JPS5959685A - Novel piperidine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [Y is R10(R10 is H, 1- 3C lower alkyl, etc.), or group shown by the formula II (m is 0-5; A is H, hydroxyl, halogen, etc.; X is O, S, carbonyl, etc.; R1 is 1-4C alkylene, etc.); Q is H, lower alkyl, etc.; n is 0-4; R2 is hydroxyl, lower alkoxy, etc.; B is -NH-, -N(R)-(R is lower alkyl, or phenyl), or -O-] and its acid addition salt. EXAMPLE:1'-Benzoylmethyl-(2-oxo-3,4-dihydro-2H-1,3-benzoxazine-4-spiro -4'-piperidine). USE:A hypotensor. PROCESS:A piperidine derivative shown by the formula III is reacted with a compound shown by the formula IV(X' is O, S, carbonyl, or methylene; Z is halogen or eliminable group) in an inert solvent, and, if necessary, it is deprotected to give a compound shown by the formula I (Q is H, or group shown by the formula II).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a group represented by the general formula [I]. When RIo is substituted or unsubstituted with a lower alkylene group having 1 to 3 carbon atoms of H1, such as methyl, methoxy, halogen or nitro group, Qij:
It is H. m is O or (.2I', an integer of 1-5. A is hydrogen, hydroxy group, haloken atom, lower alkyl group, lower alkoxy group, lower kenyloxy group, lower alkynyloxy group, lower alkylthio group, carboxyl group, lower alkoxycarbonyl group, nitro group, amino group, lower alkylamino group, lower acylamino group, sulfurioyl group, mono- or di(lower alkyl)aminosulfonyl group, lower alkylsulfonyl group, carbamoyl group, 7-ano group ' or a trifluoromethyl group.

When m is 2 or more, A is the same or different groups, and two A's may be combined to form a lower alkylenedioxy group. X is an oxygen atom (-0-) or sulfur. R1 is a straight chain alkylene group of 1 to 4 carbon atoms or a straight chain alkylene group of 1 to 4 carbon atoms having a lower alkyl substituent. Q is hydrogen, a lower alkyl group such as methyl or ethyl, a halogen group such as fluorine, chlorine, bromine or iodine, a hydroxyl group, or a lower fatty acid ester thereof. n is Oi or an integer of 1-4. R2 is a hydroxyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a trifluoromethyl group, a trifluoromethylthio group, a nitro group or an amino group. n is 2
In the above cases, R2 may be the same or different groups, and two R2 may be combined to form a lower alkylenedioxy group. B is -NH-1-N(R)-(R
is lower alkyl or as yet unsubstituted phenyl substituted with a halogen, methoxy, methyl or nitro group. ) or -〇-. ] (hereinafter referred to as compound [I]).

The present invention also relates to compounds of other formulas) and pharmacologically acceptable acid addition salts thereof.

Compound [I] shall include all optical isomers.

Acid addition salts of compound [1) include persimmon salts with inorganic acids;
Salts with various organic substances, such as hydrochloride, hydrobromic acid, iodide, nitrate, sulfate, phosphate, etc., such as formate, acetate, benzoate, maleic salt, Fumarate, succinate, tartrate, citrate, oxalate, glyoxylate, aspartate, methanesulfonate, exonsulfonate, propanesulfonate, methanedisulfonate, α, β- Examples include ethanedisulfonic acid tm and benzenesulfonate.

More specifically, the present invention relates to the general formula [I゛] (wherein A
N B % F (1, R1, It is. ] and acid addition salts thereof.

The object compound of the present invention, especially the general formula [I] (wherein A1,
A8, A and A4 are the same or different groups and have the same meaning as A, and X%R, %R3 and B have the same meanings as above. The compound represented by ) has pharmacological activity, particularly antihypertensive effect, and is expected to be used as a medicine. Compound [I"11] is also useful as a synthetic intermediate for compound [White].

Representative examples of the compounds of the present invention are shown in Table 1. Also, Table 1.3
3ijl constant values and assignments of C''-NMR of representative compounds are shown in Table V and Table 5 show the physical property values of these compounds.

/ of table 1 λ in Table 1 oBi4: represents a benzyl group.

The names of the compounds in each compound number in the first Shishi-no-he are as follows (displayed as free).

