JPS6018660B2 - Method for producing 1-(1,3-dioxolan-4-ylmethyl)piperidinol derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 1-(1,3-dioxolan-4-ylmethyl)piveridinol derivative and a method for producing the same.

More specifically, the present invention relates to general formula 1 (wherein R, .R2
and R3 are each a hydrogen atom, a hydroxy group, an alkyl group, a phenyl group or an alkylphenyl group,
In this case, R,, R2 and R3 cannot be the same at the same time; at least one of them is a phenyl group or an alkylphenyl group, or R, is a hydrogen atom, and R2 and R3 are are groups that together form a fluorene ring or a xanthene ring, and R4
and R5 are the same or different and each represents a hydrogen atom, an alkyl group, a cycloalkyl group or a phenyl group, or R4 and R5 are a group that together form a cycloalkane ring. 1-(1
, 3-dioxolan-4-ylmethyl)-3 (or 4
)-Hydroxypiveridine di- or trilayer homemade acetate, or its shark addition salt or quaternary ammonium salt, and its production process.

Although many synthetic antiacetylcholine active drugs have been researched and developed, there are still various problems that need to be improved in terms of efficacy, side effects, etc., and they have not surpassed naturally occurring atropine, scopolamine, etc.

As a result of intensive research to find a drug with excellent pore acetylcholine action, the present inventors found that the compound of general formula 1 and its acid addition salts and quaternary ammonium salts have excellent anti-acetylcholine action and are extremely advantageous as medicines. We discovered something and arrived at the present invention. In the definition of the symbols in General Formula 1 above, alkyl refers to straight chain alkyl such as methyl, ethyl, lopropyl, n-butyl, and branched chain alkyl such as isopropyl, isobutyl, 2-butyl, 3-butyl, etc. Examples of the cycloalkyl group for R4 and R5 include a cyclobentyl group, a cyclohexyl group, and a cycloheptyl group.

The compounds according to the invention can be produced by various methods.

According to the first mode of the method for producing a compound according to the present invention,
The compound of general formula 1 is a compound of general formula 0 (wherein R,,R2
and R3 have the abovementioned meanings and Y means a hydroxyl group or a functionalized hydroxyl group.
and R5 has the above-mentioned meaning, and the hydroxyl group bonded to the piperidine ring is located at the 3- or 4-position). I can do it.

Examples of the highly functional hydroxyl group in the general formula R include a halogen atom or lower alkoxy. It is particularly preferable to use a compound of general formula (b) in which Y represents alkoxy (for example, methoxy, ethoxy, etc.) to carry out a transesterification reaction with a compound of general formula m. Such compounds of formula 0 include, for example, benzylic acid methyl ester, benzylic acid ethyl ester, xanthenic acid methyl ester, xanthenic acid ethyl ester,
Tropaic acid methyl ester, mandelic acid methyl ester, p-isobutylphenyl-2-methylacetic acid methyl ester (or 2-(p-isobutylphenyl)propionate methyl ester), diphenylacetic acid methyl ester, fluorene-9-carboxylic acid methyl ester, 9 ，
Examples include 10-dihydroanthracene-9-carboxylic acid methyl ester. Also, the general formula m
For example, 1-(2,2-dimethyl-1,
3-dioxolan-4-ylmethyl)-14-hydroxypiveridine, 1-(2-dimethyl-1,3-dioxolan-4-ylmethyl)-131-hydroxypiveridine, 1-(2,2-diphenyl-1,3-dioxolane-4- ylmethyl)-4-hydroxypiveridine, 1-(
2,2-diphenyl-1,3-dioxolan-4-ylmethyl)-1-3-hydroxypiveridine to 1-(2,2-bentamethylene-1,3-dioxolan-4-ylmethyl)-4-hydroxypiveridine, 1-(2 -Methyl-2-phenyl-1?3-dioxolan-4-ylmethyl)-4-hydroxypiveridine, 1-(1,3-dioxolan-4-ylmethyl)-4-hydroxypiveridine, 1-(2,2-dibenzobentamethylene- Examples include 1,3-dioxolan-4-ylmethyl)-4-hydroxypiveridine.

These piberidinol derivatives of formula m can be used, for example, by combining 3- or 4-hydroxypiveridine with a solvent such as dimethylformamide, acetonitrile, methanol, ethanol, dimethylformamide, benzene to tetrahydrofuran, 1,4-dioxane, etc. ), preferably 60-1
In the temperature range of It can be produced in good yield by reacting with the 4-halogenomethyl-1,3-dioxolane derivative shown below.

Ester exchange (that is, when using a compound in which Y represents an alkoxy group in the general formula m) is particularly excellent for obtaining the compound of the general formula 1 from the compound of the general formula B and the compound of the general formula m. .

This reaction can be carried out without a solvent at normal pressure, preferably under reduced pressure, but it can also be carried out in the presence of an inert solvent. In the latter case, examples of inert solvents include hydrocarbons (eg, benzene, n-hexane, hexane, toluene, xylene, etc.) and ethers (eg, dioxane, tetrahydrofuran, etc.). This transesterification reaction can be carried out by a method known per se. For example, alkali metals (e.g. sodium metal, potassium metal, etc.), bases (e.g. sodium amide, sodium hydride, potassium hydride, etc.)
Alternatively, a mixture of the ester compound of the general formula 0 and the piberidinol derivative of the general formula m is heated in the presence of an organometallic compound (for example, n-butyllithium, etc.), and the generated alcohol is removed from the system. By doing this, the desired compound of general formula 1 can be easily obtained. In this case, it is preferable that the reaction temperature is not too high, and usually 10
It is advantageous to carry out below 0oo. It is advantageous to carry out these transesterification reactions under anhydrous conditions, whether in the absence of a solvent or in the presence of a solvent, and it is also advantageous to carry out the transesterification reactions while distilling the liberated alcohol out of the reaction system. In these transesterification reactions, there are no particular restrictions on the quantitative ratio of the compound of general formula b and the compound of general formula m,
At least an equimolar amount or a slight excess of the piberidinol derivative of general formula m may be used. It depends on the reaction time, the presence or absence of a solvent, its type, and the reaction temperature, so it cannot be specified unconditionally, but in general, the reaction time is about 30% in the case of no solvent.
0 minutes to 1. In the presence of a solvent, it completes in 3 to 5 hours. The compound of general formula 1 can also be produced by reacting the compound of general formula 0 (wherein Y means a hydroxyl group) with the compound of general formula m.

