SI7811482A8 - Process for the preparation of thienopyridine derivatives - Google Patents

Description

PARCOR

PROCEDURE FOR BEYOND THE TIPNOPYRIDINE DERIVATIVES

The field of technology in co is the invention

The present invention falls within the field of organic synthesis, and more specifically relates to a process for the preparation of thienopyridine derivatives. According to the International Patent Classification, this application is designated as: C O7D 495/04.

Technical problem

The present invention solves the problem of obtaining thienopyridine derivatives used as medicaments by a process that is cheaper and more easily achievable than earlier ones.

The prior art of claim 75 03 9GQ and its first additional claim; '75 23 786 discloses a process for the preparation of thienopyridine by reacation of the [b-thienyl-2-ethylamine derivative, optionally substituted. to formaldehyde in the presence of acid. This reaction of the salt is optionally realized in two steps, primarily the reaction of? -Thienyl-ethylamine on formaldehyde and then by cyclization of the product obtained in the anhydrous medium by the action of anhydrous acid. the percentage of the initial product yield is only in the order of 60-65% _{f which} makes it necessary to re-cyclize the initial product which did not respond,

I. I

Moreover, this process does not allow the preparation of thienopyridines substituted at position 4 by the Pietet Sponglor reaction by the action of an aldehyde on a thienyl-ethyl-amine derivative. ·. . ·.

i

Also known is the process for the preparation of 1,2,3,4-tetrahydroisoquinoline, 'with the initial derivatives of' N-benzoyl * * * <* ³ 'beta-arylamine and chloromethylmethyl ether, as described; in Chemical

I • Communications, 1969, 1283-4. However, it should be noted that cyclization takes place on a very active benzene ring and that, < _t with the reaction center is one amide. · '.J .z

DESCRIPTION OF 'TECHNICAL PROBLEM SOLUTIONS' This invention relates to • ¹ thienopyridine derivatives of the general formula to a process for obtaining

(I) a rt in which R ¹ 'represents a hydrogen atom ^{1 or} chlorobenzyl R 1 and R 2 are a hydrogen atom and R is a hydrogen atom, isopropyl / ethoxycarbonyl / phenyl or thienyl, wherein the compound of formula and ν \ .Ί - C '

Ra - Rp

I '^; I

CH - CH - NH - Rn (II)

-a - o - a, · 0 · i-.jp ~ ~ -V ^ΰ ~

;. χοΊ-ηι is X atom k <allo - / _- .. a as n ?. example'Article 111 2 radical, iii. aryl radical in which R ^ Rp and ^?: Rj · have the above meanings, reacts with the compound of the formula

I ⁴ "

J, - .CH.- J ...

(HI)

- in which ^: R / has a previously defined meaning, X is a chlorine atom,, ... 4 ..., 'Y' is methoxy, ethoxy or methylthio or a group of the formula -O-CR in *

·· =. ··. ·. · .-> θ to which R is tertiary butyl, or the two groups X and I of carbon atoms form a heterocyclic nucleus with Six hexahydroS-triazine bonds and urotropin iii trioxane, in a solvent such as dimethylformamide or 'dimethylsulfoxide' the presence of acid • when X if radicals close the ring, at a temperature between 45 ° C and 80 ° C and in the anhydrous medium and, where necessary, free the free base ·

The compounds of formula III used in the process of the invention can be represented by the nature of X and Ϊ by the following compounds.

- ^ 3. The compounds of formula III used in the process of the invention can be represented by the nature of X and Y by the following

J din je_njima; ·, / ·

a) * halogenomethyl ether type iii

R.

XCH - O - R ₅ 'X - CH - O - CH - X in which X is a halogen atom such as Cl or Br and is a lower alkyl radical, or an aryl radical.

b) - halogenomethyl thio ether. type

R.

· 'Iii

X - CH - S - R, X - CH - S - CH - X in which X is a halogen atom such as Cl or Br and R8 is lower alkyl or aryl radical.

T 't ,, *

c) - halogenomethyl ester type

XCH - 0 - C - R.

in which X is a halogen atom such as Cl iii Br 1 -R ^ is a lower alkyl or aryl radical.

d) - S-Hexahydro-S-triazine of the formula

iii the amino derivative of the formula

those in which the su R g, R _g, R _1Q, R ^, R ^ and _L2 ^is Alko radicals koji ranks possibly present between themselves jedan azotni bridge iii aryl radicals jednak iii Various.

e) - Trioxane of formula

iii a polyoxymethylene derivative of the formula * 13 - (O-CH ₂ ) _n - O R ₁₄ in which both R _{4 are} hydrogen atoms iii lower alcohol iii aryl radicals, equal or different, an 1.

f) - tritian formula

iii a polythiomethylene derivative of the formula '. '' ^R is'- ^(SCH 2> n- ^SR 16 in which ^R 15 and lower alcohol or aryl radicals are the same or different an 1.

