JPS58118546A - Preparation of dicyclomine hydrochloride - Google Patents

Abstract

PURPOSE:To prepare the titled compound in high yield, by reacting[1,1'-bicyclohexyl]-2-ol, etc. with formic acid, reacting the resultant carboxylic acid with 2-(diethylamino)ethyl chloride hydrochloride in the presence of a base, and converting the product to a salt. CONSTITUTION:[1,1'-Bicyclohexyl]-2-ol of formulaIand/or[1,1'-bicyclohexyl]-1-ol of formula II is made to react with formic acid in the presence of at least one kind of dehydrating agent selected from concentrated sulfuric acid, fuming sulfuric acid, phosphoric acid, and a mixture of phosphoric acid and phosphorus pentoxide to produce[1,1'-bicyclohexyl]-1-carboxylic acid of formula III. The reaction mixture is mixed with an aqueous solution of 2-(diethylamino)ethyl chloride hydrochloride, and an alkaline aqueous solution is added dropwise to the mixture to form the ester of formula IV, which is converted to the hydrochloride to obtain the compound of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing dicycloin hydrochloride represented by structural formula (1):

Dicyclomine hydrochloride can be used to treat gastric and duodenal ulcers, 2 esophageal spasms,
It is an effective compound as a therapeutic agent for pyloric spasm, gastritis, ulcerative colitis, gallbladder/cholangitis, cholelithiasis, etc.

Conventionally, the following method is known as a method for producing diachromine hydrochloride.

(11-benzyl cyanide and 1,5-dibromopentane are reacted with sodium amide in ether or toluene, 1-phenylcyclohexyl cyanide is prepared, and then in concentrated sulfuric acid. The mixture is mixed with ethanol and the mixture is vigorously refluxed for 24-48 hours to prepare l-phenylcyclohexanecarboxylic acid ethyl ester, which is then catalyzed by sodium metal in xylene. Transesterification with 2-(diethylamino)ethanol removes the reaction product in the form of hydrochloride, which is hydrogenated in glacial acetic acid using Adams catalyst to obtain dicyclomine hydrochloride [total yield:
40 Gai J, Amer, Chew, Soc,
69°2902 (1947)).

(21 Ethyl phenylacetate and 1,5-dibromopentay were reacted with sodium hydride in 1 dimethylformamide and benzene to prepare 1-7 enylcyclohexanecarbo/ethyl acid, and this compound was dissolved in xylene. Then, the reaction product was transesterified with 2-(diethylamino)ethanol using metallic sodium as a catalyst, and the resulting reaction product was taken out as a hydrochloride salt. This was hydrogenated in glacial acetic acid using a rhodium-alumina catalyst to obtain dicyclomine dihydrate. Method for obtaining [Total yield: 10%, USP 3.527,792]
.

(31 dicyclohexyltone was converted to 1-10 locyclohexylcyclohexyltone using sulfuryl chloride, which was then refluxed with potassium hydroxide in dioxane to [1,1'-bicyclohexyl]-1 - preparing the carboxylic acid and reacting it with (a) chlorination with sulfuryl chloride followed by 2-(diethylamino)ethanol in toluene; or (b) with 2-(diethylamino)ethyl chloride. A method of preparing 2-(diethylamino)ethyl ester by reaction with potassium hydroxide and kneading, and converting this into a hydrochloride by a known method [total yield: 29-34%, Bull, woe, c.
Him, France.

1952, 84 (CA, 47.4295 (19
53) ).

(411-/ethyl lomocyclohexanecarboxylate,
cyclohexanone in benzene-ether in the presence of magnesium, and the reaction product is dehydrated.
After saponification and hydrogenation process 1, this is it! Kuchi [1,1
A method of preparing '-bicyclohexyl]-1-carboxylic acid, esterifying this compound in acetone using 2-(diethylaZ))ethyl chloride hydrochloride and potassium carbonate, and finally converting it into a hydrochloride. Total yield: 6H
G.