Compound ([f4/: /”-benzoylmethyl-(no-oxo-3,≠-dihydro-λH-/, J-benzoxazine-Hiroshi-spiro-l-piperidine) compound name co, , l rλ-7 enyl-λ -hydroxyethyl)
-(λ-oxoj, !-dihydro, 2H-/,
J-benzoxazine-≠-spiro≠1-piperidine) Compound number J: /'-(j, 4t-dimethoxybenzoylmethyl)-(λ-oxo3,4A-dihirolow2
H-/, J-benzoxazine-7-spiro-4tl
-Piperidine) Compound No. 4t:/'-(co(1,4L-dimethoxyphenyl)-λ-hydroxyethyl]-(λ-oxoj, 4'-dihydro-2,H-/,!-penzoxazine- ≠-spiro-2-piperidine) Compound number: /1-benzoylmethyl-(< -chloro-λ-o #7-j, 4+'-dihydro-2H-43-
Benzoxazine-≠-spiro≠1-piveridine) Compound number 6'''-(2-phenyl-co-hydroxyethyl)-(4-/ro-ro-co-oxo j, 4A-
dihydro-,2H-/, j-benzoxazine-goosespiro-l-piperidine) Compound No. 7: /'-(Hiro-
Chlorobenzoylmethyl)-(t-chloro-2-oxo-3,cudihydro-2H-/, j-penzoxazine-goosespiro-≠1-piperidine) Compound number ff: i'-Cco(4t-chlorophenyl) -11-hydroxyethyl)-(7-chloro-co-oxo-3.l-dihydro-,2H-/,!-benzoxazine-≠-spiro-V-piperidine) Compound t=No.:/I-[co (Hiro-chlorophenyl)
-λ-hydroxyethyl)-(-2-oxo-3,4t
-dihydro-λH-/, J-benzoxazine-≠-
Spiro 4AI-piperidine) (11'a 萱 Issue to
: i'-t:λ-(cuchlorophenyl)-2-hydroxyethyl)-(3-methyl-3,4-dihydro-2
(IH)-quinazolinone-4-spiro-47-piperidine] Compound No. 11: 1'-(2-phenyl-2-hydroxyethyl)-(3-methyl-3,4-dihydro-2
(IH)-quinazolinone-4-spiro-47-piperidine) Compound No. 12: 1'-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)-(3-methyl-3,4-dihydro- 2(IH)-quinazolinone-4
-spiro-4'-piperidine] Compound No. 24: 1'-[1-(3,4-dimethoxybenzoyl)ethyl]-(2-oxo-3,4-dihydro-2H-1,3-benzoxazine-4 -Spiro-
4'-Piperidine) Compound No. 25 Nisthreo-1'-(
2-(3,4-dimethoxyphenyl)-2-hydroxy-1-methylethyl]-(2-oxo-3,4-dihydro-2H-1,3-benzoxazine-4-spiro-4
'-Piperidine) Compound No. 26: Erythro 1 '-(1-(3,4-
dimethoxyphenyl)-2-hydroxy-1-methylethyl]-(2-oxo-3,4-dihydro-2H-1,
3-penzoquivudine-4-spiro-47-piperidine) Compound No. 27: 1'-(]-(3,4,5-)
rif 1-xybenzoyl)ethyl]-(2-oxo-3,
4-dihydro-2111,3-benzoxazine-4-
Spiro-4'-piperidine) Compound No. 28 Nisthreo-
] '-(2-(3,4゜5-trimethoxyphenyl)
-2-Hydroxy-J-methylethyl]-(2-oxo-3°4-dihydro-2H-1,3-pentinoxazine-4-spiro-47-piperidine) Compound Wt No. 29: l'-[] -(3,4,6-)
rimethquinbenzoyl)ethyl] -(2-oxo-3
,4-dihydro-2H-,1,3-benzoxazine-
4-spiro74'-piperidine) Compound No. 30 Nisthreo-1'-(2-(3,4°6-1rimethoxyphenyl)-2-hydroxy-1-methylethyl]-(2-oxo-3°4 -dihydro-2H-1,3-benzoxazine-4-spiro-4'-piperidine) Compound No. 31: Erythro-1'-(2-(3°4.6
-Dorimethoxyphenylxy-l-methylethyl]-(2-oxo-3,4-dihydro-28-1.3-benzoxazine-4-spiro-4'-piperidine) Compound No. 32: 1'- (
2- (3. 4. 5-1-rimethoxyphenyl)
-2-hydroxyethyl]-(2-oxo-3,4-dihydro-2Hi.

3-pensuoxazine-4-spiro-4'-piperidine) Compound No. 33: 1'-(2-(3-hydroxy-4-methoxyphenyl)-2-hydroxyethyl)-(2-oxo-3,4-dihydro -2H-1.3-
Benzoxazine-4-spiro-4'-piperidine) Compound No. 34: 1'- (2- (3. 4~
Dime-i-xyphenyl)ethyl)-(2-oxo-3.

4-dihydro-2Hi. 3-benzoxazine-4-spiro-41-piperidine) Table C''-NMR measurement compound and position @ sign and measurement solvent II I2 / ' 1ctoHto 1〉Co, O3, 7/, 4t/
J Hita 9 133171 It)
t, 0/1. Jjλ lc,. N2. N,
O3, 7/, 00 1Jj rko! '7/, l
j t, tJ t,, 2rJ Ic2. H,
4N20. 4A,itj/,10 707E,
Aj4t t, 0! 7.04t4tC, 2) 42
6N, 0. 4j, J, 2 tJl 70.36A,
u'l t, t/ 701t C2oo2. c.
zN, o3. gaa3 jAt 7r/
'ta/i Itta 7. Itgure 7'c, oH, 8c12rq, a, J9+2
7 apt thyt'rr, yy
atx 7io: HI C2oH,. C
l2N2Cp4! Irari, t 6. r
r', 1197 1Ari1 701zoCto"1@
ClNz0.44t, l itj 71/, tlA2
J! 13 7! t10 C2, N24C/1430.
4jJ4 427 10rf true 4. J710
Yt // C2+h, 5N302 70.7774'J
/ljl '7/, 0'l 7. /7 /JL/'
1/, 2C! , N2. N30467/J710
10.2/'67JJ 70910. /22! Table 5/Table 5-2 This will be explained using an experimental example.

Example This experiment was carried out on 3pontaneOusly Hyperte.
nsive (5HR) rats Guideline
s for Blessing, (: are and
It was carried out according to the method described in Use (ST (published by 'R Council) (/7t) page ii.