In this reaction, it is preferable to use an inorganic or organic protonic acid such as toluenesulfonic acid, sulfuric acid, hydrogen chloride, etc. as a condensing agent, and as a solvent, methylene chloride,
Preferably, dichloroethane, acetonitrile, benzene, dimethylformamide, dimethyl oxide, etc. are used. Furthermore, this reaction is preferably carried out in the presence of a dehydrating agent (for example, molecular sheep). The reaction temperature is 8
The range of 0 to 120 qo is preferable, and the reaction time is usually in the range of 3 to 10 hours. This reaction can also be carried out using a dehydration condensation agent (for example, dicyclohexylcarpodiimide) that is normally used in this type of esterification. The reaction temperature in this case is preferably in the range of 0 to 300C. Compounds of general formula b and general formula m in this reaction
Although there is no restriction on the quantitative ratio with the second compound,
Equimolar amounts of each are sufficient, and the usage ratio can be increased or decreased as appropriate depending on the type of compound. Regarding the amount of the condensing agent, it is preferable to use a slightly excess amount of the condensing agent relative to the compound of general formula m in an equimolar amount. According to a second aspect of the process of the invention, the compound of the general formula 1 is a compound of the general formula ester derivatives of 1-oxiranylmethyl-3(or 4)-hydroxypiveridine represented by It can be produced by reacting a keto compound represented by (having a meaning) in the presence of a Lewis acid.

In this reaction, the compound with the general formula is a liquid at room temperature and pressure. And when it can be used in place of a solvent, it can also be used itself as a solvent. In addition, when the compound of the general formula is not liquid at room temperature and pressure, or when it cannot be used as a solvent substitute, for example, chloroform, dichloromethane, carbon tetrachloride, benzene, toluene, etc. can be used as a separate solvent. Preferred examples of the Lewis acid include anhydrous tin tetrachloride, anhydrous aluminum chloride, anhydrous zinc chloride, and boron trifluoride, and the reaction temperature is preferably in the range of -2000 to room temperature. In this reaction, the quantitative ratio between the starting compounds is not particularly limited, but if the compound with the general formula itself is used as a solvent, a relatively excessive amount is used, and if other solvents are used, an equal amount is used. A molar amount is sufficient, and the amounts of both starting compounds can be increased or decreased as appropriate depending on the type of compound. The amount of Lewis acid to be used is preferably in the range of 0.1 to 1.2 molar equivalents.

Further, when the reaction solution to which the Lewis acid is added exhibits a homogeneous phase, it is advantageous to make the molar ratio as low as possible.
A reaction time of about 10 minutes to 3 hours is sufficient, and a characteristic of this reaction is that the reaction time is short in most cases.

The reaction product thus obtained can be isolated and purified from the reaction mixture by conventional methods. The compound of general formula V, which is a raw material compound, can be produced, for example, by reacting a product obtained by reacting the corresponding hydroxypiveridine and bromomethyloxirane in the presence of an alkali with a compound of general formula 0. Alternatively, it can also be produced by directly reacting bromomethyloxirane with a compound represented by general formula W below, in which R6 is a hydrogen atom, in the presence of an alkali.

According to a third aspect of the process of the invention, the compounds according to the invention are prepared with the general formula: ,
The ester derivative of 3 (or 4)-hydroxypiveridine represented by (the ester group bonded to the piverizine ring can be located at the 31-position or the 4-position) and the compound of the general formula W. They are also produced by N-tertiary or N-quaternization reactions.

The product obtained by this method has the general formula K (wherein R,
, R2, R3, R4, R5, R6 and
It can be located in the 4- or 4-position. ).

This reaction can be carried out, for example, by using a mixture in which R6 is a hydrogen atom, a solvent,
For example, lower alcohols (e.g., methanol, ethanol, etc.), acetonitrile, benzene, toluene, tetrahydrofuran, dimethylformamide, dioxane, etc., in the presence of an alkali (e.g., sodium hydroxide, potassium carbonate, sodium carbonate, etc.), preferably This can be easily carried out by heating in the range of room temperature to 10,000 ℃.

The quantitative ratio of the compound of general formula skin and the compound of general formula W is:
Although not particularly limited, it is preferable to use an equimolar proportion or a slight excess of the compound of general formula N, and a good result is that the amount of alkali is about 1.5 to 2.0 equivalents. The reaction time depends on the type of raw material compound,
Although it depends on the type of solvent, temperature, etc., and cannot be generalized, a range of 3 to 6 q hours is usually sufficient. Furthermore, when former 6 is an alkyl group, a polar solvent (for example, lower alcohols such as methanol and ethanol, acetonitrile, dimethylformamide, etc.) is used, preferably 80 to 1
Quaternary ammonium salts can be easily produced by heating in the range of 0.00 pm for usually 5 to 8 hours. The compound of the general formula K thus obtained can be isolated and purified from the reaction mixture by a conventional method. Among the compounds produced by the various modes of the process of the invention described above, the compound of general formula 1 can be converted into an acid addition salt by a method known per se, if desired, and the acid addition salt (general formula ) can be converted into bases or other acid addition salts in a manner known per se.

Examples of acids that form such acid addition salts include organic acids such as hydrochloric acid, fumaric acid, salicylic acid, oxalic acid, and toluenesulfonic acid. Furthermore - according to a fourth mode of the process of the invention, the tertiary nitrogen atom of the piverizine ring of the compound of general formula 1 can be converted into a quaternary ammonium salt.

That is, the compound of general formula 1 is expressed as formula R6'X'
(wind) by reacting with a compound represented by the formula (wherein R6' means an alkyl group and X' means a halogen, a p-toluenesulfonic acid residue or an alkyl sulfuric acid residue).

General formula X (in the formula R,, R2, R3, R4, R5, R6'
and X' have the abovementioned meanings, and the ester group bonded to the piveridine ring can be located in the 3- or 41-position).

This reaction can be carried out, for example, in the presence or absence of a solvent.
In the range of 0 to 10,000, the target compound is given almost quantitatively under pressure if necessary, usually in about 3 minutes to 1 feeding time. Examples of the solvent include lower alcohols such as methanol and ethanol, acetonitrile, acetone,
Examples include methylene chloride, benzene, chloroform, dimethylformamide, and ether. 1-(1,3-dioxolan-4-ylmethyl)- represented by the general formula 1,K or
Di- or tri-layer acetate derivatives of 3 (or 4) monohydroxypiveridine or their acid addition salts or quaternary ammonium salts have extremely excellent anti-acetylcholine effects, especially quaternary ammonium salts or quaternary ammonium salts. X has an extremely weak effect on the central nervous system, and has low side effects such as mydriatic effect, lagoonal effect, and vomiting, which are considered unavoidable for this type of compound, but exhibits strong locksmith effect and drag field effect.

The following table shows some specific examples of the results of pharmacological tests conducted on pendylic acid esters among the compounds of general formula 1, their acid addition salts and quaternary ammonium salts.

*1), *2) The effects of competitive and non-competitive anti-acetylcholine effects on isolated intestinal tracts of guinea pigs, respectively, expressed as an index. *3) Compound pig 10 is 1-(2
, 2-dimethyl-1,3-dioxolan-4-ylmethyl)-1-methyl-4-(xanthene-9-carbonyloxy)piveridinium bromide.