Bull, sea, chinz, France,
1958.1478 (CA, 54°18328
(1960, 1).

f51 Cyclohexyl cyanide and cyclohexyl bromide are condensed in the presence of sodium amide, and the resulting reaction product is refluxed with ethanol in concentrated sulfuric acid to form [1,1'-bicyclohexyl]-1-
Ethyl carboxylate was prepared, this compound was transesterified with 2-(diethylamino)ethanol, and the obtained compound was subjected to salt-chlorination. Total yield: 27%, J.
Amer, Chem, Soe, 69°2902
(1947)).

However, the rule 1.5 used in the above conventional method
-Dibromopentane, dicyclohexyl ketone, or ethyl 1-bromocyclohexanecarboxylate, etc.
Industrially, it is not easy to carry out six steps, it is expensive, and there is a drawback that the yield of the final product is low. Therefore, it is extremely unsatisfactory to produce dicyclomine hydrochloride on an industrial scale using these raw materials. Furthermore, as in the conventional method, when using sodium amide and sodium hydride on an industrial scale, due to their stability and danger to water, great care must be taken when using them. It was an inconvenience. Furthermore, L2 is unsuitable for industrial production methods, such as difficulty in setting conditions in the reaction process and the possibility of rapid reactions. From these points,
The conventional method is not completely satisfactory as an industrial method for producing dicyclomine hydrochloride, and improvements are strongly desired.

As a result of intensive research into the synthesis of dicyclomine hydrochloride, the present inventors have found that dicyclomine hydrochloride 1 can be synthesized in high yield and high quality using inexpensive raw materials that are easily available industrially and using simple operations and mild reaction conditions. They discovered a method for obtaining jy and completed the present invention.

That is, the present invention is extremely valuable as a method for producing dicyclomine hydrochloride from a first-year perspective.

That is, the present invention provides: 1. In order to obtain dicyclomine hydrochloride represented by the following structural formula (1):
In the presence of a dehydrating agent consisting of at least one selected from concentrated sulfuric acid 1, fuming sulfuric acid, phosphoric acid, and a mixture of phosphoric acid and phosphorus pentoxide, [1.1'-bicyclohexyl-2-ol and , the following structural formula (1): At least one selected from [1.1'-bicyclohexyl]-1-ol represented by the following structural formula (1): is reacted with formic acid, whereby the following structural formula (fv ): to produce [1.1'-bicyclohexyl 3-1-carboxylic acid], (2) to the reaction mixture obtained in the above step (1), 2
-(diethylamino)ethyl chloride hydrochloride aqueous solution is mixed, and an alkaline aqueous solution is added dropwise to this mixed solution.
'-bicyclohexyl]-1-carboxylic acid-2-(diethylamino)ethyl ester, and then (3) converting the compound of formula (V) into its hydrochloride. be.

In one embodiment of the method of the present invention, first, at least one compound selected from [1,1'-bicyclohexyl-2-ol and [1,1'-bicyclohexyl]-1-ol]
The seeds are dissolved in formic acid, and the resulting solution is dropped into a dehydrating agent consisting of at least one selected from concentrated sulfuric acid, di-fuming sulfuric acid, phosphoric acid, and a phosphoric acid-phosphorus pentoxide mixture, and the reaction between the two is carried out. [1,1'-bicyclohexyl]-]
- Obtain carboxylic acid. After the reaction is completed, the reaction solution is poured into crushed ice, and then extracted with an organic solvent such as diethyl ether to separate the organic layer containing the compound. An aqueous alkali solution such as IJum (hydroxide) is added to the separated organic layer to convert the carboxylic acid compound into its alkali metal salt, which is extracted into the aqueous layer. Hydrochloric acid or sulfuric acid is added to this aqueous layer to make it acidic, and the carboxylic acid compound is obtained as crystals. The [1.1'-bicyclohexyl]-1-carboxylic acid thus obtained was added to an aqueous solution of 2-(diethylamino)ethyl chloride hydrochloride, and the mixture was added with alkali monohydroxide and/or carbonic acid. An alkaline aqueous solution such as an alkali is added dropwise to perform an esterification reaction. After the reaction is completed, the reaction solution is extracted with an organic solvent, the organic layer is washed with water, dried, and the organic solvent is distilled off under reduced pressure to obtain liquid [1,1'-bicyclohexyl)-1-carboxylic acid H-2- (diethyl az)) ethyl ester is obtained. By converting this ester compound into a hydrochloride salt by a known method, dicyclo i7 hydrochloride can be obtained.