The reaction between the compound of formula II and the compound of formula III takes place in an inert solvent at a temperature between 0 ° C and 150 ° C but also at a temperature between the room temperature and the boiling point of the most volatile compound, which is usually one of the solvents used.

This reaction is most likely via the formation of a single intermediate that is not isolated but cyclized in situ, as will be eliminated later.

Cyclization of an intermediate compound requires the presence of an acid that is either formed in the environment during the reaction, of the formation of the intermediate product, or added if it is not formed in the reaction of the construction of the intermediate product. The construction of an acid in situ depends on the nature of the compound of formula III, as well as the compound of formula III of type a, b, c, we note the construction of one such acid of formula HX which serves as a cyclizing agent, whereas, with the compounds of formula III of type d, e, if, the acid does not build.

In the latter case, an acid-containing reaction solvent is used, such as:

.

a mineral acid, if necessary, anhydrous, such as hydrochloric, sulfuric, hydrobromic, phosphoric or organic acids,. 'carbocyclic, such as oxalic acid, acetic acid, monochloroacetic or sulfonic such as methanesulfonic acid, sulfobenzolic acid.

In the case where the acid is formed in the environment itself, it is desirable to add the compound of formula III to the solution of the compound of formula II, although the opposite is possible. In other cases, it is advisable to add a mixture of compounds of formulas II and III to the acidic solution containing cyclization acid.

j θ

The reaction / usually fast, but sometimes it is advisable to warm up at the end of the reaction to speed it up.

The reaction may take place at atmospheric pressure or at a higher pressure, but usually atmospheric pressure is sufficient.

The reaction takes place in an inert solvent with respect to the reactants, in particular with respect to the compounds of formula III. That solvent must. be anhydrous because, water decomposes the compounds of formula III. Aprotic solvents that can be polar in nature, such as dimethylformamide, dimethylsulfoxide, hexameters phosphorriamide, or other solvents such as benzene, toluene, chlorinated solvents such as chlorine hydrocarbons or light ethers are commonly recommended.

It is preferable for the reaction to take place in a solvent in which the halogen compound of formula I is small or not dissolve at all, since then the salts of the compounds of formula I would be separated at the end of the reaction by filtering the precipitated precipitate. This mode provides excellent yields, in addition to the convenience of obtaining.

7.

The compounds of formula II and III to the reaction uzimaju ^'Λ u stereohemijskim quantities ,. iii possibly with a molar excess of a compound of formula III that goes up to about 50%.

The requester considers that he should indicate that the reaction takes place in the two steps shown in the reaction scheme below, since the two steps do not differ in practical implementation.

The cyclization takes place with the construction of one alcohol, one mercaptan, one amine or water.

This cyclization gives excellent yields and a high percentage of conversion of the starting compounds. Thus, in cyclizations where the reactant is chloromethyl-methyl-ether or chloromethyl-methyl-thioether, the conversion and conversion of the compounds of formula II is almost 100% and yields are in the order of 90-95%.

8.

On the other hand, by virtue of the process of the invention, it is possible to obtain · thienopyridine derivatives in which the group is a R ^ aryl group such as a phenyl group, a heterocyclic group such as a thienyl -2 group, an aliphatic or cycloaliphatic radical, or a functional group such as a example alkoxycarbonyl, carboxy group.

The construction of the initial reactants of formula III is readily accomplished by the preparation processes described in the literature which do not fall within the scope of the present invention. Some of the compounds of formula III are unstable and therefore need to be prepared immediately prior to use in the inventive process in which they are used without purification.

For ease of understanding, the process for preparing the thienopyridine derivative of the present invention is illustrated in the following embodiments, which in no way limit the scope of protection required.

