JPS60228460A - Preparation of piperidinopropanol derivative - Google Patents

Abstract

PURPOSE:To obtain a corresponding -(4-benzylpiperidino)-compound, by hydrogenating dl-erythro-2-(4-benzyl-DELTA<3>-piperidino-1-(4-hydroxyphenyl)-1-propanol in the presence of a catalyst. CONSTITUTION:A compound shown by the formula I is hydrogenated in a solvent (e.g., alcohol, THF, or dioxane) in the presence of a catalyst such as Pd-C, etc. at room temperature at atmospheric pressure for 2-10hr, to give a compound shown by the formula II. The compound shown by the formula I is a novel compound, and prepared by treating a compound shown by the formula III with a reducing agent of a metal hydride (e.g., sodium boron hydride) in asolvent. EFFECT:The desired substance can be obtained at room temperature under a mild condition at atmospheric pressure in high purity in high yield even by using a Pd-C catalyst. USE:A remedy for cerebrovascular disorders.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound represented by the following formula (1), which is known as a medicine useful for improving various symptoms associated with cerebrovascular disorders, such as aftereffects of cerebral infarction and aftereffects of cerebral hemorrhage. The parent formula for di-erythro 2-(4-penzylhyhericino)-1-(4-hydroxyphenyl)-1-pro9ol and its pharmaceutically acceptable acid addition salts, particularly the tartrate salts. Regarding the manufacturing method.

More specifically, the present invention relates to a new production method that can produce an acid addition salt represented by the following formula (n), which is industrially more advantageous and more efficient than conventional methods.

In particular, the present invention provides *dl-erythro 2-(4-benzyl-
The following formula (I) is characterized by subjecting Δ3-piperidino l-1-(4-hydroxyphenyl)-1-delononol to a catalytic hydrogenation reaction in a solvent in the presence of a hydrogenation catalyst.・(11) dl-erythro 2-(4-benzylpiperidino+ 1-(4-hydroxyphenyl)-1-10
This invention relates to a method for producing Tsukunor and its pharmaceutically acceptable acid addition salts.

The above formula (11 new compound is the following formula (IIl)...(
The known compound 1-(1-(4-hydroxybenzoyl)ethyl]-4-penzylpyridinium bromide, represented by can be prepared in high yield, and the present invention also provides for the preparation of formula (It) from compounds of formula (fill) in this way.
A novel compound tl- is prepared by subjecting the compound of formula (n) to a catalytic hydrogenation reaction in a solvent in the presence of a hydrogenation catalyst. It also relates to a method for producing the acid addition salt obtained.

The tartrate salt of the formula (11) is a known pharmaceutically active compound also known as ifenprodil tartrate 1, which is a known pharmaceutically active compound that is used as a symptom associated with after-effects of cerebrovascular disorders, such as after-effects of cerebral infarction and after-effects of cerebral hemorrhage, such as dizziness. It is useful for improving subjective symptoms such as dizziness, headache, and feeling of headache, and fourth, mental symptoms such as depression, anxiety, excitement, and impatience.
Handbook of newly developed drugs, 3rd edition, 582 drawings, 1983. reference)
.

Hitherto, several proposals have been known regarding improved manufacturing methods for producing known compounds and their added salts.

As one of the proposals for such an improved manufacturing method, Japanese Patent Application Laid-Open No. 56-8
No. 1560 discloses that 4-human axifa biophenone represented by the following formula (V2C) is converted to -C bromination using one or more compounds selected from the group consisting of methanol, ethanol and ethers as a solvent, and the following is obtained. A compound of the formula (1 % formula %
- Benzylpyridine is heated to reflux using ether as a solvent, and the resulting reaction mixture containing the compound of formula (tm+) is heated under pressure in the presence of a catalytic reduction catalyst to remove the odor of the compound of formula (1). A production method characterized by producing a hydrochloride has been proposed.

In the above proposal, the formula (!)
As a catalytic reduction catalyst used in the catalytic hydrogenation reaction to form a hydrobromide salt of a compound, only solidium-carbon is described, and the heating catalytic reduction reaction conditions under pressure are at a temperature of 60° to 95°C. It is stated that conditions of 6 to 8 hours under a hydrogen pressure of 20 to 5oky/i are suitable.