[1,1'-bicyclohexyl] used in the present invention = 2
-To produce ol, first cyclohexanone is
- In the presence of an acid catalyst such as toluenesulfonic acid, azeotropic dehydration is performed using benzene, toluene, xylene, etc. as a solvent, and this is converted into 2-(]-cyclohexanone. Next, the unsaturated bonds and carbonyl groups in the above compound are simultaneously reduced in the presence of a Raney nickel catalyst using methanol, inglobil alcohol, or the like as a solvent. Then, (1,1'-bicyclohexyl)-2-ol is easily obtained in high yield.

In addition, [1,1'-bicyclohexyl]-1-ol is obtained by producing a Grignard reagent from chlorocyclohexane or bromocyclohexane and magnesium,
When this Grignard reagent is reacted with cyclohexone, a high yield can be obtained.

The formic acid used in the method of the present invention is [1,1'-bicyclohexyl]-2-ol and/or ha[1,1
It may be used in an amount of 1 to 10 moles per mole of '-bicyclohexylcool-1-ol. In this method, 1 mol of water is produced as a by-product from 1 mol each of the alcohol compound and formic acid, so the degree of dehydrating agent and the amount used are C
This is an important factor in producing 11111 of the carboxylic acid compound of formula N). That is, when a-sulfuric acid is used as a dehydrating agent, use one with a concentration of 90 to 100%,
In the case of fuming sulfuric acid, it is preferable to use 0 to 30% oleum since it must be handled with care and 1j organisms will increase. When using phosphoric acid, (
Since the reaction for producing the compound of formula IV) is a reaction that produces water as a by-product, the phosphoric acid concentration is preferably 100%. In addition, in order to increase the dehydration ability of phosphoric acid, 10096
It is also possible to use mixtures of phosphoric acid and phosphorus pentoxide.

In this case, the mixing ratio can be arbitrarily selected, but considering the solubility of phosphorus pentoxide in phosphoric acid,
The weight ratio of 0% phosphoric acid is preferably 14 or less. The amount of these dehydrating agents to be used may be expanded to 5 to 30 mol in total per 1 mol of the all compound. It may also be used in large excess, but there is no particular advantage to doing so;
On the contrary, it becomes economically disadvantageous. The reaction at this time is carried out at a temperature of -10 to 120°C depending on the type of dehydrating agent. For example, when the dehydrating agent consists of concentrated sulfuric acid or fuming sulfuric acid, the reaction temperature is -10 to 50°C, preferably 0 to 30°C.
and when phosphoric acid and phosphoric acid-phosphorus pentoxide mixtures are used, the reaction temperature is from 30 to 120°C, preferably from 50 to 100°C. The reaction time is generally between 2 and 6 hours.

Although the details of the chemical and reaction mechanism in the production of the compound of formula (ff) are not clear, the alcohol compound represented by the structural formula (It) Fuyo and (Otori) is first dehydrated by the action of a dehydrating agent and produced. It is thought that the carbonium ion is rearranged to a more stable ion and at the same time reacts with carbon monoxide produced by the action of the dehydrating agent 1 and formic acid to produce a carboxylic acid compound represented by the above structural formula (ff).

