1, 메탄올).[

_D = -17

(c = 1, methanol).

Example 23

1- [3- (acetylthio) -2-chloropropane oil] -L-proline (isomer B)

The aqueous mother liquor of Example 22 is lyophilized and chromatographed with benzene-acetic acid (7: 1) on silica gel. 800 mg of a substance having a melting point of 90-109 DEG C is obtained by collecting, drying and concentrating the components containing the ultraviolet absorber and showing the homogeneous phase in thin layer chromatography.

〕

= -4

(c=1, (에탄올).[

]

= -4

(c = 1, (ethanol).

The mother liquor is concentrated by lyophilization and the desired compound, which is a residual material, is crystallized in ether-hexane to give 380 mg (melting point: 108-110 ° C).

〕

= -17.6

(c=1.25, 에탄올).[

]

= -17.6

(c = 1.25, ethanol).

Example 24

1- [3- (acetylthio) -2-bromopropane oil] -L-proline

In the method of Example 22, 3-acetylthio-2-bromopropanoic acid chloride was used instead of 3-acetylthio-2-chloropropanoic acid to obtain a target compound having a melting point of 109-110 °.

〕D=-162

(c=1.39, 에탄올)[

D = -162

(c = 1.39, ethanol)

Example 25

Cis-4-chloro-1- (D-3-mercapto-2-methylpropaneoil) -L-proline

In the method of Example 20, instead of cis-4-fluoro-L-proline, bromate, the compound produced using cis-4-chloro-L-proline was treated by the method of Example 21 to give cis 1- [ D-3- (acetylthio) -2-methylpropane oil] -4-chloroproline and the desired compound.

Example 26

Trans-4-bromo-1- (D-3-mercapto-2-methylpropaneoil-L-proline

Instead of cis-4-fluoro-L-proline bromate in the method of Example 20, treatment was carried out by the method of Example 21, using trans-4-bromo-L-proline, to provide trans-1- [D Obtain 3-((acetylthio) -2-methylpropaneoyl] -4-bromo-L-proline and the target compound.

Example 27

Cis-4-iodo-1- (D-3-mercapto-2-methylpropaneoil-L-proline

Compounds produced using cis-4-iodo-L-proline instead of cis-4-fluoro-L-proline bromide in the method of Example 20 were treated by the method of Example 21, cis-1- [D -3- (acetylthio) -2-methylpropaneoyl] -4-iodo-L-proline and the desired compound are obtained.

Example 28

Cis-4-fluoro-1- (3-mercaptoto-2-rifluoromethylpropaneoil) -L-proline

The resulting compound was treated in the method of Example 20 using 3-acetylthio-2-trifluoromethylpropanoic acid chloride instead of 3-acetylthio-2-methylpropanoic acid in the method of Example 21, thereby preparing cis Obtain the desired compound with -1- [3- (acetylthio) -2-trifluoromethylpropaneoyl] -4-fluoro-L-proline.

Example 29

Cis-3-fluoro-DL-proline, bromate

Instead of N-carbenzyloxy-4-hydroxy-L-proline in the method of Example 19, N-carbobenzyloxy-3-hydroxy-DL-proline is used to obtain the desired compound.

Example 30

Cis-3-fluoro-1- (D-3-mercapto-2-methylpropaneoil-DL-proline

Instead of cis-4-fluoro-DL-proline in the method of Example 20, the compound produced using cis-3-fluoro-DL-proline hydrobromide was treated in the method of Example 21 to give cis- Obtain 1- [D-3- (acetylthio) -2-methylpropaneoyl] -3-fluoro-DL-proline and the desired compound.

Example 31

Cis-3-chloro-1- (D-3-mercapto-2-methylpropaneoil-L-proline

Instead of cis-4-fluoro-L-proline-bromate in the method of Example 20, the compound produced using cis-3-chloro-L-proline was treated by the method of Example 21 to give cis-1- Obtain the desired compound with [D-3- (acetylthio) -2-methylpropaneoyl] -3-chloro-L-proline.