The experimental animals were spontaneously hypertensive rats (8 HR) (/j weeks of age, blood pressure/I OmmHy or higher), with j animals in each group. The drug is θ, 3% (”/v) CM'C
J7r was suspended in an aqueous solution at a concentration of 3 μ/d, and then administered to rats.
It was administered orally in an amount of q/100f body weight.

Changes in blood pressure were measured by caudal artery plethysmography (see reference above). The degree of decrease in maximum blood pressure (mm Hy) after administration relative to the pre-administration value is shown in Table 6.

Table 69 Example 3 or 4 DD strain male mice (body weight 18-20 g
) were used as one group.

Each compound was added to physiological saline and administered orally to mice at a dose of 300 μ/kg or even 200.100 or 1000 μ/kg. The number of deaths was then counted after 7 days of observation. A dose that kills half of the test animals! Ir1
It is shown in Table 7.

Table 7 (1) The compound [r'] is produced as follows.

Compound [I'] is a piperidine conductor represented by the general formula (II) . Ko and R1 are 1;1, ri11-! Oxygen (-
3-)・, sulfur(-9-one, carbonyl(te-)-merized methylene(-汀,-)zusu, Zi; halogen or t-
J It is the basis of the eyebrows. 4-? I can do that.

In the definition of Z in compound [and], lj as halogen
4. The radicals include alkylsulfonyloxy, iH (what, eh) methanesulfonyloquinato), arylsulfonyloxy group (
Examples include (e.g., benzenesulfonyloxy, valatoluenesulfonyloxy, etc.). Inert solvents include ketones (such as acetone), halogenated hydrocarbons (such as chloroform and methylene chloride),
Amides (e.g. dimethylformamide), sulfoxides (e.g. dimethylsulfoxide), substituted or unsubstituted aromatic hydrocarbons (e.g. benzene, toluene, chlorobenzenato), low? :i 7 le cole (
(methanol, ethanol, isopropanol, etc.) may be used alone or in combination.

Depending on the reactivity of the group Z to be exchanged, the reaction takes place between O and izo°C.
It is preferably carried out within the range of room temperature and the boiling point of the solvent used.

If the above reaction is carried out in the presence of a base, the reaction will generally be enhanced.
It can proceed smoothly.

The bases used include low-grain alcoholades (e.g., sodium methylate, sodium ethylate, etc.), alkali hydroxides (e.g., sodium hydroxide, etc.), alkali carbonates (e.g., sodium carbonate, potassium carbonate, etc.),
Examples include tertiary amines (eg, triethylamine, pyridine, etc.). The amount of base used is determined by the amount of base used in compound [11
) for /, 0- /, λ times When using an acid addition salt such as the hydrochloride of compound i, it goes without saying that an extra base is needed to neutralize the acid. ).

However, the use of a reaction accelerator such as potassium iodide is also suitable for smooth progress of the reaction.

The above reaction is usually completed in 30 minutes to ≠ hours. Particularly when heated under reflux, the process is completed in 30 minutes to 3 hours.

When either R3 or A is hydroxyl, amino or 1-alkylamino, these 1-stage substituents are protected in advance by a known method and then reacted. After the reaction, the target compound can be obtained by removing the Hokoma group by a conventional method.

When X is carbonyl, the obtained product is further refined to form a compound [I°] where X is hydroxymethylene.
can lead to.

In this reaction, a compound [l°] in which The reaction is carried out at a temperature ranging from °C to the boiling point of the solvent used. This reaction also applies to compounds where X is carbonyl [■
9] can also be carried out by catalytic reduction of 20°C using a hydrogenation catalyst such as palladium carbon in a lower alcohol such as methanol or ethanol, a lower fatty acid such as acetic acid, water or a mixed solvent thereof. . These reactions may be carried out in the open or in a closed container under pressure.

Isolation of compound [I"] can be carried out by methods commonly used in the field of organic synthetic chemistry, such as reduction, extraction, recrystallization,
This can be done by chromatography. For example, since compound [1] generally has good crystallinity, the solvent may be distilled off from the reaction-completed solution, and the remaining solution may be recrystallized from an appropriate solvent (eg, ethanol).

The acidifying power of the compound [1°] can be obtained by reacting the compound [Il] with an appropriate acid in an appropriate solvent (for example, ethanol, etc.).

Compound [ll], which is a raw material for the synthesis of compound [l°] and is also one of the target compounds of the present invention, is also a new compound and can be obtained by the method described below.

Compound [H] is a piperidine derivative represented by the general formula [B] (wherein R2 and n have the same meanings as above) and a carbonic acid halide (for example, phosgene, trichloromethyl chloroformate, alkyl chlorocarbonate, etc.), The piperidine derivative is refluxed by reacting a carbonic acid diester (for example, diphenyl carbonate, etc.) with t'-carbonyldiimidazole, or a lower alkyl (methyl, ethyl, propyl, etc.) incyane is added to the piperidine derivative. -1 or a substituted or unsubstituted phenyl isocyanate to form the general formula [V] (wherein, R2 and n have the same meanings as above, R is hydrogen,
It is a C1-3 lower alkyl group or a substituted or unsubstituted phenyl group. ), then acid (
oxidized by treatment with mineral acid or Lewis acid),
Then, the benzyl group at the 7-position of the piperidine ring is removed by using a method for removing the N-benzyl group such as catalytic reduction. Also, compound Ell) via compound [v]
In order to obtain the compound [■], the benzyl group at the 1-position of the piperidine ring of the compound [VI may be eliminated and then cyclized to obtain the compound [■].