The ester compound represented by the structural formula (v) has a carboxylic acid compound represented by the structural formula (IV) and 2-
(Diethylamine) is obtained by reacting a mixed aqueous solution with ethyl chloride hydrochloride while dropping an alkaline aqueous solution, such as an aqueous solution containing at least one residue selected from alkali hydroxide and alkali carbonate.

The reaction is generally carried out at a temperature of 0 to 100°C, preferably 30 to 80°C, for 1 to 6 hours. Examples of alkali hydroxides and alkali carbonates include sodium hydroxide, potassium hydroxide, and sodium carbonate.

Sodium bicarbonate, potassium carbonate and potassium bicarbonate are used. Such alkaline compounds,
It is used in an amount of 2 moles or more per mole of 2-(diethylamino)ethyl chloride hydrochloride.

In the above ester compound production reaction, the carboxylic acid compound of structural formula (rW) does not dissolve in water, so this t2-
(diethylamino)ethyl chloride fil! An aqueous salt solution may be added to 1111 NJ, and an aqueous alkali solution may be added dropwise to this suspension, or a solvent for dissolving the carboxylic acid compound may be added to this suspension. Solvents used for this purpose include alcohols such as methanol, ethanol, and isopropyl alcohol, diethyl ether, and tetrahydrofuran.

Ether compounds such as inglobil ether, aliphatic hydrocarbons such as hexane and octane, and benzene.

Aromatic hydrocarbons such as toluene and xylene and gamma setone,
Ketones such as 2-butanone can be used.

After the reaction, the reaction solution was cooled to room temperature, extracted with an organic solvent such as ethyl ether, hexane, benzene, toluene, etc., and the resulting organic skin was washed with an aqueous alkali solution to remove unreacted carboxylic acid compounds. After collection, the residual liquid is washed with water and further concentrated. Then, [1,1'-bicyclohexyl]-]-carboxylic acid 2-(diethyl ai)
) ethyl ester is obtained.

The ester compound represented by the structural formula (V) obtained as described above is dissolved in a solvent, and hydrogen chloride gas is blown thereinto, or a solvent that has absorbed hydrogen chloride gas or hydrochloric acid is added to the solution. Dicyclomine hydrochloride can be obtained by dropping. Acetone is used as a solvent for hydrochlorination.

2-butanone, acetonitrile, isopropyl alcohol, ethanol, benzene, toluene diethyl ether, etc. are used. When the crystals produced by the hydrochlorination reaction or the crystals produced by cooling the reaction solution are subjected to Fi/A and the obtained crystals are dried under reduced pressure, dicyclomine hydrochloride represented by the above structural formula (1) is obtained. is obtained.

Hereinafter, the present invention will be explained in more detail with reference to Examples. In the examples, "yield" refers to the theoretical yield.

Example 1 540 g of 97-thiosulfuric acid was placed in a 1 ton reaction flask, stirred vigorously, and cooled to 10'C.

3 WJ of formic acid was added dropwise to this, followed by 50. (l [
1,1'-bicyclohexyl"-2-ol 5052
A solution of formic acid was added dropwise over a period of 3 hours, during which time the temperature of the reaction solution was maintained at 10 to 20°C. After the addition was completed, the reaction mixture was stirred at 10 to 20° C. for an additional 1 hour, and then the reaction mixture was poured into #1 crushed ice with stirring. A white solid was then formed. Add 2001L of toluene to this reaction solution.
After adding t and separating the toluene layer containing the reaction product,
The remaining aqueous layer was extracted with toluene 20017 to separate the toluene turbidity. Combine the obtained toluene layers into one! Then, 5% hydroxide (IJ) aqueous solution 2001117 was added thereto. After separating the resulting aqueous layer, the remaining toluene layer was extracted with a 200% IJ aqueous solution.
Combine the alkaline aqueous solution layers and add toluene 2001
Washed with 7. Concentrated hydrochloric acid was added to the alkaline aqueous solution layer while stirring under cooling to make it acidic, producing white crystals. The crystals were filtered under suction, washed twice with 100-g water, and then dried under reduced pressure. 48.51! (DC
1,1'-bicyclohexyl J-1-carboxylic acid was obtained as white crystals (melting point: 120-121°C, yield:
Section 84.1). The IR and NMR spectra of this crystal (2) matched those of the standard product of [1,1'-bicyclohexyl]-1-carboxylic acid.