The above is an in vitro experiment using isolated guinea pig intestines, but according to an in situ experiment using rabbits, compound M. When compound No. 2 was administered intravenously, it showed a strong effect of 2.97 times that of atropine and 1.43 times that of scopolamine-N-butylfuromide.

. In addition, when looking at the side effects of these compounds, both mydriatic and oral lagoonal effects in mice are clearly weaker than atropine, and the acute toxicity (intravenous injection in mice) is also lower than that of scopolamine-N.
- significantly lower than butyl bromide. In this way, all of the compounds in this series have chopstick and mirror dust effects, but especially compound M. Compound No. 2 has remarkable effects in in situ experiments, has very few side effects, is highly safe, and has extremely high value as a medicine.

Next, specific examples will be described in detail, but the present invention is not limited to these examples.

Example 1 4-benzyloyloxy-11-(2,2-dimethyl-1
, 3-dioxolane-4-ylmethyl)piveridine 1-(2,2-dimethyl-1,3-dioxolane-4
-ylmethyl)-4-hydroxypiveridine (0.012 mol) to 55.2% (0.0
．． 0024 mol) and heated to 800C to dissolve.

After hydrogen gas generation stopped, methyl pendylate was added for 3.48 hours (
0.0144 mol) was added, and the generated methanol was distilled off under reduced pressure. This methanol generation is almost completed in about 30 minutes, but heating is continued for an additional 30 minutes at 80° C. under a constant reduced pressure of 2 yards of Hg. Then add 50 g of benzene and wash twice with 50 g of water. The benzene layer is separated, dried with molasses, filtered, and concentrated. This residue is dissolved in 20 parts of ethanol, 1.38 molar (0.012 mol) of pyridine hydrochloride synthesized separately is added to the solution to perform hydrochloride exchange, and the solution is directly recrystallized from this ethanol. Hydrochloride of 1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-4-piveridinyl pendylate 4.912 (yield 88.6%) has a melting point of 1
Obtained as colorless acicular crystals of 69 to 17,100 mm. IR
Solution: 1735 NMR6C.

Phantom D 1.30, 1, 40 (QH, Double S)? ．． 30
(10 days, arom, m) Elemental analysis value (HC salt) C25 day 32 C SO N05 molecular weight 461.98 C day N (HC salt) Calculated value 64.99 6.98 3.03 Actual value
65.11 6.72 3.12 This method is particularly advantageous because it allows the synthesis, isolation and purification of the acid addition salt of the target compound to be carried out all at once.

Note that 1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-4-hydroxypiveridine used as a raw material compound was produced as follows. First, by a known method, 4
-furomomethyl-2,2-dimethyl-1,3-dioxolane was produced.

The properties of this compound are as follows. Boiling point 75.0
-76.0oo/18 ribs MASS (3 Mr. V) m/e
181,179 (M+15), 101NMR6CDC
〆31-35, 1.44 (Mother's Day, double s) 3.35 (
2 days, Br-C ratio, m) 3.80 to 4.30 (mother's day, m) 97.5 moles (0.5 mol) of this compound and 50.5 moles (0.5 moles) of 4-hydroxypiverizine mol) is refluxed for 2 hours in acetonitrile in the presence of 69.0 molar (0.5 mol) of potassium carbonate.

The reaction mixture is then heated, the filtrate is concentrated, 200 parts of dichloromethane is added and washed twice with 50 parts of water. Next, the dichloromethane layer is separated, dried with trisnitrogen, filtered, and concentrated. The residue is distilled under reduced pressure to obtain oily 1
-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-4-hydroxypiveridine 96.1 hours (yield: 89.39%) was obtained. Boiling point 159qC/11 days and evenings, melting point 37-39 o'clock NMR 6CDs.

So31.331.38 (8th, double s) 4.08 (I
H, OH, S) IR Isoto t 6.

Day 3380MASS (3 ratio V) M+218h no e20
0(M-15), 129,103,95 Example 2 4-benzyloyloxy-1-(2,2-dimethyl-1
, 3-dioxolane-4-ylmethyl)piveridine 1-(2,2-dimethyl-1,3-dioxolane-4)
-ylmethyl)-4-hydroxypiveridine (0.0242 mol) and sodium hydride (115 parts) (
0.0048 mol) is added.

Hydrogen gas is generated immediately, but after it stops (approximately 2
After 0 minutes), 6.44 mol (0.0266 mol) of methyl pendylate was added while heating to 80°C, and the generated methanol was removed under reduced pressure. This methanol generation is approximately 30
It will stop after 20 minutes, but continue to heat for another 3 minutes at 80 qo under a constant pressure of 20 days and evenings. Next, 50 ml of benzene is added upstream, washed twice with 30 ml of water, and the benzene layer is dried with trinitrile, filtered through three doors, and concentrated. The target product can be isolated as an acid addition salt in the same manner as in Example 1, but here, silica gel (Wako gel C-200) column chromatography is used to isolate and purify the target product as an oily 9.2M (
A yield of 89.49%) was obtained. IR Isogo t 60 days 347
5'6C=. 1730NMR6coc evening 3 1.32,
1.37 (thin, double s) 5.01 (IH, m) 3.43 (IH, OH, s), 7.35 (10 days, ar
om, m) MASS (7 positive Vm/e425 (M+), 4
10 (M-15), 324 (base peak), 215
200, 182, 114, 105 96 77 Examples
3 Production of 4-benzyloyloxy-1-(2,2-diphenyl-1,3-dioxolan-4-ylmethyl)piveridine 1-(2,2-diphenyl-1,3-dioxolan-4-ylmethyl)-4-hydroxypiveridine 10.
20 parts (0.030 mol) is dissolved in 50 parts of dry benzene. To this, 72 parts (0.003 mol) of sodium hydride is added and dissolved by heating under reflux.

Then methyl pendylate 7.26 mol (0.030 mol)
A solution of 30% of benzene is gradually added dropwise, and the methanol generated at this time is azeotropically removed along with the benzene. After adding the entire amount of benzene solution of methyl pendylate, approx.
The methanol generated is also azeotropically removed while dry benzene is added dropwise over a period of time. Next, benzene and residual methanol were removed under reduced pressure, and benzene was added again to 50%
was added, washed twice with 30 parts of water, and the benzene layer was dried with bitter salt, filtered and concentrated. The obtained residue was purified using silica gel (Wako Gel C-200) column chromatography to obtain the target compound in the form of an oil (15.05 min.
A yield of 91.3%) was obtained. IR ladder t.

Day 3475'=. 1728NMR6.

DC〆3 1.72 (4 days, m), 2.42 (thin, , m), 3.66 (IH, m), 4.15 (2 days, m), 4.9
5 (IH, m), 7.30 (20 days, aroma, m).
0.0072 mol) was dissolved in 10 mol of acetonitrile, 8.27 parts of pyridine hydrochloride (0.0072 mol) was added and dissolved to perform hydrochloride exchange, and directly recrystallized from the acetonitrile to obtain the above-mentioned The hydrochloride of the target compound was obtained as colorless needle crystals for 3.19 days (yield 75.5%).