Example 32

4,4-dichloro-1- (D-3-mercapto-2-methylpropane oil) -L-proline

Compounds produced using 4,4-dichloro-L-proline prepared from 4-keto-L-proline diketoperazine and phosphorus pentachloride instead of cis-4-fluoro-L-proline bromate in the method of Example 20 Is treated by the method of Example 21 to obtain 1- [D-3- (acetylthio) -2-methylpropaneoyl] -4,4-dichloro-L-proline and the target compound.

Example 33

1,1 '-[Dithiobis- (2-D-methylpropaneyl)]-bis- (cis-4-fluoro) -L-proline

Cis-4-fluoro-1- (D-3-mercapto-2-methyl instead of 1- (3-mercapto-2-trifluoromethylpropanoyl) -L-proline in the method of Example 9 Propaneyl) -L-proline is used to obtain the desired compound.

Example 34

4,4-difluoro-1- (3-mercaptobutan oil) -L-proline

In the method of Example 11, instead of 3-acetylthio-2-trifluoromethylpropanoic acid, the compound produced using 3-chloroacetylthiobutanoic acid was treated by the method of Example 12 to obtain 1- (3 Acetylthiobutanoyl) -4,4-difluoro-L-proline and the desired compound are obtained.

Example 35

1- (3-propaneylthio-2-trifluoromethylpropaneoil) -L-proline

In the method of Example 1, instead of thioacetic acid, the compound produced using thiopropanoic acid was treated by the method of Examples 2 and 3 to give 3-propanoylthio-2-trifluoromethylpropanoic acid, 1- ( 3-Propanoylthio-3-trifluoromethylpropane oil) -L-proline-t-butylester and the target compound are obtained, respectively.

Example 36

3- (4-methoxybenzyl) thio-2-trifluoromethylpropanoic acid

A mixture of 1-trifluoromethylacrylic acid (3.9 g) and 4-methoxybenzylthio (4.3 g) was stirred at 100-110 ° C. for 1 hour, then cooled to room temperature, recrystallized from cyclohexane, and the solid target compound was obtained. It obtains (melting point; 72-74 degreeC).

Example 37

1- [3- (4-methoxybenzyl) thio-2-trifluoromethylpropaneoil] -L-proline t-butylester

A solution of 3- (4-methoxybenzyl) thio-2-trifluoromethylpropanoic acid (6.5 g) and proline t-butyl ester (3.76 g) in dichloromethane (500 ml) was stirred at 0 ° C. Treated with dicyclohexylcarbodiimide (4.53 g). After 30 minutes at 0 ° C., overnight at room temperature, the mixture is filtered and the filtrate is washed with neutrality. The organic layer is dried and concentrated to dryness in vacuo. Thin layer chromatograph [using methylene chloride-ethyl acetate (95: 5) of silica gel] treatment gives two diastereomers.

Example 38

1- (3-mercapto-2-trifluoromethylpropane oil) -L-proline

Solution of 1- [3- (4-methoxybenzyl) thio-2-trifluoromethylpropane oil) -L-proline t-butylester (4.47 g) and anisol (10 ml) obtained in Example 37-0 Cool to 占 폚, add phase fluorinated acetic acid (100 ml), and add mercury acetate (3.18 g). The cooling bath is removed and the mixture is stirred at room temperature for 1 hour, after which the mixture is concentrated to dryness in vacuo and treated with ether-hexane. Suspension of insoluble material in water generates hydrogen sulfide for 10 minutes. The precipitate is filtered off and the filtrate is lyophilized to give the target compound as an amorphous solid. Rf 0.29-0.31 (silica gel-benzene: using 7: 1 acetic acid).

Example 39

Chloride 3-acetylthio-2-chloropropanoic acid

Instead of 2-trifluoromethylacrylic acid in the method of Example 1, the compound produced using 2-chloroacrylic acid is reacted with thionyl chloride to give 3-acetylthio-2-chloropropanoic acid and the desired compound.