Example: 1

Preparation of Chlorhydrate (Chloro-2 Benzyl) - 5 Tetrahydro 4,5,6,7 'Thieno (3,2-c) Pyridine

A solution of 50.8 g (0.2 M) of N- (chloro-2 benzyl) (thienyl-2) - 2 ethylamine in 70 cm ^{3 of} dimethylformamide, heated to 60OC, was added over a period of 7 minutes 22.7 gr (0 , 24 M) chloromethylmethyl ether. The temperature of the reaction mixture was maintained at 60 ° C throughout the addition phase, cooling it in water. Thirty minutes after the addition of chloromethylmethyl ether, the mixture was cooled to 20 ° C. The expected product, which settles, is filtered and then washed with two 70 cm ³ acetone portions. 45.1 g of the hydrochloride (chloro-2 benzyl) -5 tetrahydro 4,5,6 'thieno (3,2-c) pyridine are obtained. (yield: 75%).

Re-treatment of the filtrate allowed to collect about 9 g of the desired compound (yield: 90% - melting point = 190 ° C).

Example:

f

Preparation of Chlorhydrate (Chloro-2 Rice; 1 H - 5 'ethoxycarbonyl -4 tetrahydro 4,5,6,7 thieno (3,2-c) pyridine.

A 25.1 g (0.1 14) N- (chloro-2-benzyl) (thienyl-2) -2-ethylamine solution was introduced into a 3 cm-wide balloon in 3 0 cm. .. dimethyl formamide. 18.3 g (0.11 M) of chloro-2 ethoxy-2 ethyl acetate were then added over 6 minutes and heated at 80 ° C for 4 hours. The expected product begins to settle. After cooling, the product was filtered and recrystallized three times in 20 cm of acetone. 20.5 g of (chloro-2 benzyl) -5 ethoxy-carbonyl-4 tetrahydro 4,5,6,7 thieno (3,2-c) pyridine hydrochloride are obtained (yield: 55%).

Treatment of the filtrate allows a further 10 g of crude product to be obtained (melting point: 156 ° C). The crude product can be obtained analytically pure by recrystallization in a mixture of isopropyl ethanol ether. (total yield: 81.8%). .

Example: 3

Preparation of (chloro-2 benzyl) -5 (thienyl-2) -4 tetrahydro 4,5,6,7 thieno (3,2-c) pyridine hydrochloride.

a) Preparation of (thienyl-2) chloromethylmethyl ether.

Pour 112 g (IM) (thienyl- ·,

-2) carboxaldehyde, 50 g (1.55 M) of methanol, 125 cm of methylene chloride and 150 g of sodium sulfate. The reaction mixture was cooled at -35 ° C and permeable to saturation of gaseous hydrogen chloride, J not allowing the temperature to spin - 20 ° C. After ceasing- | To remove the hydrochloric acid bubble, the reaction mixture was left at -20 ° C for 2 hours with stirring. Then, the methylene chloride was evaporated at -20 ° C to give crude (thienyl-2) / chloromethyl methyl ether.

10.

b) Preparation of (chloro-2 benzyl) -.5 (thienyl-2) -4 tetrahydro 4,5,6,7 thieno (3,2-c) pyridine hydrochloride.

Take N- (chloro-2 benzyl) (thienyl-2) -2 ethylamine to react in ether, prepared as a) explained as. above in Example 1 to obtain the desired compound (melting point of base: 1O9 ° C).

Example 4. 15.

In the analogous manner described in Example 1, the following compounds are prepared:

chloride (chloro-2 benzyl) 5 phenyl-4 tetrahydro?

4,5,6,7 thieno (3,2-c) pyridine.

(melting point of base: 95 ° C), chlorhydrate (chloro-2 benzyl) - 5 isopropyl - 4 tetrahydro 4,5,6,7 thieno (3,2-c) pyridine.

, (melting point of base: 172 ° C),

And, respectively, starting from N - (chloro-2 benzyl) (thienyl-2) - 2 stylamine and the following compounds:

- cC chlorobenzyl methylether,

- chloro-1 ethoxy-1 methyl-2 propane.

Example: 6

Preparation of tetrahydro 4,5,6,7 thieno (3,2, -c) pyridine tetrahydrochloride.

To a solution of 12.7 g (0.1 M) (thienyl-2) -2-ethylamine in 20 cm &lt; 2 &gt; of dimethylformamide, heated at 55 [deg.] C., 8.05 g (0.1 M) of chloromethylmethyl ether dissolved over 10 minutes in 10 cm of dimethylformamide. After the addition of chloromethyl methyl ether, the mixture was maintained at 70 ° C for 2 hours and then cooled to room temperature. The expected product which is deposited is acetone. 5.5 g of tetrahydrochloride is obtained

4,5,6,7 thieno (3,2-c) pyridine. (mp: 225 ° C). (yield: 31%).