Melting point 203.5-20 is 0 1R solved.

Day 3220, C=. 1733NMR6C.

Target D 5.18 (IH, m), 7.33 (2 Cape, aroma, m) Elemental analysis value (C35 days $C〆N05, molecular weight unevenness 6.11
) (HC salt) C Day N Calculated value 71.71 6.19 2.39 Actual value 71.58 6.31 2.27 This acid addition salt can be obtained not only by this method but also directly from the reaction solution as described above. ,
Therefore, it can be produced without isolating the compound as a base, and in addition to the acid addition salt exchange method exemplified here, any method commonly used for producing acid addition salts can be used.

Moreover, 1-(2,2-diphenyl-1,3-dioxolan-4-ylmethyl)-4-hydroxypiveridine used as a raw material compound was manufactured as follows.

First, 4-furomomethyl-2,2-diphenyl-1,3-dioxolane was produced by a known method.

The properties of this compound are as follows. Melting point 71.0
~73.0oo (in-prop alcohol) NMR6c
. c Evening 3 3.40 (ga, m), 4.00 (2nd, m)
, 4.50 (IH, m), 7.35 (10 days, aroma
, m) MASS (3 Mr. V) m/e320 (M++2)
318 (M+), 243, 241, 197, 182,
105,77 This compound 31. Potassium carbonate (0.1 mol) was dissolved in 300 mol of acetonitrile, 11.11 mol (0.11 mol) of 4-hydroxypiveridine was dissolved therein, and 13.8 mol (0.1 mol) of potassium carbonate was dissolved in the solution. .1 mol).

After refluxing this mixture for 1 hour, the reaction solution was separated in a furnace and concentrated. Add 100 parts of dichloromethane to the remaining bamboo to dissolve it, wash twice with 50 parts of water, separate the dichloromethane layer, dry it with trisulfuric acid, filter it in an oven, and remove the solvent. The residual solution was recrystallized from acetone to give the target compound at a yield of 28.7 mm (yield: 84.
7%) with a melting point of 101. ? Obtained as acicular crystals. M.A.
SS (3 ratio V) M1339 m/e262 (M+17
7), 225 182, 157, 114, 105 77
Example 44-benzyloyloxy-1-(2,2-bentamethyl-1,3-dioxolan-4-ylmethyl)
Production of Piveridine 4-Hydroxy-1-(2,2-bentamethylene-1,3-dioxolan-4-ylmethyl)
Add 48 o (0.002 mol) of sodium hydride to 5.1 mol (0.02 mol) of piveridine and
Pray for a minute.

Next, 4.84 molar (0.02 mol) of methyl benzate was added, heated to 85 to 90 qo, and stirred at that temperature for 5 hours while distilling off methanol liberated under a reduced pressure of about 10 Yanagi Hg. do. Then add 20M water and extract with dichloromethane. The extract was dried with potato salt, heated in an oven,
After distilling off the solvent, column chromatography (Wako Gel C
-200100 evening) to purify the target compound 8.56
Yield (92.0% yield) was obtained as a pale yellow oil. IR
Mother 9-tei.

Day 3400, C:. 1735NMR6CDC So3 1
．． 55 (10 days, br), 5.20 (IH, m) 7.3
5 (10 days, arom, m) Note that 4-hydroxy-1-(2
, 2-bentamethylene-1,3-dioxolan-4-ylmethyl)piveridine was produced as follows.

First, 4-furomomethyl-2,2-bentamethylene-1,3-dioxolane was obtained in good yield from bromomethyloxirane and cyclohexanone by a known method.

The properties of this compound are as follows. boiling point 1150
0/1 NMR6cDc So3 1.55 (1 plate, m), 3.40
(Team, m>, 3.70-4.50 (3 days, m) MASS (3 ratio V) m/e236 (M + 12), 23
4 (M 10), 207, 205 193, 191, 141
,98 4-furomomethyl-2 thus obtained,
2-bentamethylene-1-,3-dioxolane (235 mmol) (0.01 mol) was dissolved in 30 ml of ethanol, and 4-hydroxypiveridine (1.0 mmol) (0.01 mol) was dissolved therein.
and then 1. potassium carbonate. Madarayu (0.01 mol)
Add.

The mixture was heated under reflux for 1 hour, filtered in a furnace, concentrated, and then subjected to column chromatography (Wakogel C-200).
) to obtain an oily target compound of 2.06 m (yield: 8
0.7%). NMR6CDCSo3 1.55(1
0 days, m), 3.45-3-85 (2 days, m), 3.9
5~4.50 (phantom, m) MASS (3 Mr. V) M+255, m/e212 (M+
-43), 156,141,114,98 Example 5 4-mandeloyloxy-1-(2,2-dimethyl-1
, 3-dioxolane-4-ylmethyl)piveridine 1-(2,2-dimethyl-1,3-dioxolane-4
-ylmethyl)-4-hydroxypiveridine (0.01 mol) to 24:9 (0.0 mol) of sodium hydride
After the hydrogen gas generation is completed, 1.66 mol (0.01 mol) of methyl mandelate is added.

The mixture was heated to 100°C and heated for 1.5 hours while the liberated methanol was distilled off under a constant pressure of 10 days. Next, 50 units of dichloromethane were added, and 20 units of water was added.
Wash each skin twice. After the dichloromethane layer is separated, it is dried with a sulfur solution, filtered, and the solvent is removed from the solution. The residual liquid was subjected to column chromatography (Wakogel C
-200) to obtain 2.91 g of the target compound as an oil (yield: 83.2%). IR Tanghan” Shi.

Day 3420, C=. 1740NMR6coc evening 3 1
．． 31, 1.36 (dark blue, double s) 3.40 (IH.
OH, s), 5.15 (IH, s), 7.15-7.5
0 (spot, arom, m) MASS (Mr. 3 V) M + I 9
m/e334 (M+15), 249,248 198
Example 6 1-(2,2-dimethyl-1,3-dioxolane-4-
Production of 1-(2,2
-dimethyl-1,3-dioxolan-4-ylmethyl)
Add 48:9 (0.01 mol) of sodium hydride to 1.29 (0.006 mol) of 1-4-hydroxypiveridine, and after the completion of hydrogen gas generation, 2-p-isobutylphenylp .