Example 40

Chloride D-3-acetylthio-2-methylpropanoic acid

〕

=-61.8°(CHCI₃)〕에 염화티오닐(증류물)(83ml, 1.173몰)을 가하여, 생성되는 용액을 실온에서 18시간 교반하여 가스를 방출시킨다. 과잉의 염화티오닐을 진공 상태의 50℃에서 증발시키고 잔류물을 감압증류하면, 비점이 40-44°(0.17-0.2mmHg)인 6.9g의 목적 화합물을 얻는다.A suspension of 1- (D-3-percapt-2-methylpropane oil) -L-proline (150 g, 690 mmol) in 1247 ml of water and 426 ml (5.526 mol) of concentrated hydrochloric acid were refluxed for 8 hours with stirring in a nitrogen atmosphere. The solution was kept at room temperature overnight and extracted 10 times with 400 ml of chloroform. The chloroform extracts are combined and dried over magnesium sulphate under nitrogen atmosphere and then evaporated. 81.2 g (176 ml, 1.809 mole) of acetic anhydride and 180 ml of pyridine were added to the evaporation residue, and the mixture was kept at room temperature for 20 hours, and then the oily residue obtained by evaporation was dissolved in 1000 ml of ethyl acetate. Wash with 200 ml of sodium chloride saturated solution (this time pH 2), followed by two washes with 200 ml of saturated sodium chloride solution, washing to pH 7 in the second wash. After washing, remove solvent. The resulting oily substance [96.9 g, 86.5%, [

]

= -61.8 ° (CHCI ₃ )] is added thionyl chloride (distillate) (83 ml, 1.173 mol) and the resulting solution is stirred at room temperature for 18 hours to release the gas. Excess thionyl chloride was evaporated at 50 ° C. in vacuo and the residue was distilled under reduced pressure to yield 6.9 g of the desired compound having a boiling point of 40-44 ° (0.17-0.2 mmHg).

]=

-42.5

(C=2, 메탄올).[

] =

-42.5

(C = 2, methanol).

Example 41

3-acetylthio-2-bromopropanoic acid chloride

In the method of Example 1, the compound produced using 2-boromoacrylic acid instead of 2-trifluoromethylacrylic acid is reacted with thionyl chloride to obtain 3-acetylthio-2-bromopropanoic acid and the desired compound.

Example 42

Trans-1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -4-fluoro-L-proline

A) trans-1-carbobenzyloxy-4-fluoro-L-proline

To a solution of 6.2 g of trans-1-carbobenzyloxy-4-fluoro-L-proline methyl ester dissolved in 50 ml of methanol, 11.5 ml of 2N sodium hydroxide solution was added dropwise at 0-5 ° C., and after 1 hour at 0 ° C. Heat to room temperature to prevent sun.

The reaction mixture is concentrated to about half of the original volume under reduced pressure and then diluted with 100 ml of water. The aqueous solution of the reaction mixture is extracted with ether and the ether extract is discarded. The solution was acidified to pH 2 with dilute hydrochloric acid while cooling the aqueous solution, and then extracted four times with 50 ml each time using ethyl acetate. The ethyl acetate extracts were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired product. This target product is then converted to cyclohexylamine salt for purification. Melting point, 194-196 °

]

= -44

(c=1%, 메탄올).[

]

= -44

(c = 1%, methanol).

This cyclohexylamine salt is suspended in 25 ml of ethyl acetate, treated with 22 ml of 1N hydrochloric acid, and extracted three times with 35 ml each time using ethyl acetate to obtain a free acid. The ethyl acetate extract mixture is dried over anhydrous magnesium sulfate and the solvent is concentrated under reduced pressure to afford the desired compound.

B) trans-4-fluoro-L-proline hydrobromide

A mixture of 15 ml of hydrogen bromide and 3 g of trans-1-carbobenzyloxy-4-fluoro-L-proline in acetic acid (30-32%) is stirred for 1 hour, and then 150 ml of anhydrous ether is added. The solvent is decanted from the precipitate, and then the precipitate is treated with ether and finally treated with methyl ethyl ketone to obtain the target compound having a melting point of 162-164 ° (decomposition).

]

=-30

(c=1%, 메탄올).[

]

= -30

(c = 1%, methanol).