The above reaction will be explained in more detail with respect to the case where B==O and the case where B=-N(6)-.

When B=00, that is, the general formula [11-/] (wherein, R
2 and n have the same meanings as above. ) is a piperidine derivative represented by the general formula [IV] (wherein R2 and n have the same meanings as above) and a carbonic acid/10-genide (e.g., phosgene, trichloroformate, alkyl chlorocarbonate, etc.) , a compound represented by the compound [V1] (wherein R2 and n have the same meanings as above) by reaction with a compound selected from carbonic acid diesters (such as diphenyl carbonate) or 4/1-carbonyldiimidazole. be led to.

All of the above reactions can be carried out by known methods, but the case where lI-carbonyldiimidazole is used will be described. In this case, the reaction is carried out using non-chlorogenic hydrocarbons (e.g. methylene chloride, chloroform, etc.), ethers (e.g. ethyl ether, tetrahydrofuran, dioxane, etc.), aprotic polar solvents (single or mixed solvents) such as acetonitrile, dimethylformamide, dimethyl sulfoxide, etc. ), preferably with stirring.

Otsu/The amount of 1-carbonyldiimidazole used is the compound [
IV) is suitably i, o-xo times equivalent. The reaction temperature is suitably within the range of room temperature to the boiling point of the solvent.

The appropriate reaction time is 1 to 3 hours when the reaction is carried out below the boiling point of the solvent, and 1 to 12 hours at room temperature. Compound El-/) is then obtained by removing the benzyl group of compound (Vl:).

Debenzylation can be carried out using a method using alkyl chlorocarbonate (such as vinyl chlorocarbonate), a catalytic reduction method, or other methods generally using N.
- the benzyl group is removed by an alcohol (e.g. methanol,
ethanol, isopropanol, etc.), water, or a mixed solvent of these.
This is carried out by catalytic reduction in the presence of a catalytic reduction catalyst such as carbon (carbon, etc.). The reaction is carried out in the presence of an acid catalyst (for example, mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, or fatty acids such as acetic acid and propionic acid) (the amount used is l-λ). (appropriate amount). The reaction temperature is suitably between room temperature and 0°C.

B = -R (in the case of r-Q-, that is, the general formula [■-
λ] (In the formula, R, R2 and n have the same meanings as above.)
The compound represented by is produced as follows.

First, the compound [■] is reacted with a lower alkyl (methyl, ethyl, propyl, etc.) isocyanate or a substituted or unsubstituted phenyl isocyanate to form a compound [V] represented by the general formula [■].

(In the formula, B2, R and n have the same meanings as above, 2). )
As the organic solvent used in this reaction, any inert organic solvent that does not participate in the reaction can be used, but aromatic hydrocarbons such as benzene, toluene, and xylene, methylene chloride, chloroform, dichloroethane, and tetrachloroethane are preferably used. Non-logenated hydrocarbons such as carbon chloride, esters such as methyl acetate and ethyl acetate, ethers such as diethyl ether, dioxane and tetranohydrofuran, ketones such as acetone and methyl ethyl ketone, acetonitrile/l/, LN- Dimethylformamide and the like can be used alone or in combination. The reaction is -SO℃~! 0°C, preferably -! It is carried out in the range of ℃ to 23℃. The reaction is usually completed in 30 minutes to 3 hours, but may be completed overnight.

Next, compound (V) is treated in an aqueous solution containing a mineral acid to lead to compound [VII] (wherein R, R2, and n are as defined above). At that time, if necessary, methanol, ethanol,
Alcohols such as propatool, ethers such as dioxane and tetrahydrofuran, and aprotic polar solvents such as dimethyl sulfoxide may be added. The reaction temperature may be within the range of room temperature to the boiling point of the solvent, but may be 60°C to i
o.

A range of 0.degree. C. is preferred.

The concentration of the mineral acid may range from tN to 30N, but the compound [11- 21 is obtained. The debenzylation reaction is carried out in the same manner as the debenzylation of compound [VI], but it is appropriate to use fatty acids (acetic acid, propionic acid, etc.) as the acid catalyst. Further, the appropriate amount to be used is 1 equivalent. Compound [11=1 is also a compound [■°] obtained by debenzylating compound [V] (in the formula, R, R,, n are the same as above) (Debenzylation means debenzylating compound [vI]. benzylated to form compound [1
1-/] under the same conditions. ) can also be obtained by cyclizing. The reaction conditions at this time are the same as those for obtaining compound [VIJ] from compound CVI.

Compound [IV), which is a raw material for the synthesis of compound [11], is also a new compound. Compound []V] is produced as follows.

Anhydrous ether@
(ethyl ether, tetrahydro7ran, etc.) and n-
n-butyllithium using a mixed solvent of hexane as a solvent,
After forming the dilithium salt of the compound [Vl] using a lithium-forming agent such as lithium inpropylamide, the compound [Vl] is reacted with a compound represented by the formula [IX] Formula [X] (R2)
A compound represented by n (wherein R2 and n have the same meanings as above) is produced. In the above reaction, the lithiation is carried out in the range of -j°C to 30°C for 2 to 2≠ hours. The amount of the lithiation agent to be used is preferably 1 to 15 times the molar amount of the compound [■]. The following compound [IX
), the reaction temperature is -! ~30°C, reaction time λ ~, 24 hours is appropriate. The appropriate amount of compound [IX) to be used is /-/j times mole relative to compound [■]. Next, the obtained compound [X] is hydrolyzed in a mineral acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc.) to lead to compound [1v]. This hydrolysis reaction is from 1 to
The reaction is carried out in the above mineral acid with a normal range of /θ, but more preferably in a normal mineral acid of -. The reaction temperature is θ
C. to the boiling point of the reaction solution, but it is usually appropriate to carry out the reaction at the boiling point of the reaction solution. The reaction usually ends in 5 hours when λ≠.