Add 1.50 molar (0.00 molar) of methyl pionate. The mixture is heated to 75-85°C and stirred for 1 1/2 hours while removing methanol liberated with a trowel on the side. After the liberation of methanol has ended, 40 parts of ether are added and washed twice with 20 parts of water. The ether layer is separated, dried over E-nitrogen, filtered, and the solvent is removed from the reaction solution. The residue was purified by column chromatography (Wako Gel C-200) to obtain the target compound 1 as an oil.
．． 92 ml (yield 79.49%) was obtained. Melting point (as hydrochloride) 144-1470 (decomposition) IR powder No. t female =. 1
735 NMR6coc so3 0.89 (fine, , d) 1.33, 1.39 (fine, , double S) 1.31 (spotted, , d) 2.45 (ga, , d) 4.80 (IH , m) 7,17 (Misaki, arom, m) Elemental analysis value (hydrochloride C24 day 28C〆N04, molecular weight 4
40.01) C Day N Calculated value 65.51 8.71 3.18 Actual value 65.63 8.59 3.24 Example 73
-benzyloyloxy-11-(2,2-dimethyl-1,
Preparation of 3-dioxolan-4-ylmethyl)piveridine 1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-13-hydroxypiveridine A solution of 1.075 g (0.005 mol) dissolved in 20 ml of anhydrous toluene. 20% n-hexane solution of n-butyllithium 1
．． 2' was added and heated under reflux for 300 minutes.

Then 1.45 mol (0.006 mol) of methyl pendylate
A solution prepared by dissolving 30% of anhydrous toluene was added dropwise over 45 minutes, and the liberated methanol was azeotropically distilled off with the toluene. After the completion of the dropwise addition, 100 g of anhydrous toluene was further added dropwise over a period of 3 hours, and liberated methanol was similarly removed. After the reaction is completed, the solvent is removed, and 3 hours of dichloromethane is added to the solution, followed by washing twice with 20 parts of water. The dichloromethane layer was separated, dried with ramie salt, heated in the oven, the solvent was distilled off from the oven solution, and the residue was purified by column chromatography (Wakogel C-200, 100) to obtain the oily target compound 1. 9M (yield 89.5%) was obtained. IR Powder 3440, M=.

1730NMR6coo evening 3 1.30, 1.35 (thin, double s) 1.60 (misaki, m), 245 (misaki, m)
, 3.52 (IH, t), 4.95 (IH, m), 7.
30 (10 days, arom., m) 839 capes (0.00196 mol) of the target product 3-benzyloyloxy-1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)piveridine thus obtained were Ethanol 5
231-9(0) of pyridine hydrochloride
．． 002 mol) was added and melted, the solvent and liberated pyridine were distilled off, and recrystallized from methanol-ether. P. 856 o (95.3%) of colorless needle-like crystals with a resolution of 194.5 to 195.5 o were obtained.

Elemental analysis value (hydrochloride C 25 days 32C NQ molecular weight 461
．． 98C day N calculated value I. 99 6. Spot 3
．． 03 Actual value 6507 6.81 3.14 Note that 1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-3-hydroxypiveridine used as the raw material compound was produced as follows. did.

4-bromomethyl-2,2-dimethyl-13-dioxolane (19.5 mol) was added to 300 mol of acetonitrile.
3-Hydroxypiveridine 10.
1 mole (0.1 mole) and potassium carbonate 13.8 mole (0.1 mole)
mol) and heated to reflux for 1 hour.

Next, after separating in a furnace and concentrating, 100 parts of dichloromethane is added to dissolve, washed twice with 30 parts of water, the dichloromethane layer is separated, dried with bitter salt, and then separated in a furnace and concentrated. The residue was purified by vacuum distillation to obtain an oily target product of 17.2 days (79
．． 8%). b. p. 163oo (NMR of 6 ribs)
8cDcZ3 1.32, 1.37 (thin, double s)
3.60 (IH, OH, s) MASS (3 plans V) M1215, m/e200 (M+
115), 140,114 Example 8 Production of 3-pendyloyloxy-1-(2,2-diphenyl-1,3-dioxolan-4-ylmethyl)viveridine 1-(2,2-diphenyl-1,3-dioxolan-4-ylmethyl) -3-hydroxypiveridine 10.
9 of 72 sodium hydride in 20 evenings (0.030 mol)
(0.003 mol) and heated at 100q0 for 30 minutes.

Then methyl pendylate 7.26 mol (0.030 mol)
was added, and liberated methanol was distilled off under reduced pressure at 90° to 100° C. for 4 hours on both sides. Then 100' of dichloromethane is added and the solution is washed with 50' of water. The dichloromethane layer is separated, dried over sweet potato salt, filtered, and concentrated. The residue was purified by column chromatography (Wako Gel C-200) to obtain the target compound as a pale yellow oil (yield: 69).
．． 3%). This compound 3.93 m (0.0072
mol) in acetonitrile 50Z, to which was added pyridine hydrochloride 827 (0,0072 mol), and after standing at room temperature for 3 hours, the solvent was distilled off. The residue was recrystallized from dichloromethane ether to obtain the hydrochloride salt of the target compound.
Melting point 174.6-177.0 (yield 61.0%)
Obtained as colorless needle-length crystals of qo. Elemental analysis (hydrochloride C3
5th day 36C SoN05, molecular weight 586.11) C day N Calculated value 71.71 6.19 2.39 Actual value 71.62 6.12 2. 1-(2,2-diphenyl-1,3-dioxolan-4-ylmethyl)-3-hydroxypiveridine used as a raw material compound was produced as follows.

4-furomomethyl-2,2-diphenyl-1,3-dioxolane 31.9 mol (0.1 mol) and 3-hyde.

10.1 moles (0.1 mol) of xipiveridine was dissolved in 200 ml of acetonitrile, and 13 mol of potassium carbonate was added to the solution.
．． 8 (0.1 mol) was suspended and heated under reflux for 15 hours. Next, the reaction mixture was heated in a furnace, the furnace liquid was concentrated, and the residue was purified by column chromatography (Wako Gel C-200) to obtain the target compound as an oil at 28.3 m (yield: 83,
4%). NMR8cDcSo31,50 (4 days, m
), 2, 50 (fine, m), 2.73 (IH, OH, s)
, 3.50~4.50 (Misaki, m) MASS (3 plans V) M+339, m/e 321 (M
+118), 262 (M1177), 182,114,
105,77 melting point (179.5-181.
500 (Decomposition) Example 94-Pendyloyloxy-1
Preparation of 1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)piveridine 662 o (0.002 mol) of 4-pendyloyloxypiveridine was dissolved in acetonitrile, and 276 mol of potassium carbonate was dissolved in it. Female (0.0
02 mol) and further 4-furomomethyl-2,2
-dimethyl-1,3-dioxolane 390 part 9 (0.0
02 mol) is added and dissolved.

After heating the mixture under reflux for 4 hours, the solvent is removed, 30 parts of dichloromethane is added to dissolve the solution, and the solution is washed twice with 20 parts of water. The dichloromethane layer is separated, dried with trisnitrogen, filtered, and concentrated.
The residue was purified by column chromatography (aluminum oxide 9, manufactured by Merck & Co., Ltd.) to obtain oily target compound 672 (yield 79.1%). This compound is the same as the target compounds of Examples 1 and 2 and IR, NMR.
, MASS, thin layer chromatography, and melting point and fringe melting tests with the hydrochloride salt. Example 10 Preparation of 4-benzyloyloxy-1-(2,2-diisopropyl-1,3-dioxolan-4-ylmethyl)piveridine 6.66 units of 4-pendyloxypiveridine (0.002 x 4 mol) was dissolved in 50 ml of acetonitrile, and further 6.45 ml (0.0257 mol) of 4-furomomethyl-2,2-diisopropyl-1,3-dioxolane was dissolved.