I

11.

Example: 7

Preparation of Chlorhydrate (Chloro-2 Benzyl) - 5 Tetrahydro 4,5,6,7 Thieno (3,2-c) Pyridine.

a) Preparation of chloromethylmethylthioether

To a three-liter three-liter balloon was added 274 gr (2.3 M) of thionyl chloride and 400 cm of methylene chloride. It is heated in a water bath (41 ° C) and 156 g of dimethyl sulfoxide are slowly added. During the addition, a strong separation of gases consisting of SC ^ and HCI is observed. A slight warming should be maintained so that the reaction mixture is constantly boiling slowly.

After completion of the dhmethylsulfoxide addition, nitrogen is leaked to eliminate dissolved hydrochloric acid.

The reaction mixture (333 gr) was used as described late in the cyclization operation. The quantitative chromatographic test in the gas phase gives the following results:

- Chloromethylmethylthioether: 56.77%,

- methylene chloride: 33%

b) Chlorohydrate (chloro-2 benzyl) - 5 tetrahydro!

4,5,6,7 thieno (3,2-c) pyridine. !

i

In 52 gr (0.2 M) N - (chloro-2 benzyl) (thienyl-2)

-2 of ethylamine dissolved in 60 cm of dimethylsulfoxide and heated to 60 ° C was added over 30 minutes 51 g (0.3 M) of crude chloromethylmethylthioether obtained in step a) as described above.

The temperature of the reaction mixture begins to increase progressively and is maintained between 80 and 85 ° C throughout the addition phase by cooling in water. After the addition of chloromethylmethylthioether was completed, the mixture was cooled to 6 ° C. The expected product is very easy to deposit.

Filtration and washing with 2 x 70 cm acetone yielded 44.1 grams of chlorohydrate (chloro-2 benzyl) -5 tetrahydro 4,5,6,7 and thieno (3,2-c) pyridine. (yield: 73.5%). Treatment of the filtrate orno- and pushed to obtain another 10 g of the desired compound (yield: 90%, j

m.p. = 190 ° C). The crude product thus obtained contains 1 - 2% impurity and can be purified to analytical purity by recrystallization in ethanol.

Example: 8 1'Hydrochloride (chloro-2 benzyl) - 5 tetra hydro 4,5,6,7 thieno (3,2-c) pyridine hydrochloride.

The same compound as in Example 1 is prepared as follows.

It still has to react, by heating for 3 hours,

66.5 g (0.44 M) of chloromethyl methyl pivalate. to a solution of 103 gr (0.4 M) N · - (chloro-2 benzyl) (thienyl-2) - 2 ethylamine in 300 <

dimethylsulfoxide to give the yield of 51% of the compound indicated in the title above.

Examples 9

Preparation of Chlorhydrate (Chloro-2 Benzyl) - 5 (tetrachloride 4,5,6,7 thieno (3,2-c) pyridine.

In 42 cm of dimethylformamide in which 0.25 mol of hydrochloric acid gas is dissolved and heated at 40 ° C, a mixture of 25.15 g (0.1 M) of N - (chloro-2 benzyl) is added over 2 minutes. (thienyl-2) - 2 ethylamines i

15.3 gr (0.033 M) s.hexahydrotriazine;. · ?; o.chlorobenzylamine. The reaction is exothermic and must be cooled in water during addition to maintain the temperature of the reaction mixture below 70 ° C. After the addition is complete, the mixture is allowed to stir for 30 minutes and then cooled. The resulting product was filtered and washed twice with acetone. Obtain 17.3 g of chlorhydrate (chloro-2 benzyl) - 5 tetrahydro 4,5,6,7 thieno (3,2-c) pyridine Treatment ^- filtrate provides an additional 10 g of expected product (approximate yield: 90% ).

Examples: 10-12 · ·.

Preparation of Chlorhydrate (Chloro-2 Benzyl) - 5 Tetrahydro 4,5 / 6,7 Thieno (3,2-c) Pyridine.

According to the method described in Example 9, the compound indicated in the title above was obtained by substituting s.hexahydrotriazine o.chlorobenzylamine with:

n.butylamine hexahydrotriazine (90% yield)

- urotropin (yield: 60%)

- paraformaldehyde (yield: 83%)

Example: 13

Preparation of tetrahydro tetrahydro 4,5,6,7 thieno (3,2, ^ - c) pyridine hydrochloride.