C) trans-1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -4-fluoro-L-proline

To a solution in which trans-4-fluoro-L-proline hydrobromide was dissolved in 25 ml of cold water, 1 g of sodium carbonate was added to adjust the pH to 8.2. Stirring was then continued with cooling (5 ° C.) and dropwise addition of 1.8 g of D-3-acetylthio-2-methylpropionyl chloride in 2.5 ml of ether was added dropwise and the pH was maintained at about 8.2-8.3, which was 25% sodium carbonate The solution is added dropwise. Stirring and cooling are continued for 1 hour after the dropping. The reaction mixture is extracted and discarded twice using 25 ml of ethyl acetate once. 50 ml of ethyl acetate is added to the aqueous layer, stirred, cooled, and adjusted to pH 2 by dropwise addition of concentrated hydrochloric acid. The aqueous layer is saturated with sodium chloride and the ethyl acetate layer is separated. The liquid layer was further extracted three times using 25 ml of ethyl acetate at a time, and the ethyl acetate extract was mixed, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the target compound. In preparing the cyclohexylamine salt, the compound is dissolved in 25 ml of ethyl acetate and prepared by adding a solution of 1.8 g of dichlorohexylamine in 35 ml of ethyl acetate. The precipitated salt was filtered off and the recrystallized isopropane in trans--1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -4-fluoro-L- having a melting point of 209-211 °. The dicyclohexamineamine salt of proline is obtained.

]

=-85

(c=1%, 메탄올).[

]

= -85

(c = 1%, methanol).

The dicyclohexylamine salt is dissolved in 5% potassium sulfate solution and extracted with ethyl acetate to recover the free acid. The ethyl acetate solution is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired compound.

Example 43

Trans-4-fluoro-1- (D-3-mercapto-2-methyl-1-oxopropyl) -L-proline

]

=-112

(c=1%, 메탄올).Argon was passed through a cold solution in which 4.2 ml of ammonium hydroxide was dissolved in 16 ml of water, and trans-1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -4-fluoro- was added to the solution. 1.8 g L-proline is added under stirring under argon atmosphere. The reaction mixture is stirred for another 2 hours and then extracted with ethyl acetate. The aqueous layer is stirred, 30 ml of ethyl acetate is added and acidified with concentrated hydrochloric acid. Next, the aqueous layer was saturated with sodium chloride and the ethyl acetate layer was separated, and the aqueous layer was extracted three times using 30 ml of ethyl acetate at a time. The ethyl acetate extracts are combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the desired compound. [

]

= -112

(c = 1%, methanol).

Example 44

1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -4,4-difluoro-L-proline

1-carbobenzyloxy-4,4-difluoro-L-proline, methyl ester

In 80 ml of methylene chloride, 3.3 ml of 1-carbobenzyloxy-4-keto-L-proline and methyl ester were stirred and dissolved, and 3.3 ml of diethylaminonosulfatrifluorolide was added dropwise to the cooled solution. After the reaction mixture was left at room temperature overnight, about 100 g of ice cubes were added with stirring and stirred for 45 minutes. The organic layer was separated and the aqueous layer was extracted twice using methylene chloride at a time of 40 ml each time. The extract is mixed, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired compound.

B) 1-carbobenzyloxy-4,4-difluoro-L-proline

To a solution of 5.6 g of 1-carbobenzyloxy-4,4-difluoro-L-proline and methyl ester in 50 ml of methanol, 11.5 ml of a 2N sodium hydroxide solution was added dropwise at 0-5 占 폚. The reaction mixture is kept at 0 ° C. for 1 hour and then heated to room temperature and left overnight. The reaction mixture is concentrated under reduced pressure to about half the original volume, and diluted with 100 ml of water. The reaction mixture aqueous solution is extracted with ether and the ether extract is discarded. Next, the solution was acidified to pH 2 with dilute hydrochloric acid while cooling, and extracted three times with 50 ml each time as ethyl acetate. The ethyl acetate extracts are combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give 1-carbobenzyloxy-4,4-difluoro-L-proline. This product is purified by conversion to cyclohexylamine salt.

]

=-24

(c=1%, 에탄올).Melting Point: 180-185 ℃, [

]

= -24

(c = 1%, ethanol).