2.95 moles (0.0214 mol) of potassium carbonate are suspended in this mixture, and after heating under reflux for 124 hours, the solvent is distilled off. Add 50 ml of dichloromethane to dissolve the residue,
Wash it twice with 20' of water. The dichloromethane layer is separated, dried over E-nitrogen, filtered, and the solvent is distilled off.
Dissolve the residue in 30 parts of ethanol and add 2 parts of pyridine hydrochloride.
．． After 20 minutes,
The resulting precipitate was recrystallized from acetone ether to obtain the target compound 8.19 (yield 74.0%) as colorless needle crystals with a melting point of 166 quarts. IR box r.

Day 3300, ratio=. 1725 Elemental analysis value (Hydrochloride, C 4 o C SO N 05, Molecular weight 518.08) The 4-furomomethyl-2,2-diisopropyl-1,3-dioxolane was prepared by known methods as described above.

The properties of this compound are as follows. Boiling point 85oo
/7 legs Hita NMR6CD.

Evening 3 0.95 (12th, d), 2.1-2.6 (spots,
m) MASS (3 Mr. V) m/e 251 (M+12)
, 249(M+), 209,195,181 Example 11 1-(2,2-dimethyl-1,3-dioxolane-4-
ylmethyl-4-(9-xanthenecarbonyloxy)
Preparation of Piveridine 4-(9-xanthenecarbonyloxy)piveridine 5.62 (0.0182) and 4-
4.26 ml (0.0218 mol) of furomomethyl-2,2-dimethyl-1,3-dioxolane was dissolved in 5 ml of acetonitrile.
0.0', and to this was added 2.51 g of potassium carbonate (0.
0182 mol) was suspended and then refluxed for 2 hours.

Next, precipitates such as inorganic salts are taken up in the furnace, and the furnace liquid is concentrated.
The residual liquid was subjected to column chromatography (Wakogel C-200
, 200 evening) to obtain target compound 4 as a pale yellow oil.
．． 94 units (yield 64.2%) was obtained. IR powder oath yC
=.

1735 NMR6coo evening 3 1.32, 1.38 (bait,, double s) 1.63 (4th, m), 4.71 (IH, m),
4.93 (IH, s), 7.15 (spots, m) Example 1
24-Pendyloyloxy-1-(2,2-dimethyl-
Preparation of 1,3-dioxolan-4-ylmethyl)piveridine 1.14 mmol (0.005 mol) of penzylic acid was dissolved in benzene 40, and 1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)- 1.075 moles (0.005 mol) of 4-hydroxypiveridine are added and dissolved.

Then p-toluenesulfonic acid 947 (0.005
5 mol) and refluxed for 10 hours. Thereafter, an aqueous solution of sodium hydroxide is added to the reaction solution at room temperature until it becomes alkaline, and the benzene layer is further washed with 30 parts of water. The benzene layer is dried with sulfur glass and then heated in an oven to concentrate. Column chromatography of the residue (Wakogel C-200)
The oily target compound 701-9 (33.0
%) was obtained. This compound matched the target compounds of Examples 2 and 9 above in NMR, IR, gas chromatography, thin layer chromatography, and melting point and compatibility tests with hydrochloride. Example 13 4-(9-fluorenecarbonyloxy)-1-(2,
Preparation of 2-dimethyl-1,3-dioxolan-4-ylmethyl)piveridine 9.0 mol (0.0428 mol) of 9-fluorenecarboxylic acid and 1-(2,2-dimethyl-1,
8.36 mols (0.0 total 9 mol) of 3-oxolan-4-ylmethyl)-4-hydroxypiveridine were dissolved in 50 ml of acetone.
to which 8.829 (0.0428 mol) of dicyclohexylcarbodiimide was quickly added,
React at room temperature for 1 hour while stirring.

Thereafter, the precipitate is filtered, the solvent is removed once, ether is added thereto, the precipitate is filtered again, and the filtrate is concentrated.
Afterglow is dissolved in 30 ml of ethanol, and 4.49 ml (0.0389 mol) of pyridine hydrochloride, which was separately synthesized, is added thereto to exchange the hydrochloride. This was concentrated and recrystallized from acetone ether to give colorless needle-shaped crystals. p207-2080
was obtained in 15.7 days (91.3%). IR pledge female=
. 1730 NMR6c o l, 35, 1.45 (thin, double s)
4.80 (IH,,S) 7.50 (group, arom, m) MASS (7 ratio V) m/e 407 (HC〆), 39
2,300 165MASS (7 ratio V) However, as base m/e 407 (M+), 392 (M-15), 308
, 306 (base peak), 165 Example 14 4-benzyloyloxy-11-(2,2-dimethyl-1
, 3-dioxolan-4-ylmethyl)piveridine 9 of 4-benzyloyloxy-1-oxiranylmethylpiveridine 183 (0.0005 mol) was dissolved in acetone 1
Dissolved in 1.0% of tin tetrachloride (0.0%) while stirring.
．． 004 mol) is gradually added dropwise.

The color of the liquid immediately changes to a dark brown color, but the lantern continues for an hour. After the reaction is complete, potassium carbonate is added to the reaction solution until it becomes sufficiently alkaline, and the process is continued. The reaction solution takes on a slightly yellow color. Separate the precipitate by furnace, concentrate the furnace liquid,
After adding 30 parts of dichloromethane to the residue and dissolving it, add 2 parts of water.
Wash on 0. The dichloromethane layer is decomposed, dried over reed sulfur, filtered, and concentrated. The residue was purified by column chromatography (Wako Gel C-200) to obtain the target compound in the form of an oil, 95.3 o (yield: 44.8%). This compound matched the target compounds of Examples 2, 9 and 12 above in IR, NMR, gas chromatography, stacked chromatography, melting point with hydrochloride, and compatibility test. Note that 4-benzyloyloxy-1-oxiranylmethylpiveridine used as a raw material compound was produced by the following two methods.

Production method 1 4-hydroxypiveridine 1.01 mole (0.01 mol)
and bromomethyloxirane 2.06 m (0.015
mol) was dissolved in 30 ml of acetonitrile, 1.38 ml (0.01 mol) of potassium carbonate was suspended therein, and the mixture was heated under reflux for 8 hours.