Furthermore, JP-A-56-13546g discloses the above-mentioned JP-A-56-13546 which requires a catalytic hydrogenation reaction step under pressurized and heated conditions.
An improved manufacturing method of the previous proposal of No. 6-81560 has been proposed.

JP-A-56-135468 discloses that the aqueous bromide produced during the bromination is removed by bubbling an inert gas through the reaction mixture enriched with the precursor, and then:
To this is added 4-benzylpyridine and heated to reflux using methanol or ethanol as a solvent. A production method has been proposed which is characterized in that the hydrobromide salt of the above formula (summer) compound is completely produced by adding a catalyst and flowing hydrogen without applying pressure or heating.

In the proposal of JP-A No. 56-135468, the above-mentioned JP-A No. 56-81560 (Japanese Patent Application No. 54-1
58112), it is described that it has been discovered that the above reduction reaction can proceed smoothly, and furthermore, in the conventional method, when carrying out the above reduction reaction, palladium-carbon is used as a hydrogenation catalyst. Be sure to heat (50 to 50 kliJ/c+a") under pressure (25 to 50 kliJ/c+a") using
xoo"c+gold", but it is stated that in these conventional methods, the desired reduction reaction does not proceed unless the conditions of heating under pressure are provided.
In the proposal of No. 6-135468, the reduction reaction can proceed without applying pressure and heating, which was essential in the previous proposal, so there are no problems in terms of equipment, work safety, and operation name in industrial implementation. It is stated that it provides significant benefits.

However, although this method avoids the industrially disadvantageous catalytic hydrogenation reaction under pressure and heating conditions that was essential in the prior proposal, the radium-carbon catalyst used in the prior proposal In comparison, it is about 50 times more expensive or more expensive than that, and requires the use of an expensive platinum oxide catalyst, which is disadvantageous for industrial implementation.

Regarding the above catalytic hydrogenation reaction, JP-A-57-814
It is also proposed in No. 62 that the pressure and temperature of hydrogenation rt1- to 100 Yu/cIi is preferably 40 to 60 to 9
The conditions include a hydrogen pressure of /cIl and a reaction temperature Vi2-100°C, preferably id55-65°C. and,
A specific example is a hydrogen pressure of 50/cri, ? It is described that the conditions are M degree 60°C.

As mentioned above, conventionally, the catalytic hydrogenation reaction of 1-[1-(4-humanmixibenzoyl)ethyl]-4-benzylpyridinium bromide of formula (ml) forms the hydrobromide salt of a compound of formula (ll). When a radium-carbon catalyst is used as a hydrogenation catalyst in the reaction, the reaction is required to be carried out under pressurized and heated conditions, which are disadvantageous from an industrial standpoint. , it was necessary to use a platinum oxide catalyst, which is disadvantageous for industrial implementation.

The present inventors have conducted research to develop a new method for producing the compound of formula (1), which can overcome the problems encountered in industrial implementation in conventional methods, as described above.

As a result, F description (ml...
A new compound represented by the U eye erythro-(4-benzyl-Δ3-piperidino)-1,-14-hydro a
Xyphenyl l-1-fronoenolka can exist stably and novel compounds of the formulas (It) are, for example, those of the formula (1)
+11 It can be easily produced industrially with high purity and high yield from the known compound 1-[-+4-humanmixybenzoyl)ethyl]-4-penzylpyridinium bromide using a metal hydride reducing agent. discovered.

Furthermore, according to the research of the present inventors, the hot type (11) novel ornament can be used as a hydrogenation catalyst, for example, even if a palladium-carbon catalyst, which conventionally required reaction under pressure and heating conditions, is used. It has been found that the compound can be smoothly and easily converted to the compound of the formula (Iris) under conditions of slag temperature and atmospheric pressure, and that it is possible to produce the compound of the formula (Iris) with high purity and high acidity.

Therefore, the object of the present invention is to provide di-erythro-2-(4-penzylhyheridino)-1-(4-hydroxyphenyl)-1-dea represented by the following formula (N...(11)
The present invention provides a novel method for producing 9-nol and its classically acceptable acid addition salts.

Another object of the present invention is to provide a novel compound of the formula (III) and a method for producing the same.

The above objects and many other objects and advantages of the present invention include:
This will become clearer from the description below.