The cyclohexylamine salt solution is treated with hydrochloric acid and ethyl acetate is extracted four times using 30 ml each time to obtain a free acid. The ethyl acetate extract is dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the target compound.

C) 4,4-difluoro-L-proline hydrobromide

A mixture of 12 ml of hydrogen bromide and 2.4 g of 1-carbobenzyloxy-4,4-dioxydifluoro-L-proline in acetic acid (30-32%) was stirred at room temperature for 30 minutes, followed by addition of 300 ml of anhydrous ether. . The mixture is cooled and the precipitated solid is filtered and dried under reduced pressure to give a compound having a melting point of 163-165 ° (decomposition).

]

= -14

(c=1%, 메탄올).[

]

= -14

(c = 1%, methanol).

D) 1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -4,4-difluoro-L-proline

To 30 ml of water, 2.7 g of 4,4-difluoro-L-proline and bromate were added and stirred to adjust the pH to 8.4 by adding solid carbonate to the solution cooled to 5 ° C. Subsequently, 2.4 g of D-3-acetylthio-2-methylpropionyl chloride was added dropwise to 3 ml of anhydrous ether while cooling and stirring were continued. At this time, 25% sodium carbonate solution was added to adjust the pH of the solution to 8.1-8.3. Keep it. After the dropping, the stirring and cooling are continued for 1 hour. The reaction mixture is extracted with ethyl acetate (2 × 25 ml) and the extract is discarded. 50 ml of ethyl acetate was added to the aqueous layer, stirred and cooled, and concentrated hydrochloric acid was added thereto to adjust the pH to 2.0. The aqueous layer is then saturated with sodium chloride and the ethyl acetate layer is separated. The aqueous layer is extracted with ethyl acetate (3 × 25 ml), the combined ethyl acetate extracts are dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the desired product. This product was dissolved in 40 ml of ethyl acetate and a solution of 2.3 g of dicyclohexylamine dissolved in 5 ml of ethyl acetate was added to prepare a dicyclohexylamine salt. The precipitated salt was filtered and recrystallized in ethanol to give the dicyclohexylamine salt of 1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -4,4-difluoro-L-proline ( Melting point: 225-227 ° C).

]

= -70

(c=0.5%, 메탄올).[

]

= -70

(c = 0.5%, methanol).

The dicyclohexylamine salt is dissolved in 5% potassium sulfate and extracted with ethyl acetate to recover the free acid. The ethyl acetate solution is dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the target compound.

Example 45

4,4-difluoro-1- (D-3-mercapto-2-methyl-1-oxopropyl) -L-proline

1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -4, while stirring in an argon atmosphere to the solution which passed argon in the cold solution which melt | dissolved 4.6 ml of ammonium hydroxide in 11 ml of water, 2.1 g of 4-difluoro-L-proline is added. The reaction mixture is stirred for two more hours and extracted with ethyl acetate. The aqueous layer is stirred and acidified with concentrated hydrochloric acid by adding 30 ml of ethyl acetate. The aqueous layer is then saturated with sodium chloride and the ethyl acetate layer is separated. The aqueous layer is extracted with ethyl acetate (3 × 25 ml), the ethyl acetate extracts are combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the target compound.

Example 46

1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -5-fluoro-2-pipecolic acid

A) Carbobenzyloxy-5-hydroxy-L-pipecolic acid, methyl ester

To a solution of 5 g of 1-carbobenzyloxy-5-hydroxy-L-pipecolic acid in 60 ml of dioxane is added dropwise an ether solution of diazomethane to yellow. At this time, the temperature is maintained at about 5 ℃. The resulting solution is treated with glacial acetic acid and the resulting solution is dried over anhydrous magnesium sulfate. The solution is concentrated under reduced pressure to obtain the target compound as a pale yellow viscous oil.