(2) Compound CI” in which Y=R, o in compound [1]
'] is manufactured as follows.

Compound CI'"1] has the general formula (Xll) (wherein R2,
nsQ and R1° have the same meanings as above. ) and a carbonic acid halide (e.g., phosgene, trichloromethylchloroformate, alkyl chlorocarbonate, etc.), a carbonic acid diester (e.g., diphenyl carbonate, etc.), or di-carbonyldiimitasole. The piperidine derivative may be cyclized or the piperidine derivative may be substituted with a lower alkyl (methyl, ethyl, propyl, etc.) incyanate or substituted or non-fif'
The phenyl isocyanate of FA is reacted to form the general formula [X
1ll] (wherein, Q and R have the same meanings as above), and then chlorified by treatment with acid (mineral acid or Lewis acid), and if necessary, By further subjecting the reaction product to catalytic reduction or acid hydrolysis, R1° is removed by one state, resulting in a compound in which R1o=H.

The above reaction will be explained in more detail for the case of B=O and the case of B--hJ(u)-.

In the case of B=0, that is, general formula [XIV] (wherein, R1
'H2, n and Q have the same meanings as above. ) is selected from piperidine derivatives represented by the general formula [Xl1), carbonyl halides (for example, phosgene, trichloroformate, alkyl chlorocarbonate, etc.), carbonic diesters, 4/-carbonyldiimidazole, etc. Manufactured by reacting with a compound.

All of the above reactions can be carried out by known methods, but the case where 4/-carbonyldiimidazole is used will be explained. In this case, the reaction is carried out using halogenated hydrocarbons (e.g. methylene chloride, chloroform, etc.), ethers (e.g. ethyl ether, tetrahydrofuran, dioxane, etc.), aprotic polar solvents such as acetonitrile, dimethylformamide, dimethyl sulfoxide, etc.
It is preferably carried out in a single or mixed solvent) under stirring.

The amount of 4-nocarbonyldiimidazole used is the compound [■
], an amount of i, o-, z, o times equivalent is excessive. The reaction temperature is suitably within the range of room temperature to the boiling point of the solvent.

The appropriate reaction time is 7 to 3 hours when the reaction is carried out below the boiling point of the solvent, and t to 72 hours at room temperature.

In the case of B=-N(8)-, that is, the general formula [XV':1
(In the formula, Rr o s R2, H, n and Q are the same as above.) is the combination of compound (Xl) and lower alkyl (methyl, ethyl, propyl, etc.) incyanate or
, l-substituted or unsubstituted phenyl isocyanate are reacted to form a compound [Xl].

As the organic solvent used in this reaction, any inert organic solvent that does not participate in the reaction can be used, but aromatic hydrocarbons such as benzene, toluene, and xylene, methylene chloride, and chloroform are preferred.・Esters such as methyl acetate and ethyl acetate, ethers such as diethyl needle, dioxane, and tetrahydrofuran, ketones such as acetone and methyl ethyl ketone, Acetonitrile, N,N-dimethylpolamide, and the like can be used alone or in combination. The reaction takes place at 0℃~! θ℃,
Preferably −j℃～ko! It is carried out in the range of °C. The reaction is completed in about 30 minutes to 3 hours, but may be completed overnight. Next, this is cyclized to lead to the above-mentioned compound [XV].

This method will be explained below.

Compound CX1) can be easily led to compound [XV':l by treating it in an aqueous solution containing a mineral acid; however, if necessary, methanol or ethanol may be added to increase the solubility of the compound. , alcohol such as propa tools, etc.
For J and t*, ethers such as dioxane and tetrahydrofuran, and aprotic polar solvents such as dimethyl sulfoxide may be added. The reaction temperature may range from room temperature to the boiling point of the solvent, but preferably from 60°C to 100°C.

The concentration of the mineral acid may range from Otsu normal to 30 normal, but it is preferably carried out in 10 to 12 normal, especially 1/C/2 normal hydrochloric acid. The compound R1,=H can be obtained by eliminating RIO either before or after the cyclization.

That is, in the step before cyclization, R + o of compound α■]
Ic k separated, in the general formula [Xl1i), R, o
Compound [XVI) (wherein R, R2, and Qsn have the same meanings as above) in which =H was also subjected to the same cyclization reaction treatment as compound [XI].
It is possible to lead to a compound included in V), that is, a compound in which R1°=H in the general formula [XV].

The removal of R1° is carried out by a reaction commonly used to remove the protective group of the amino group, and the elimination method will be explained by selecting the case where the protective group R1° is benzyl.

Debenzylation is performed on compound [XIl] or compound [XV
) to lower alcohols (e.g. methanol, ethanol,
The reaction is carried out by catalytic reduction in the presence of a catalyst for catalytic reduction such as a palladium catalyst (for example, palladium on carbon), water, or a mixed solvent thereof. The reaction is carried out in the presence of an acid catalyst (for example, mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, and perchloric acid, or fatty acids such as acetic acid and propionic acid) (
The appropriate amount to be used is 2 to 2 commercial quantities per starting compound [Xl'3 or [XV]. ). Compound [XV
], the coexistence of fatty acids is preferred. The reaction temperature is suitably between room temperature and 0°C.