According to the method of the present invention, the following -1cll+) novel compound
... nl The compound of formula (1) and its pharmaceutically acceptable acid addition salts, such as tartrate (ifenglodil tartrate), are prepared by catalytic hydrogenation reaction in the presence of a hydrogenation catalyst in gold and a solvent. It can be easily produced with high purity and high yield, industrially advantageously, for example, by using a noradium-carbon catalyst, for example, by catalytic hydrogenation reaction at room temperature and atmospheric pressure conditions. The formula il + novel compound may be in the form of its acid addition salt, and in the method of the present invention, a compound of formula (Vl) is subjected to a catalytic hydrogenation reaction in a solvent in the presence of a hydrogenation catalyst. It is meant to include such embodiments.

The above formula (1) novel compound can be obtained, for example, by reducing the above formula +1) known compound 1-(1-14-humanmixibenzoyl)ethyl-4-penzylpyridinium pamide with a metal hydride reducing agent in a solvent. By doing so, it can be easily produced with high purity and high yield. The compounds of formula (III) can be produced by any method known per se.

Formula ([111] Including one form of producing a known compound from formula (v) 4-hydroxypropiophenone, one form of producing a formula CIl + new compound from a compound of formula [1111,
Formula (H) dl-erythro 2-+4-benzyl-Δ4-
Piperidino l-1-(4-human mixyphenyl)-1
- One embodiment of the production of a compound of formula (+) from propatool, and the fourth step including the tartrate step, can be shown as follows.

(Vl (1 (ml NαBB.

OHCH.

(1) Ht/Pd-C OHCM.

(1) CM (ON)CUOH CM (OH)COOK The starting material compound, 4-hydroxypropiophenone, is available on the market, and can also be produced by a method known per se. The formula (P/1 compound is, for example, Pharmaceutical Journal and Dan 0.844 (198G) or dJ, C
hIIIm, Soc, 103411954), it can be easily produced by fully reacting 4-hydroxypropiophenone with bromine in an acetic acid solvent, or alternatively, it can be produced by the method described in Sukeki-an Kaisho 56. -81560
No., JP-A-56-t35468, JP-A-57-814
It can also be produced by the method described in No. 62 and other known methods.

The compound of formula tm) can also be produced by any known method; for example, it can be easily produced by completely reacting the compound of formula (F/) with 4-benzylpyridine in a reaction solvent according to the method described in JP-A-57-81462. can be manufactured.

Examples of the reaction solvent include ethers such as diquinane, tetrahydrofuran, and 1,2-dimethoxyethane; ketones such as acetone and methyl ethyl ketone; and alcohols such as methanol, ethanol, and gropanol. There is no particular limit to the amount used, but
For example, the amount used may be about 1 to about 5 times as large as that of the compound of formula (IVI).

Further, the amount of 4-benzylpyridine to be used can be selected as appropriate, but it is preferable to use an equimolar amount or approximately an equimolar amount to the compound of formula (t)). The reaction temperature and time can be appropriately selected, and examples thereof include a reaction temperature of about 40'' to about iooo<0>C and a reaction time of about 2 to about 7 hours.

The novel compound of the formula (Otori) of the present invention can be obtained, for example, by the formula (IUI), which can be obtained as described above. It can be easily obtained with high purity and high yield. Examples of reaction solvents include water, alcohols such as methanol and ethanol, tetrahydrofuran, 1.2
Examples include ethers such as -dimethoxyethane and ethylene glycol, and mixed solvents thereof. There is no particular restriction on the amount used, but for the compound of formula (II),
For example, a usage amount of about 5 to about 20 times capacity maintenance can be exemplified.

Examples of metal hydride reducing agents used in the reduction reaction include sodium borohydride, lithium borohydride, and lithium hydride. The amount to be used can be appropriately selected, and for example, the amount to be used can be about 4 to about lθ times the mole of the compound of formula (+111).

The reaction can be carried out under atmospheric pressure conditions, eg, about θ.

Reaction temperatures of from to about 30° C. and reaction times of from about 1 to about lθ hours may be exemplified.

According to the method of the present invention, for example, a novel compound having the formula (which can be obtained by
It can be easily converted to a compound of formula (+) with high purity and stability. The reaction proceeds smoothly and easily under conditions of room temperature and atmospheric pressure, and can be carried out with remarkable advantage over palladium-carbon catalysts, which conventionally did not proceed smoothly unless under pressure and heating conditions.