B) 1-carbobenzyloxy-5-tosyloxy-L-pipecolic acid, methyl ester

To a solution obtained by stirring and dissolving 1-carbobenzyloxy-5-hydroxy-L-pipecolic acid and 5.7 g of methyl ester in 12 ml of pyridine, a mixed solution of 4 g of tosyl chloride and 6 ml of pyridine was added dropwise at 5 ° -8 ° C. The reaction mixture is held at 5 ° C. for 72 hours and then treated with 200 ml of ice-cold 2N hydrochloric acid while cooling. The precipitate is dissolved in chloroform and this solution is further extracted with chloroform (3 × 75 ml). The chloroform solutions are combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the target compound having a melting point of 74-76 ° C. which is crystallized in isopropanol.

]

=-5

(c=1%, 메탄올), [

]

=-11

(c=1%, 클로로프름).[

]

= -5

(c = 1%, methanol), [

]

= -11

(c = 1%, chloroform).

C) 1-carbobenzyloxy-5-fluuro-L-pipecolic acid, methyl ester

In 50 ml of this ethylene glycol, 5.2 g of 1-carbobenzyloxy-5-tosyloxy-L-pipecolic acid and 5.2 g of methyl ester was suspended and stirred with an aqueous solution of 5.2 g of potassium fluoride anhydride and the mixture was stirred for 14 hours at 80 ° C. Heat. The cooled solution is diluted with 50 ml of water and extracted with ethyl acetate (3 × 100 ml). The acetyl acetate extracts are combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to give the desired compound as a yellow oily substance.

D) 1-carbobenzyloxy-5-fluoro-L-pipecolic acid

7.3 ml of 2N sodium hydroxide solution was added to a cold solution (0 ° C.) in which 4.6 g of 1-carbobenzyloxy-5-fluoro-L-pipecolic acid methyl ester was added in 32 ml of methanol. The reaction mixture is left overnight at 0-5 ° C. and at room temperature. The solution is concentrated under reduced pressure to about half and diluted with 20 ml of water. The solution is extracted with ester and the extract is discarded. The aqueous solution was cooled, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (3 × 50 ml). The ethyl acetate extract is dried over magnesium sulfate sulfate and then concentrated under reduced pressure to give 1-carbobenzyloxy-5-fluoro-L-pipecolic acid. Next, it converts to the cyclohexylamine salt and refine | purifies.

]

=-11

(c=메탄올).Melting point 158-161 °, [

]

= -11

(c = methanol).

The aqueous solution of this salt is treated with hydrochloric acid, extracted with ethyl acetate (4 × 25 ml), and the dried extract is concentrated under reduced pressure to obtain a free acid.

E) 5-fluoro-L-pipecolic acid hydrobromide

12 ml of hydrogen bromide and 2.2 g of 1-carbobenzyloxy-5-fluoro-L-pipecolic acid were mixed in acetic acid (30-32%), stirred at room temperature for 30 minutes, and 300 ml of anhydrous ether was added thereto. The cooled mixture is filtered and the precipitated solid is dried under reduced pressure to afford the desired compound.

F) 1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -5-fluoro-L-pipecolic acid

10 g of 1N methylpropoline is added to a suspension of 5.1 g of 5-fluoro-L-pipecolic acid hydrobromide suspended in 100 ml of dimethylacetone. 5.4 g of D-3-acetyl-2-methylpropionyl chloride was slowly added to the mixture with vigorous stirring and heated at 90 ° C. for 3 hours. The cooled reaction mixture is filtered and concentrated under reduced pressure. The residue is treated with dilute hydrochloric acid and extracted with ethyl acetate (3 × 150 ml). The ethyl acetate extract is dried and concentrated under reduced pressure to obtain the target compound. The acid is purified by conversion to dicyclohexylamine salt followed by crystallization of the salt in acetonitrile.

Example 47

5-Fluoro-1- (D-3-mercapto-2-methyl-1-oxopropyl) -L-pipecolic acid

Nitrogen was passed for 30 minutes in a solution (5 ° C.) in which 11 ml of ammonium hydroxide was dissolved in 25 ml of water, and then 1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -5- 1.6 g of fluoro-L-pipecolic acid is added and the mixture is stirred at 5 ° C. for 15 minutes and at room temperature for 4 hours. The solution is cooled, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (3 × 50 ml). The ethyl acetate extract was concentrated under reduced pressure, dried over anhydrous magnesium sulfate, to obtain the target compound.