Compound [XV] also has the general formula [XVII] (wherein I
The piperidine enzyme conductor represented by (to% bird, n and Q have the same meanings as above) is treated with acid (mineral acid or Lewis acid) or with halogens such as chlorine, bromine, iodide, etc.
Chlorosuccinimide (NC8), r+-bromosuccinimide (NB8), N-iodosuccinimide (NI
It can be obtained by treatment with a commonly used halogenating agent such as S).

The method for producing compound [XV) using bromine will be described below. In this case, the reaction is carried out in an organic acid such as acetic acid, propionic acid, trifluoroacetic acid (single or mixed solvent) or in a mixed solvent of an ether solvent such as dioxane and water, preferably under stirring. The amount of bromine used is /, 0 for the compound [xVII].
-YuO Baitouji is Hisho. The reaction temperature is from −j℃ to λ・
, 3°C is suitable. Reaction time is 7~! The time is appropriate.

Compound [Xl1), which is a raw material for the synthesis of compound [1], [X
VI) and [XVI[) are new compounds.

Compound (XID) is produced as follows.

The pivaloylaminobenzene enzyme derivative represented by the general formula After using a mixed solvent of as a solvent and a lithium-forming agent such as n-butyllithium or lithium isopropylamide to form a dilithium salt of the compound [XVl), the general formula [XIX] Q RIO-N'-\=o [XIX] \ / (In the formula, % Rto and Q have the same meanings as above.) to react with a compound represented by the general formula [XX] (in the formula,
RIO1R2, n and Q tLj R4]. ) is produced. In the above reaction, lithiation is carried out for 2 to 2 hours at a temperature of -j℃ to 30℃.
It will be held during Kojiki.

The amount of lithiation agent used is as follows for compound [XVl):
It is preferable to use 2 to 2j times the molar amount. The following compound (XI
In the reaction with X), the reaction temperature is -j to 30°C, and the reaction time is λ to λg. The amount of compound [XIX] to be used is /~/j times molar relative to compound [XVI).

Next, the obtained compound [XX] is hydrolyzed in a mineral acid (hydrochloric acid, hydrochloric acid, hydriodic acid, imitation plate, etc.) to lead to a compound (Xll': l). The hydrolysis reaction is carried out in the above-mentioned mineral acid with /~/Q normality, but is preferably carried out in λ~6 normal mineral acid.The reaction temperature is between j0°C and the boiling point of the reaction liquid. However, it is usually appropriate to carry out the reaction at the boiling point of the reaction solution.The reaction is usually completed in 2t/- to jj hours.

Compound [XVIl) can also be obtained by further extending the reaction time in the reaction for synthesizing compound [X11:].

A period of 7.2 hours to one week is appropriate for a reaction to occur. In addition, [XVI) can be prepared by using the method generally used to remove the atom group from the amino group of the compound [Xl].
It can be obtained by eliminating ゜.

The compounds of the present invention and the starting compounds can be isolated and synthesized by methods commonly used in the field of synthetic organic chemistry.

Examples are shown below to further illustrate aspects of the present invention. In addition, some of the methods for synthesizing raw materials are described in reference examples.

Example/l-benzoylmethyl-(,2-yrxo-3,≠-
Dihydro, 2H-/, j-benzoxazine-≠
Production of ω-bromoacetophenone (2-oxo 3゜≠-dihydro 2H-/) by the method described in Example/l,
J-benzoxazine-+-spiro-hiro 1-piperidine hydrochloric acid jXg3A, RiR9, methanol/-αt and 0.7 mg of triethylamine were mixed and stirred overnight at room temperature. After removing the precipitated white crystals, they were washed with water and dried to obtain crude crystals of the target product 7.21. , Ong
I got it. This was recrystallized from chloroform and t j /
, the target compound of u■ was obtained.

Example λ/'-(,2-phenyl-hydroxy/ethyl)-(
,2-O1)-dihiro-dihydro-,2i4- /, 3
-Penzoylmethyl-(2-oxo-3,4t-dihydrocoH-/-, obtained by the method described in Example/)
j-benzoxazine-Hiro-Subirow 4t+-piperidine) Aλri■ and ethanol! 0txll and 30ozg of sodium boronohydride while stirring at room temperature.
was added and stirred for 27 hours. Here, 00 mg of sodium borohydride was further added and stirred for 75 hours. One portion of the precipitated white crystals was washed with methanol (-0d), water (JOrxl), methanol (/il) m/), and ether (10xt), and dried to obtain jll' powder.

On the other hand, the mother liquor and the first methanol wash were combined and concentrated under reduced pressure. To the resulting crystalline residue, 10ral of water was added to collect f, which was further washed with water and dried to give /001g.
I got it. These were combined and recrystallized from a mixed solvent of dimethylformamide and methanol (l:λV/V).
The target compound of V was obtained in L4t,r.