Next, the mixture was separated from the furnace, and the furnace liquid was concentrated and purified by column chromatography (Wako Gel C-200) to obtain 1.36 g of the target compound as a pale yellow oil (yield: 86.9%). -R
N skin fin r Reho 3350 To 1.0 molar (0.0064 mol) of this compound was added 24:9 (0.001 mol) of sodium hydride, and after the generation of hydrogen gas was completed, 1.57 ml of methyl pendylate Evening (0.
0065 mol) and while heating to 80oo
The liberated methanol' is distilled off under reduced pressure.

After 4 hours, 50 parts of dichloromethane was added to this, and 2 parts of water was added.
Wash with [0].

The dichloromethane layer was separated, dried over primary nitrogen, filtered, and concentrated. The residue was purified by column chromatography (aluminum oxide 90), and the product was recrystallized from acetone. Target compound: 1.95 min (yield: 83.1
%) was obtained as colorless rod-shaped crystals with a melting point of 98.5-99.5%. IR hina r ri. Daily milk 10, C=. 1729N
MR6coc evening 3 2. Group (IH,,m), 4.51 (IH, OH,s), 4. Group (IH, , m), 7.32 (1 book, arom, m) MASS (3 Mr. V) M+367, m/e 324,1
83,182,105,77 Elemental analysis value (C2Pan2buQ, molecular weight 367.43)C
Day N calculated value 71.91 6.86 3.81
Actual value 72.06 6.83 3.69 Production method 24-benzyloyloxypiveridine 1.56 units (0
．． 005 mol) and bromomethyloxirane 1.37
(0.01 mol) was dissolved in 20 molar acetonitrile, and 690 molar potassium carbonate (0.005 mol) was dissolved in this.
Suspend and heat under reflux for 1 hour.

Next, the reaction solution is filtered, and after concentrating the solution, 50 parts of dichloromethane is added and washed with 20 parts of water. The dichloromethane layer is separated, dried over reeds, filtered and concentrated. The residue was subjected to column chromatography (aluminum oxide 9
0) and then recrystallized from acetone to obtain the target compound of 1.10% (yield 59.95%) with a melting point of 98.0.
Obtained as colorless rod-shaped crystals of ~99.0oo. This compound is the same as the compound obtained in Production Method 1 and IR, NMR, MAS
S, gas chromatography, thin layer chromatography and mixed melting test showed agreement. Example 15 4-benzyloyloxy-11-(2,2-dimethyl-1
, 3-dioxolane-4-ylmethyl)-1-methylpiberidinium bromide 4-benzyloyloxy-1-(2,2-dimethyl-1,3-dioxolane-4
5.10 g (0.012 mol) of piveridine (methyl-methyl) are dissolved in 30 ml of ethanol and cooled to 0°C.

To this solution was added 5.70 g of pre-chilled methyl bromide (0.
060 mol) was added, the reaction vessel was tightly stoppered, and the reaction vessel was left at room temperature for 8 hours. Next, excess methyl bromide and the solvent were distilled off, and the remaining residue was recrystallized from acetonitrile ether to give the target compound 5.922 mm (yield 94.9%) with a melting point of 1.
Obtained as colorless needle crystals of 86-19 (decomposition). I
R is OK. 3400 les C=. 1733 elemental analysis value (C26 days 34BrNQ, molecular weight 520.46) C days N Calculated value 60.00 6.58 2.69 Actual value 59.76 6.82 2.81 Example
164-benzyloyloxy-11-(2,2-diphenysole-1,3-dioxolan-4-ylmethyl)-1-
Preparation of methylpiveridinium bromide 4-benzyloyloxy-1-(2,2-diphenyl-1,3-dioxolan-4-ylmethyl)piveridine 5.50 mg (0.
010 mol) was dissolved in 50% ethanol and cooled on ice to 0°C.

Add 4.75 ml of methyl bromide (0.0
Immediately seal the reaction vessel and bring it to room temperature.
Leave it for a while. Next, excess methyl bromide and the solvent were distilled off, and the residue was recrystallized from ethanol to obtain the target compound 6.
09 g (yield 94.5%) was obtained as colorless needle crystals with a melting point of 218~00 (decomposition). Elemental analysis value (C36 day 3
8BrNQ, molecular weight 644.59) C day N calculated value
67.08 5.9L, 2.17 actual value 66.
89 6.15 2.23 Example 173-benziloyloxy-1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-1-methylpiberidinium bromide production 3-benziloyloxy- 1-(2
, 2-dimethyl-1,3-dioxolan-4-ylmethyl)piveridine 102 (0.00024 mol) was dissolved in 10 ml of acetonitrile and cooled to 0°C.

Add 68 o (0.00
072 mol) was added, and the reaction vessel was immediately sealed and left at room temperature for 6 hours. Next, excess methyl bromide and the solvent were distilled off, and the residue was recrystallized from acetonitrile ether to obtain the target compound 124-2 (yield 100%) with a melting point of 22.
Obtained as colorless needle crystals of 8.8 to 229.6 qo (decomposed). IR Foundation J Le. Day 3350, C=. 1745 elemental analysis value (C26 day 34B NQ, molecular weight 520.46
)C Day N Calculated value 60.00 6. Spots 2.
69 Actual value 60.21 6.31 2.61 Example 183-benzyloyloxy-1-(2,2-difer-1,3-dioxolan-4-ylmethyl)-1
-Production of methylpiberidinium bromide 3-benzyloyloxy-11-(2,2-diphenyl-1,3-dioxolan-4-ylmethyl)piveridine 535-9(0
．． 001 mol) in 20% acetonitrile and heated to 0°C.
Cool on ice.

Add 950 parts of methyl bromide (0.0
10 mol) was added thereto, the reaction vessel was immediately sealed and left at room temperature for 8 hours. Next, excess methyl bromide and the solvent were distilled off, and the residue was recrystallized from ethanol to obtain the target compound 6.
30m9 (yield 97.74%) with a melting point of 215.8-21
Obtained as colorless needle crystals of 7.60 (decomposition). Gourmet
Les skin spots 75riC=.

1743 Elemental analysis value (C3 pan-38BrNQ, molecular weight 644.59
C day N calculated value 67. Female 5. Group 2.17
Actual value 67.14 5.89 2.26 Example 191-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-4-mandeloyloxy-1-methylpiberidinium bromide production 1-( 2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-4
-mandeloyloxypiveridine 698-9 (0.00
2 mol) in 20°C of acetonitrile and cooled on ice to 0°C.

To this solution was added 1.36 ml of methyl bromide (0.0
143 mol) was added thereto, the reaction vessel was immediately sealed and left at room temperature for 1 incubation period. Next, excess methyl bromide and the solvent were distilled off, and the target compound was obtained in quantitative yield as a residue. No impurities were found by thin layer chromatography. IR Scale at Jichi 3385, female =.

1735NMR6c side.