Example 48

1- (3-Mercapto-2-trifluoromethylpropane oil) -L-pipecolic acid

Instead of L-proline-t-butyl esder in the method of Example 2, the compound produced using L-pipecolic acid t-butylesder is treated by the methods of Examples 3 and 4 to obtain the target compound.

Example 49

1- (2-Mercapto-3,3,3-trifluoropropane oil) -L-pipecolic acid

Instead of L-proline in the method of Example 7, treatment with the method of Example 8 using L-pipecolic acid to obtain the target compound.

Example 50

1- (3-Mercapto-2-trifluoromethylpropane oil) -5,5-difluoro-DL-pipecolic acid

Compounds produced using 5,5-difluoro-DL-pipecolic acid prepared from 5-keto-DL-pipecolic acid instead of 4,4-difluoro-L-proline in the method of Example 11 Is treated by the method of Example 12 to obtain the target compound.

Example 51

1,1 '-[dithiobis- (2-trifluoromethyl-3-propaneyl)] bis-5,5-difluoro-DL-pipecolic acid

1- (3-mercapto-2-trifluoromethylpropane oil) -5 in place of 1- (3-mercapto-2-trifluoromethylpropane oil) -L-proline in the method of Example 9. , 5-Difluoro-DL-pipecolic acid is used to obtain the desired compound.

Example 52

1- (3-mercapto-4,4,4-trifluorobutan oil) -L-pipecolic acid

In the method of Example 14, instead of L-proline t-butylester, the compound produced using L-pipecolic acid t-butylester is treated by the method of Example 15 to obtain the target compound.

Example 53

1- (3-mercapto-2-trifluoromethylpropanoyl) -5,5-dichloro-DL-pipecolic acid

Instead of 4,4-difluoro-L-proline in the method of Example 11, produced using 5,5-dichloro-DL-pipecolic acid prepared from 5-keto-DL-pipecolic acid and phosphorus pentoxide The obtained compound is treated by the method of Example 12 to obtain the target compound.

Example 54

1- (3-Mercapto-2-methylpropanoyl-5,5-difluoro-DL-pipecolic acid

Instead of 3-acetylthio-2-trifluoromethylpropanoic acid chloride in the method of Example 11, the compound produced using 3-acetylthio-2-methylpropanoic acid chloride was treated by the method of Example 12. Obtain the desired compound.

Example 55

1- (3-Mercapto-2-methylpropane oil) -5-fluoro-DL-pipecolic acid

In the method of Example 11, instead of 3-acetylthio-2-trifluoromethylpropanoic acid, 3-acetylthio-2-methylpropanoic acid was used, and 4,4-difluoro-L-proline was used. Instead, the compound produced using 5-fluoro-DL-pipecolic acid prepared from 5-hydroxypipecolic acid by the method described in Biochemistry No. 4, 2507 (1965) was treated in the same manner as in Example 12 to give 1- Obtain the desired compound with (3-acetylthio-2-methylpropaneoyl) -5-fluoro-DL-pipecolic acid.

Example 56

1- (3-mercaptopropane oil) -5-bromo-DL-pipecolic acid

In the method of Example 11, 3-acetylthiopropane oil was used instead of 3-acetylthio-2-trifluoromethylpropanoic chloride, and instead of 4,4-difluoro-L-proline, Austria Compounds produced using 5-bromo-DL-pipecolic acid prepared from 5-hydroxypipecolic acid by the method described in Aust. J. Chem 20, 1493 (1967) were prepared by the method of Example 12. Treatment with 1- (3-acetylthiopropaneyl) -5-bromo-DL-pipecolic acid affords the above target compound.

Example 57

1- (3-acetylthio-2-trifluoromethylpropaneoil) -DL-pipecolic acid methyl ester

Instead of L-proline t-butyl ester in the method of Example 2, DL-pipecolic acid methylester is used to obtain the desired compound.

Example 58

1- (3-mercapto-2-trifluoromethylpropane oil) -DL-pipecolic acid methyl ester

In the method of Example 2, instead of L-proline t-butyl ester, DL-pipecolic acid methyl ester and 3-mercapto2-trifluoromethylpropanoic acid instead of 3-acetylthio-2-methyl propanoic acid To obtain the desired compound.