Example 3゜/'-(j, 4'-dimethoxype/zoylmethyl)
-(,2-okinoman≠-dihydro-λH-43-pe/
Production of zooxoxade/-≠-spiro≠1-beveridine): 3. ≠-dimethoxy ω-bromoacetophenone J j
J', 5' fifF, co-oxo obtained by the method described in Example 1B; 3. ≠-dihydro-, 2H-/,
゛J-benzoxazine≠-spiro-hiro 1-piperidine hydrochloride λj4t, In8methanolhego and triethylamine 0. Jrxl was mixed and stirred at room temperature overnight. After removing the precipitated crystals by d′J, they were washed with water (10πl
) L, dry and coarse crystals of the target product 3! ! 19't-In
Ta. This was recrystallized from a chloropormoeta/-luno mixed solvent to obtain 376 mg of the target compound.

Example ≠ /I-[-1(3,Gudimethoxyphenyl)-cohydroxyethyl]-(Cooxo3.4 as monodihydro, 2H-/, j-penzoxazine-V-spiro-ψ-piperidine ) Production of /'-(J,≠-dimethoxybenzoylmethyl)-(obtained by the method described in Example 3)
j-oxo-j, p-dihydro-coba 43-penzoxazine-goose pi-o-4t+-piperidi7) /
, 0901A9, ethanol jOytl and sodium borohydride 1700 tag were mixed and stirred overnight at room temperature.

The next day, an additional 100 ml of medium borohydride 2ide was added, and the mixture was stirred overnight at room temperature. Collect the precipitated white irises,
Methanol (20ml water (3oNe), methanol (
/17 punishment), washed with ether (10 tpl) and dried to obtain crude crystals of the target substance? / got Omg. On the other hand, after concentrating the ethanol solution of solution F under reduced pressure, 10 liters of water was added to the residue, and the precipitated crystals were separated by f, washed with water (20 πl), and dried to obtain 27 mg.

These were combined and recrystallized from a mixed solvent of DMF and methanol to obtain 611 mg of the target compound.

Example: Preparation of /I-benzoylmethyl-(,4-chlorocooxo,cudihydro-,2H-/,?-benzoxazine=μm spiro=≠1-piperidine): ω-bromoacetophenone 3 7wt9. O-Chlorose-oxo-3,4 obtained by the method described in Example/r
t-dihydrocoH-43-benzoxazine-goosespiro-4tl-piperidine hydrochloride 171 mg, ethanol coθd and triethylamine 70. j 7g scraps
were mixed and stirred overnight at room temperature. This reaction solution was concentrated under reduced pressure, and the resulting crystalline residue was triturated with 10 mg of water and collected.

This was washed with water (10 ml) and dried to obtain the desired crude crystal t7λxyl. Recrystallize this from ethanol!
The target compound of 41η was obtained.

Example 2゜/'-(u-phenyl-1-hydroxyethyl)-(6
-Chloro-2-oxo-3,≠-dihydro λH-43
Production of -benzoxadi/-ri=spiro-ψ-piperidine): 11-benzoylmethyl-(ot-chlorocooxo-3,4) obtained by the method described in Example j was converted into monodihydro, 2H-/, !−Penzoxazine−≠−Spiro−
1I+-piperidine), ethanol λOmi and sodium boronohydride J 7219 were mixed and stirred overnight at room temperature.

Collect the precipitated crystals, add ethanol (, txt) and water (
λ0ytt) to obtain crude crystals of the target product. On the other hand, the ethanol solution of Solution F was subjected to vacuum purification, water was added to the residue, and the precipitated crystals were collected in abundance. After washing this with water (04), it was dried to obtain a rag. These were combined and recrystallized from a mixed solvent of DMF and ethanol to obtain the desired product JI Omg.

Example Z Production of /'-(4(-chlorobenzoylmethyl)-C6-chloro-2-oxo-3, Hiro-dihydrocoH-/, 3-penzogisazine-≠-spiro-≠1-piperidine): V-chloro-ω-promoacetophenone Hiroshi &711/
, 6-chloro-2- obtained by the method described in Example it.
Oxo-J, 4L-dihydro-λH-43-penzoxazine-≠-spiro-tAl-piperidine hydrochloride j7
1r*g, ethanol 10tne and triethylamine 0. ! t vtl was mixed and stirred overnight at room temperature. Collect 773 precipitated crystals and add methanol (! station l)
After washing with water (λ0rnl), the product was dried to obtain crude crystals of the target substance, λβg.

This was recrystallized from a mixed solvent of DMF and ethanol to obtain the desired product, Omg.

Example and /'-(:, 2-(≠-chlorophenyl)-!-hydroxyethyl)-(Otsu-chloroco-oxo-dihydrocoH-/, J-benzoxazine-7-spiro-piperidine) Production: 11-(Hiro-chlorobenzoylmethyl)-(7-
Kurorokookin 3. +L-dihydro-λH-43
-penzoxazine-≠-spiro-4L'-piperidine)6! OPg and ethanol dOmt were combined, and while stirring in a chamber, add sodium borohydride tr.

Added Q. - After stirring overnight at room temperature, 1jJ of precipitated crystals were collected and washed with ethanol jtxl and water λ0tst to obtain J/7 crude crystals of the target product. Of these, 4t41
II pg was recrystallized from a mixed solvent of DMF and ethanol to obtain 327*g of the target compound.

Example 2 /l-[λ-(4t-chlorophenyl)-cohydroxyethyl)-(,2-oxo-4goodihydro-j H
-/, ! -Benzoxazine-Goose Spiro-+Ll-
3. Co-oxo obtained by the method described in Example/B. ≠-dihydro-J H-/, J-benzoxazine-trans-spiro lIt+-piperidine.
1g of 42-yield 7", ethanol, 30ynl, and 0.rllrd of triethylamine were mixed and stirred overnight at room temperature. After concentrating this under reduced pressure, water and 20% of the residue were added to solidify. After washing with water≠0rttl, jml of methanol was added to crystallize.