This (1,1'-bicyclohexyl]-1-carboxylic acid, 78.8 y of a 50% aqueous solution of 2-(diethylamino)ethyl chloride hydrochloride, and 100% of toluene.
was placed in a flask, and while the mixture was kept at 50° C. and stirred, 5 tons of an aqueous solution of sodium hydroxide and 370 tons of an aqueous solution of sodium hydroxide were added dropwise into the flask over 2 hours. Further add 40 to 50% of the reaction solution.
After stirring for 1 hour at 0°C, room g! After cooling to A and separating the layers, the obtained toluene layer was washed twice with an aqueous solution of 501 sodium hydroxide, and further washed with water until it no longer showed alkalinity. After drying the toluene layer thus treated with sodium sulfate, the toluene was removed under reduced pressure (and a pale yellow liquid at 67.5 F was obtained. This liquid had its IR and NMR spectra as follows:
[1,1'-bicyclohexyl]-1-carvone H-2
It was confirmed to be -C diethylamino)ethyl ester (yield: 946 mm).

This ester compound was dissolved in diethyl ether of 2501, and when hydrogen chloride gas was blown into the solution while stirring while cooling, white crystals were generated. The crystals were separated by f, dried, and recrystallized from methyl ethyl ketone 65ON to obtain white crystals of 65.79 (melting point: 172
．． 6-173.1°C).

The IR and NMR spectra of this crystal were consistent with those of the hydrochloric acid/cyc cIin preparation (yield: 87 g II
). Total collected vehicles: 68.5 units Example 2 810 f of 97 units of sulfuric acid was put into 11 reaction flasks,
This was cooled to 15° C. with vigorous stirring. After dropping 31 of formic acid thereto, a solution of 75.1' of (1,1'-bicyclohexyl]-1-ol dissolved in 76 of of formic acid was added dropwise over 3 hours). During this time, the reaction solution was
The temperature was kept at 5-25°C. Thereafter, the same treatment as in Example 1 was carried out to obtain 37.2 F of [1,1'-bicyclohexyl].
-1-Carmenic acid was obtained as white crystals (melting point: 120
．． 5-121.3°C, yield: 428%).

This was suspended in 60.42 of an aqueous solution of 2-(diethyl az))ethyl chloride hydrochloride, and the temperature was adjusted to 7.
It was kept at 0°C. While stirring this suspension, 10-potassium carbonate aqueous solution 5902 was added dropwise over 4 hours, and the reaction solution was further stirred at a temperature of 70 to 80°C for 2 hours.

Thereafter, processing was performed in the same manner as in Example 1, and 51.55' [1
, 1'-bicyclohexyl]-1-carboxylic acid-2-(
Diethylamino)ethyl ester was obtained (yield: 94.
11), This ester is mixed with isopropyl alcohol 20
01/[II.
Chidan @ 17.4 f was dropped. After heating and dissolving the nine crystals produced, the reaction solution was cooled to -10°C. The generated crystals were dried under reduced pressure after death by rotating them, and white crystals of 50.09 were obtained (melting point: 172.6-173.6°C).

Yield: 286.8To). The IR and NMR spectra of this crystal matched those of the standard dicycloin hydrochloride (total yield: 35.116).