Examples of reaction solvents include alcohols such as methanol, ethanol, and glopanol. A'RL Examples include ethyl acetate, acetone, tetrahydrofuran, 1,2-dimethoxyethane, dioxa 7, and a mixed solvent thereof. There is no particular restriction on the weight amount, but for a compound of formula tit), for example, from about lθ to about 30 ft! An example of this is the usage amount such as f capacity.

Noble metal hydrogenation catalysts can be used as hydrogenation catalysts, but for industrial practice it is preferred to use inexpensive radium-carbon catalysts, such as 5-10% radium-carbon catalysts. The 70-year-old dose can be selected appropriately, but the formula (m
For example, the amount used may be about 0.1 to about 0.5 times the weight of the compound.

The reaction can be carried out at room temperature and at atmospheric pressure, and there is no particular need for heating and pressurizing, but it may be carried out if desired. As the reaction time, for example, a reaction time of about 2 to 10 hours can be exemplified. The formula (U+) may be used in the form of an acid addition salt, such as a hydrochloride, and can be subjected to reduction in the same manner as above.

Compounds of formula (11) obtainable as described above can be reacted with the desired acids, preferably of the pharmaceutically acceptable class, such as L-(t)-a6, in a suitable solvent.
Accordingly, the compound of formula 0) can be converted into an acid addition salt. Examples of solvents used for salt formation include alcohols such as methanol and ethanol, and mixed solvents of water and alcohols. The amount used can be appropriately selected, and for example, about 4
An example of this is a occlusal INr with a capacitance of about 10 times. The amount of L-(+)-tartaric acid to be used can be approximately 0.5 times the molar amount of the compound of formula (+1).

The salt-forming reaction can be carried out by bringing the compound of formula (1) and an acid into contact with each other by heating and dissolving them in a solvent. A desired trowel addition layer can be obtained by depositing it.

Acids to be used - 0 Examples include -1, L-(4-)-tartaric acid, 11 acids, f1 sulfuric acid, hydrogen bromide beak, milk standard, succinic acid, citric acid, fumar + W→ For example, each acid addition salt of the compound of formula (1) can be prepared in the same manner as above.

Hereinafter, several embodiments of the present invention will be illustrated in detail in ψ-.

Reference example l 4-human axy-α-promode σ biophenone [generation (II)].

4-Hydroxydemibiophenone? Vinegar e on 5.89.9
T! Uu 500-, bromine there? 9.91.9. A solution of m125Wt vinegar was added over a period of 1 hour at room temperature.

- At night, reduce the pressure of the apparatus to 4fL to remove hydrogen bromide by suction, and then remove all acetic acid under reduced pressure.1. Ta.

The residue was extracted with chloroform, the chloroform layer was washed with deuterated water, and the aa form was distilled off to obtain Compound 114.5Ii in Table 4.

NMR (CDCI, -TMS)-21.8-ZO (a#, d, J-=rHz r5.25-
&4 (IB, q, J='lHz) IIi, 9-8
．． 15 (4/, ml Reference example 2 1-[1-(4-hydroxybenzoyl)
ethyl]-4-benzylpyridinium bromito [Formula (1)].

]4-Hydroxy-α-bromozolobiophenone 114
5Ii, 4-benzylpyridine 84.6 F and dioxane 1541! was heated for 2 hours.

After cooling to room temperature, the precipitated crystals were collected and dried to obtain the title compounds 16 & 411.

164G, 160G, 1570.1510.1470.
1445.128G, 1210.1155.111G,
965.870.73G, 69G, 630, NMR (DMSO-d, -TMSn δ: L8G-20(
3H, d, J=8Hz ) 135 (1#, s) 4.35 (2B, 81 6.80-8.25 (9H, m,) 9.05-9.25 (4HXd, J=611z 11
0,75 (1//, 8) Example 1 dl-erythro 2-(4-benzyl-Δ
3-piperidino)-1-(4-hydroxyphenyl)-1-pro-benol (formula tlI)).

1-Cx-(4-humanmixybenzoyl)ethyl]-4
- 79.7 g of pendylpyridinium pamide dissolved in 1 part of total methanol, 45.4.9 g of sodium borohydride
The sample was heated at f4 for 2 hours at 20°C or lower and dried. 10 more degrees
Stir at ~room temperature for 4 hours. 10% methanol distilled off
After adding 500ml of hydrochloric acid, add 28% water to 200ml of water.
Added mj. After extraction with methylene chloride, the methinone chloride was distilled off to give the title compound 62.71! I got it.