Example 59

1- (3-Propanoylthio-2-trifluoromethylpropaneoyl) -5-fluoro-DL-pipecolic acid

Instead of thiol acetic acid in the method of Example 1, the compound produced using thiopropanoic acid is treated by the method of Example 26 to obtain the target compound.

Example 60

Sodium salt of 1- (3-mercapto-2-methylpropane oil) -5-fluoro-DL-pipecolate

The 1- (3-mercapto-2-methyl-propaneyl) -5-fluoro-DL-pipecolic acid solution is mixed with an equimolar amount of an aqueous 1N-sodium hydroxide solution and freeze-dried.

Example 61

1- (3-mercaptopropanoyl) -5,5-dichloro-DL-pipecolic acid

Instead of 3-acetylthio-2-trifluoromethylpropanoic acid in the method of Example 53, 1- (3-mercaptopropanoyl) -5,5-dichloro- was substituted with 3-acetylthiopropanoic acid chloride. Obtain DL-Pipecolic acid.

The various examples described above are prepared using the racemic form of the final compound prepared in each as DL-form instead of the L-form of the starting amino acid.

Likewise, the DL-form is used instead of the L-form of the starting amino acid to prepare the D-form of the final product of each of the foregoing embodiments.

Example 62

1000 tablets containing 100 mg of 1- (D-3-mercaptopropane oil) -cis-4-fluoro-L-proline are prepared as follows.

1- (D-3-mercaptopropane oil) -cis-4-fluoro-L-proline and corn starch are mixed with gelatin solution, dried and ground to a fine powder. Avicel and magnesium stearate are mixed in order and then granulated. The tablets were pressed into tablets to prepare 1000 tablets containing 100 mg of the active ingredient.

Example 63

1000 tablets containing 200 mg of 1- [D-3-acetylthio) -2-methylpropane oil] -cis-4-fluoro-L-proline are prepared as follows.

1- [D-3- (acetylthio) -2-methylpropanoyl] -cis-4-fluoro-L-proline-lactose and Avicel are mixed and corn starch is added to mix. Magnesium stearate was added and the dried mixture was compression molded into tablets and coated with a solution in which yellow # 6 pigment was added to methyl cellulose.

Example 64

A capsule is prepared by combining a mixture of the following composition ingredients in gelatin capsule # 1 each containing 250 mg of 1- (3-mercapto-4,4,4-trifluorobutanoil) -L-proline.

Example 65

Injection solutions are formulated with the following compositions:

The active substance, preservative and sodium chloride are dissolved in 3 l of water for injection and the total is made up to 5 l. The solution is passed through a sterile filter, filtered, injected into a sterile vial and sealed with a sterile rubber stopper. This will contain 100 mg of active substance per ml of injection as a concentration in 5 ml of liquid in each vial. The products in each example can be prepared in the same manner as in Examples 62-65.

Claims (1)

A method for producing a halogen-substituted mercaptoacylamino acid of the following general formula (I) and a basic salt thereof, wherein the acid of the following general formula (IV) is subjected to a coupling reaction with an amino acid of the following general formula (V).

In the above formula, R is a hydrogen atom or a lower alkanoyl group, m is 1 or 2, n is 0 or 1, R ₁ is a hydrogen atom or a lower alkyl group, R ₂ and R ₂ ′ are each a hydrogen atom or a halogen atom, R ₃ is a hydrogen atom, a lower alkyl group or a trifluoro methyl group, and when n is 1, it is a halogen atom, R ₄ is a hydrogen atom, a lower alkyl group or a trifluoro methyl group, R ₆ is a hydrogen atom, when m is 1 it is a halogen atom, At least one of R ₂ , R ₂ ′, R ₃ , R ₄ and R ₆ is a halogen atom or a trifluoro methyl group (CF ₃ ) as indicated by symbols, and R ₂ and R ₂ ′ are both halogen atoms at the same time.

In the above formulas, R is a hydrogen atom, a lower alkanoyl group or a p-methoxy-benzyl protecting group which is later released, Other groups are as defined above.