1.39, 1.45 (thin, double s) 5.10 (IH, m) 5.34 (IH, , S) 7.42 (spotted, arom, m) 3,20 (thin, =N-CH3 , ratio, s) Example 20 4-(2-p-isobutylphenylpropionyloxy)-1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-1-methyl-piveridinium bromide Production of 4-(2-p-isobutylphenylpropionyloxy)-1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)piveridine 403M(0
．． 001 mol) in 10' of ethanol and cooled on ice to 0°C.

Methyl bromide 965 female (0.01
01 mol) was added, and the reaction vessel was immediately sealed and left at room temperature for 8 hours. Then, the solvent and excess methyl bromide were removed, and the solution was washed with ether and dried to obtain the target compound 4.
84 o (yield 97.1%) was obtained. No impurities were found by thin layer chromatography. IRN
Three skin trout.

=. 1735 NMR6cocso3 0.89 (fine, , d) 1.27, 1.36 (spotted, , double S) 2.48 (2 days, , d) ■ 3.29 (pongee, =N-CH3, br ,s)4.31(
,,m) 5.09 (IH, m) 7.15 (Rainbow day, amm, m) Example 21 4-benzyloyloxy-111 (2,2-diphenyl-
Preparation of 1,3-dioxolan-4-ylmethyl)-1-methylpiberidinium bromide 1.40 molar (0.004 mol) of 4-benzyloyloxy-1-methylpiberidine was dissolved in 20 molar dimethylformamide. Dissolve and further 4-
Adding 1.27 moles (0.004 mol) of bromomethyl-2,2-diphenyl-1,3 oxolane and melting;
Heat to 90q0 for 7 minutes.

Next, an excess of ether is added at room temperature, and the resulting precipitate of the target compound is taken up in a furnace and separated from the unreacted raw material compound and dimethylformamide as a solvent. The obtained precipitate was recrystallized from ethanol to obtain 1.65 kg of colorless needle crystals (yield: 63.95%) with a melting point of 217 to 219 qo (decomposition). This compound is the target compound of Example 15, m,
Matched with NM old. Example 224-benzyloyloxy-1-(2-cyclohexyl-2-phenyl-1,3
-Dioxolan-4-ylmethyl)-1-methylpiberidinium bromide According to the method described in Example 2, 1-(2-cyclohexyl-2-phenyl-1,3
-dioxolan-4-ylmethyl)-4-1-hydroxypiveridine (melting point 110.0-111.5oo) and methyl pendylate to react with 1
, 3-dioxolan-4-ylmethyl) piberidine was obtained as an oil.

m powder eagle J li.

Day 3488 indulgence=. 1730NMR6C.

Cso 34-90 (IH, m), 7.30 (1 beat. aro
m. S), MS (7V) m/e: 555 (M1) 4-benzyloyloxy-1-(2-cyclohexy-2-phenyl-1,3-dioxolan-4-ylmethyl)piveridine 1.11% (0.002 mol) was dissolved in 30°C of acetonitrile and cooled on ice to 0°C.

To this solution was added 1.36 ml of methyl bromide (0.0
143 mol) was added thereto, the reaction vessel was immediately sealed, and the mixture was left at room temperature for 1 hour. Then, excess methyl bromide and the solvent were distilled off, and the title target compound was obtained as a residue in a nearly quantitative yield. This product was further crystallized from acetonitrile-acetone to obtain colorless needle-like crystals. Melting point 211-213
00 m change.

Day 3400, C=. 1735

Claims (1)

[Claims] 1 ▲ Numerical formulas, chemical formulas, tables, etc. R_1, R_2
and R_3 are never the same at the same time. At least one of them is a phenyl group or an alkylphenyl group, or R_1 is a hydrogen atom and R_2 and R_3 are combined to form a fluorene ring or a xanthene ring, and Y is a hydroxy group. (means a hydroxyl group or a functionalized hydroxyl group)
A di- or tri-substituted acetic acid derivative represented by the general formula (I
II) ▲ Numerical formulas, chemical formulas, tables, etc.
5 is a group that together forms a cycloalkane ring), and the resulting product is optionally converted into an acid addition salt or a quaternary ammonium salt. General formula (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1, R_2, R_3, R_4 and R_5
has the above-mentioned meaning), or an acid addition salt or quaternary ammonium salt thereof. 2 General formula (V) ▲ Numerical formulas, chemical formulas, tables, etc. , R_1, R_
2 and R_3 are not the same at the same time, and at least one of them is a phenyl group or an alkylphenyl group, or R_1 is a hydrogen atom and R_2 and R_3 are combined to form a fluorene ring. 1-oxiranylmethyl-3 (or 4)-hydroxypiperidine ester derivatives represented by In the formula, R_4 and R_5 are the same or different and each represents a hydrogen atom, an alkyl group, a cycloalkyl group, or a phenyl group, or R_4 and R_5
is a group that together form a cycloalkane ring), and the resulting product is optionally converted into an acid addition salt or a quaternary ammonium salt. General formula (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1, R_2, R_3
, R_4 and R_5 have the above meanings. ) A method for producing an ester derivative of 1-(1,3-dioxolan-4-ylmethyl)-3(or 4)-hydroxypiperidine, or an acid addition salt or quaternary ammonium thereof. 3 General formula (VII) ▲ Numerical formulas, chemical formulas, tables, etc. , R_1, R_2
and R_3 are never the same at the same time,
At least one of them is a phenyl group or an alkylphenyl group, or R_1 is a hydrogen atom and R_2 and R_3 are combined to form a fluorene ring or a xanthene ring, and R_6 means a hydrogen atom or an alkyl group) 3- or 4-hydroxypiperidine ester derivatives represented by the general formula (IV) ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_4 and R_5 are the same or or different, meaning a hydrogen atom, an alkyl group, a cycloalkyl group or a phenyl group, respectively, or R_4 and R_5
is a group that together forms a cycloalkane ring, and X means a halogen atom) 1
, 3-dioxolane derivative, optionally converting the obtained product into a base or other acid addition salt or optionally changing an anion into another anion (IX) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1, R_2, R_3.R_4, R_5 and R_6 have the above-mentioned meanings, and X' means an anion) 1-(1,3 -dioxolane-4-
A method for producing an acid addition salt or quaternary ammonium salt of an ester derivative of (methyl)-3(or 4)-hydroxypiperidine, or a base thereof. 4 General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. , R_1, R_2
and R_3 are never the same at the same time,
At least one of them is a phenyl group or an alkylphenyl group, or R_1 is a hydrogen atom and R_2 and R_3 together form a fluorene ring or a xanthene ring, and R_4 and R_
5 are the same or different and each represents a hydrogen atom, an alkyl group, a cycloalkyl group, or a phenyl group, or R_4 and R_5 are groups that together form a cycloalkane ring) Represented 1-
General formula (X) characterized by treating an ester derivative of (1,3-dioxolan-4-ylmethyl)-3(or 4)-hydroxypiperidine with an alkylating agent▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1, R_2, R_3, R_4 and R_5
has the above-mentioned meaning, R_6 is an alkyl group, X is an anion) Method for producing tetraammonium salt.