To 73 cm @ 2 of dimethylformamide heated to 45 [deg.] C., in which 0.45 moles of hydrochloric acid was dissolved, a mixture of 17 g (0.2 M) of s.hexahydrotriazine n.butylamine and 26 gr · (25 g) was added over a 25 minute period. thienyl-2) -2 ethylamine. The temperature of the mixture was maintained at 45 ° C during the addition, using a cold water bath. Upon completion of the addition, the expected product is deposited. Filtration gave 22.16 g of tetrahydro 4,5,6,7 thieno (3,2-c) pyridine hydrochloride (yield: 65%).

Example: 14

Preparation of Chlorohydrate (Chloro-2 Benzyl) - 5 Tetrahydro 4,5,6,7 Thieno (3,2-c) Pyridine.

To 2.25 g (0.075 M) of paraformaldehyde suspended in 20 cm @ 2 of dimethylformamide, 9.61 g (0.1 M) of methanesulfonic acid are added. As the mixture was maintained at 72 ° C, 13 g (0.05 M) of N- (chloro-2 benzyl) (thienyl-2) -2 ethylamine dissolved in 5 cm ^ of dimethylformamide were added over 2 minutes.

The sraese temperature reaches 90 ° C. The mixture was then cooled to 20 ° C 3 - and poured into 50 cm 4 N sodium carbonate ^- ; then extra cation of 30 cm is carried out followed by 20 cm of methylene chloride. The organic phases are combined, dried over sodium sulfate and evaporated. He gets it

- 'is an oil which is placed in 30 cm of ethanol in which 0.15 mol of hydrochloric acid gas is dissolved. After partial ethanol evaporation, the expected product is precipitated. It is filtered, washed with acetone and dried. 11.35 g of hydrochloride are obtained.

N - (chloro-2 benzyl) -5 tetrahydro 4,5,6,7 thieno (3,2-c) pyridine (yield: 75.6%).

· '' ·· 1 ^ -1482 / 78

APPLICANT'S STATEMENT Ο THE MOST KNOWN WAY FOR THE ECONOMIC USE OF THE APPLICATION- FINDING

As the best way to commercially use the claimed invention, the applicant states the following:

• Preparation of Chlorohydrate (Chloro-2 Bonzyl) - 5 tetrahydro 4,5,6,7 thieno (3,2-c) pyridine

To a solution of 50.8 gr (0.2 M) N- (chloro-2 benzyl) (thienyl-2) - 2 ethylamine in 70 crP dimethylformamide, heated to 60 ° C, was added 22.7 gr (0, over 7 minutes). 24 M) chloromethylmethyl ether. The temperature of the reaction mixture was maintained at ^r, 60 ° C throughout the addition phase, cooling it in water. Thirty minutes after the addition of chloromethylmethyl ether is complete, the mixture is stirred _; cool to 20 ° C. The expected product, which settles, is filtered and then washed with two 70 cm @ 2 acetone portions. Gets *

45.1 g of chlorchldrate (chloro-2 benzyl) -5 tetrahydro 4,5,6,7 thieno (3,2-c) pyridine. (yield: 75%).

Re-treatment of the filtrate allows the collection of about 9 g of the desired compound (yield: 90% - melting point = 190 ° C).

Claims (2)

1, The process of 'obtaining / derivatives, thienop ir idine of general' .. of formula (I) wherein R 2 '_; represents a hydrogen atom or a radical -.chlorobenzyl., .R? and R ₇ represents a hydrogen atom and IL is a hydrogen atom, isopropyl radical, ethoxy carbonyl, 'phenyl or thienyl, named (II) in which R 1, R 8 and R 4 have the meanings given above, having the compound of the formula .., . ^: 'j' · '' · ·. ' · L- 'and'':' .. X - CH - Ϊ. · '© Λ. v (Or). \ in which R ^ has a predefined meaning, X is a chlorine atom, i . Is .methoxy, ethoxy. iii methylthio iii group ^: formulas -OQR H ⁰ in which R is the radical of the tert-butyl * or two groups of X and Y with the carbon atom to which they are attached form a heterocyclic nucleus with six hexahydro-S-triazine bonds, urotropin or triox in a solvent such as dimethylformamide iii.dimethylsulfoxide and in the presence of acid when the radicals X and Y close the ring, at a temperature between 45 ° C and 80 ° C and in the anhydrous medium, freeing the free base as necessary. 2. The process according to claim 1, wherein, in the case where the radicals X and Y close the ring, the solvent contains hydrochloric or methanesulfonic acid.