Example 3 30-oleum 91651 in a 300-mL reaction flask! and cooled to 5-10°C while stirring vigorously. Add VclllLt of formic acid dropwise to this, and then add CLI
'-bicyclohexyl]-2-ol 30.09 and formic acid 16.5 f! was added dropwise over 2 hours while maintaining the reaction solution temperature at 5 to 10°C. After the dropwise addition was completed, the reaction mixture was stirred at 5 to 10° C. for another hour, and then poured into ice water at 300 f, and extracted with ether. The obtained ether layer was extracted with aqueous sodium hydroxide solution. Next, the obtained alkaline layer was acidified with 10-thiosulfuric acid to form crystals. After extracting this crystal suspension with ether, the resulting ether layer was washed with water, dried over sodium nitrate, and the ether was distilled off.
'-bicyclohexyl]-1-carboxylic acid was obtained (yield: 54.39). This carboxylic acid compound was dissolved in 50-methanol and 60.4% of 2-(diethylamino)
It was mixed with 30.59 ml of an aqueous solution of ethyl chloride hydrochloride and the temperature of the mixture was maintained at 50°C. Aqueous 5-sodium hydrogen oxide solution 3107 was added dropwise to this over 2 hours, and the mixture was further stirred at a temperature of 50 to 60°C for 3 hours. After that, ether extraction, alkaline washing, and water washing.

When dried and concentrated, it becomes a pale yellow liquid, 24.72
(Yield: 89.3%). IR and NM of this
The R spectrum matched those of the ester compound obtained in Example 1. Dissolve this in 100-acetone,
After stirring, a 14.6 F hydrogen cyclide-methanol solution of 20qIb was added dropwise. Once the generated crystals were heated and dissolved, they were cooled to -10°C, and the generated crystals were dried for f times to obtain crystals of 22.99 (melting point: 172.1-1
73.7°C, yield: 82.9%). IR of this
and NMR spec) kF'! The results were consistent with those of the standard dicyclomine hydrochloride (total yield: 40.2 cm).

Example 4 Obtained from 85% υ/500 ml of acid and phosphorus pentoxide 1979]00-Phosphorus II! Pour 150F into a 500-degree reaction flask, cool with ice water, and gradually add 1 liter of phosphorus pentoxide while stirring.
00v was added. This mixture was then kept at 70°C,
111 of formic acid was added, and then a solution of [1,1'-bicyclohexyl-2-ol 30.09 and 4M16,59 was added dropwise over 3 hours while keeping the reaction solution at 65-75°C, and then for another 1 hour. After stirring, it was poured into crushed ice at 300 f C). Thereafter, the same treatment as in Example 3 was carried out, and 2
2.35'[1,1'-bicyclohexyl]-1-carboxylic acid was obtained (yield: 644%).

Acetone 5031+7 and 2-(
Diethylamino)ethyl chloride acid salt aqueous solution 36
, 29 was added and its a degree was kept at 30°C. This is KIO
- Potassium hydroxide aqueous solution 1209 was added dropwise over 4 hours, and the mixture was further stirred at 30 to 40°C for 1 hour. After distilling off acetone under reduced pressure, extraction with ether was carried out.

After washing with alkali, washing with water, drying, and concentrating, a pale yellow liquid of 27.99% was obtained (yield: 85.0%). Dissolve this in 120-mL acetone, cool it, and add 35 liters of hydrochloric acid 9.5-mL.
9 was added dropwise. The white crystals formed were filtered and dried.
7.9 g of crystals were obtained (melting point: 172.3-173.
0°C, yield: 89.5 times). IR and N of this
The MR spectrum matched that of the standard dicyclomine hydrochloride (total yield: 49.0%).

Procedural amendments (11) Director General of the Patent Office Shima 1, 1983 1) Haruko 1, Indication of the case 1981 Patent Application No. 1008 2, Title of invention Process for producing acid-resistant dicyclomine 3, Amendment Relationship with the case of the person who filed the patent application: Name of the patent applicant: Kawaken Fine Care Co., Ltd. 4. Agent (2 others) 5. Subject of amendment A. The "Scope of Claims" column of the specification.