Yield, 4N 96.9%.

1600.1510X149 (1,1450°138
0, 1240, 1160, 1030.1000.960
．． 830,740, 700.600, NMR (CDCL, -TMS la ;0.90 (
3E, d, /=7Hz 11.90-λ27(2//:
, 01 SL50-190 (3H, customary) 3.10-450 (4R, fit 4.97 (111, d, J=2-8H215,40-
5, e 7 (311, Shu 16.73-7.33 (1/
Example 2 dl-Elis a-2-(4-benzylpiperidino-1-1-+4-hydrogycuphenyl)-1-propatol [Formula (1)].

di-erythro 2-(4-benzyl-Δ3-hyheridino)-1-(4-hydroxyphenyl)-1-deronognol 1.39 J% 5% palladium-carbon 0.56.9
, methanol and 14 grams was stirred in a hydrogen stream at 20° C. and normal pressure for 330 minutes.

After the reaction was completed, the catalyst was separated and methanol was distilled off to obtain the title compound 1.3111'i. Yield 9'A, 6%.

NMR (CDCI, -TMS lδ: 0.82 (3u, d, J=&81) 4.76 (
IH, d, /=3.9516.71-7.26 (9
B, m) Example 3 dl-Nilis I:l-2-(4-pen formula C
I] Zilpiperidino)-1-14-hydroxyphenyl)-1-pronognol tartrate [Formula (13-tartrate)].

dl-varnish 0-2- (4-benzylpiperidino)-1
-(4-hydroxyphenyl)-1-deronosonol 1
．． 4 tnef of methanol was added to 30.9 and dissolved by heating. To this, L be → - taraseki eo, 3011. Methanol 1.
A solution of 3- was added and cooled, and the precipitated crystals were collected and dried to obtain P, 1.32.

Summary p145°-149°C [α]”+IL5° (cL, o, ethanol) 1-4 people for patent 1 person other than Nippon Pharmaceutical Industry Co., Ltd. Procedural amendment July 20, 1980 Mr. Manabu Shiga, Commissioner of the Japan Patent Office 1. Indication of the case...No. 59-83672 2. Name of the invention Process for producing biperisonoglopanol fat conductor 3. Person making the amendment Relationship to the case Patent applicant address 1-6 Sokuruwa, Toyama City, Naiyama Prefecture Kaoru 214th Osamu
Person: 107 (and 1 other person) (Attachment) (1) In the 6th line from the bottom of page 4 of the specification, the phrase "new manufacturing method" is corrected to "new manufacturing method."

(2) “Reduced to reducing agent” on page 6, lines 5-6 of the specification.
Correct the statement to ``Reduce using a reducing agent.''

(3) On page 29, line 10 of the specification, [0,82(3H%d
, J=6. s 1) After J, change the line,
r 1.12-3.20 (14J7., m) Join J.

(4) On page 30, line 1 of the specification, 1dt-Nislow 2-”
Correct the statement to "di-Erythro 2-".

Claims (1)

[Claims] 1. di-erythro 2-(4-benzyl-Δ
3-piperidino 1- (4-hydroxyphenyl)
dl-erythro2-14- represented by the following formula (1) % formula % (1) characterized by subjecting -1-gulono(nol to a catalytic hydrogenation reaction in a solvent in the presence of a hydrogenation catalyst. -S ndylhyheridino)-1-14- and droxyphenyl)-1-
Process for making glopanol and its pharmaceutically acceptable acid addition salts. 2 1-(1-(4-hydroxybenzoyl) represented by the following formula +I[lJ...(11!+)
Ethyl]-4-penzylpyridinium bromide is reduced in a solvent under the pressure of a metal hydride reducing agent to obtain the following formula (Ill011CH3...(nl) dl-ErisCff-2-( 4-benzyl-Δ3-piperidino)-1-(4-hydroxyphenyl)-1-propatool, and the compound of formula tut is
dl-erythro 2-(4-benzylpiperidino l-1-(4 -Hydroxyphenyl)-1-propatol and its pharmaceutically acceptable acid addition salt. 3. Di-erythro 2-(4-benzyl-Δ) represented by the following formula 1ll)...(1)
3-piperidino)Lt-(4-hydroxyphenyl)-
1-propa-tool.