6 next to ``Detailed Description of the Invention'' in the specification, Contents of the amendment A, Attachment entry, 6th line from the bottom of the 4th member of the specification, ``Diacycloken'' is amended to ``Dicyclomine J.''

7. @9.9 amended features of attached tatami mats lff-Claims 1 copy 2. Claims 1. To obtain dicyclomine hydrochloride represented by the following structural formula (I):

+IJ dark fi11. In the presence of a dehydrating agent consisting of at least % l'Ia selected from oleum, phosphoric acid and phosphoric acid-phosphorous pentoxide mixtures.

The following structural formula (■): l:l,1'-bicyclohexyl)-2-
and at least one kind selected from [1.1'-bicyclohexyl]-1-ol represented by the following structural formula (III).

t-reaction with formic acid, thereby producing (1,1'-bicyclohexyl] -1, + represented by the following structural formula (Iv):
Carbon s! Kurage generation.

+23 Add 2 to the reaction mixture obtained in the above step flJ.
-(diethylamino)ethyl chloride hydrochloric acid base water bath solution is mixed, and an alkaline aqueous solution is added dropwise to this mixture,
As a result, the following structural formula (■): [1,
1'-Bicyclohexyl-1-carboxylic acid-2-(diethylaminocoethyl ester is produced in the first step.

(3) The compound of formula (v) is modified into its #R salt.

It is characterized by this. *Process for producing dicycloquine hydrochloride of formula (1).

2. The reaction in previous construction 8 (1) is -lO to +1200
It is carried out at a temperature within the range of C. Method according to claim 1
'-H'/l o hexyl-2-ol and/
or (1,1'-bicyclohexyl-1-ol)
210 moles of formic acid are used per mole. A method according to claim 1.

4. The method according to claim 1, wherein in step (2), the alkaline water bath liquid contains at least 111 alkali compounds selected from alkali hydroxides and alkali carbonates. 2. A process according to claim 1, wherein the reaction of 1% to 100'C is carried out at a temperature of 0 to 100'C.

6. In the step (2), 2 moles or more of the alkali compound is used per 1 mole of 2-(diethyladenoneethyl chloride hydrochloride. Method according to claim 4)

Claims (1)

[Claims] 1. In order to obtain dicyclomine hydrochloride represented by the following structural formula (I), (1)
Concentrated sulfuric acid 1 At least 12 selected from oleum, phosphoric acid, and phosphoric acid-phosphorous monopentoxide mixtures! In the presence of a dehydrating agent consisting of the following structural formula (1); '-bicyclohexyl]-1-ol and formic acid to form [1,1'-bicyclohexyl] represented by the following structural formula (IV): -1-carboxylic acid is produced, (2) 2-(
An aqueous solution of diethylamino)ethyl chloride hydrochloride is mixed, and an alkaline aqueous solution is added dropwise to the mixture, whereby (1,1'-
Bicyclohexyl-1-carboxylic acid-2-(diethyl-i)) ethyl ester is produced, and then (3) the compound of formula (V) is converted into its hydrochloride. A method for producing dicycloin hydrochloride of the formula 11, characterized in that the reaction in the step (1) is from 11'O to +120
The method according to claim 1, which is carried out at a temperature within the range of °C. 3. In the step (II), 10 mol of formic acid is added to 1 mol of [1,1'-bicyclohexyl-2-ol and h[1,1'-bicyclohexyl'-1-ol]. 4. In the step (2), the alkaline aqueous solution contains at least one alkali compound selected from alkali hydroxides and alkali carbonates. range 4th
The method described in section. 5. The method according to claim 1, wherein the reaction in step (2) is carried out at a temperature of 0 to 100°C. 6. The method according to claim 4JJ, wherein in the step (21), 2 or more moles of the alkali compound are used per 1 mole of 2-(diethylamino)ethyl chloride hydrochloride.