Take one of these and methanol! After washing with 1, dry % shite 1l
-(4t-chlorobenzoylmethyl)-(co-oxo-3,4t-dihydro-λH-/, 3-benzoxazine-goosespiro-hiro-piperidine)4'-2-tjyl
! Ta. On the other hand, after concentrating liquid f (methanol layer) under reduced pressure, ethyl acetate (jml) was added to the obtained oily residue, and the mixture was concentrated under reduced pressure again. The resulting 1" crystal residue was tricerated with ethyl acetate, P was removed, and after washing with 1 and 3 times of ethyl, it was dried to obtain Hiroki ♂■. Of these crystals obtained, Iooxg was This was used in the next reduction reaction.

t'-(a-chlorobenzoylmethyl)-(-2-okino 3,4t-dihydro-211-/, j-benzoxanone-≠-spiroq1-piperidine) 100*g
, ethanol♂Oyi, nodium borohydride r
o o zi! "T: Mixed and stirred at room temperature overnight.

The reaction solution was condensed under reduced pressure, and the residue was poured with methanol to 10°C and condensed again under reduced pressure. This crystal residue is mixed with water Oh=
It was triturated with 1 and the percentage was taken.

After washing this with water and drying, it is dried to obtain coarse crystals of the target substance.
! ! I gained skill. Is this i D ) i F recrystallized from a mixed solvent of ethanol to 3♂3π? The target compound 'f was obtained.

Example, + (λ-(+-chlorophenyl)-2-hydroxyethyl)-[j-methyl-3,≠-dihydroco(/
Preparation of 3-methyl-3,≠ H)-quinazolinone-V-subirogue piperidine] obtained by the method described in Example 1≠
-dihydro2(/)()-quinazolinone-goosespiro-≠11-biperidine lI 63g, α-promo p-chloroacetophenone III, 7mg, triethylamine 0. Mix λItrrl and 10tt of methanol,
Stir for hours at room temperature.

Next, sodium borono hydride 10019 was added to this reaction solution under ice cooling, and the mixture was stirred. After 30 minutes, another 20
After adding 0xg, the mixture was stirred at room temperature overnight. After concentrating this reaction solution under reduced pressure, 10 zl of water was added to the crystalline residue containing inorganic substances, and the mixture was tricerated.

I got f. This was washed with water λOat and then dried to obtain 72λη of crude crystals of the target product. This was recrystallized from a mixed solvent of DMF and methanol to obtain the desired compound of 2.

Example/ /.

l'-(z-phenyl-cohydroxyethyl)-(3
Production of α-bromoacetophenone J y tmg, 1 Example/
3-Methyl-3, 3-methyl-3-dihyde obtained by the method described in
'0-u(/H)-quinazolinone-Hiroshi-Subirow≠1-
Piperidine 4L63νO, ethanol jIX/ and triethylamine 0. ．． 21' m, l were mixed and stirred at room temperature for 3 hours. This reaction solution was vacuumed for 6 hours, then 10 ml of chloroform was added and washed with water (!w+lX). This chloroform solution was solidified under reduced pressure to obtain an oily residue. Ethanol/Qml was added to this to dissolve it. While stirring this ethanol solution at room temperature, undium borohydride AO (.
was added, and the precipitated crystals were collected. Wash this with water (208
After rinsing and drying, 360 μm of the target product (e) 1 crystals were obtained. This was recrystallized from ethanol to obtain the desired compound.

Example 12 /l-[co(3,≠-dimethoxyphenyl)-λ-hydroxyethyl:]-[:3-methyl-44C-dihydro, 2(/H)-quinazolinone-≠-subirou p+-
Production of piperidine]: 3. Hiro-dimethoxy-α-bromoacetophenone jit
That is, 3-methyl- obtained by the method described in Example/4t
4 μm dihydro(/H)-quinazolinone-≠-spiro 4/11-piperid: y4AtJ cape, ethanol 7
117 and triethylamine θ, 21 yrl were mixed and stirred at room temperature for 3 hours.

This reaction solution was concentrated under reduced pressure, and the resulting crystalline residue was mixed with 10 ys of water.
Trigueylate p was collected using l. Wash this with water (,2(7u
/) and dried to obtain /'-(J, goudimethoxybenzoylmethyl)-(3-methyl-J, !-dihydroJ (IH)-quinazolinone-≠-spiro φ1
Ethanol λ0WLt was added to the crude crystals of -piperidine). While stirring this at room temperature, 140 m of indium borohydride was added. - The mixture was stirred at room temperature overnight, concentrated under reduced pressure, and 30 parts of water was added to the resulting residue. The precipitated white crystals of the desired product were collected, washed with water (-0 ml), and dried to obtain the desired product 7/j■. This was recrystallized from a mixture of DMF and ethanol to obtain the target compound of 117.

Example/J.

/1-benzyl-[3-methyl-3,≠-dihydro,
Production of l-benzyl-q-hydroxy-<X-(Z-aminophenyl)piperidine/' synthesized by the method of Reference Example/
731 and ethyl acetate/J,! mt was mixed and 1 jpl of methyl isocyanate was added while stirring at room temperature. After stirring overnight at tM temperature, l-benzyl-≠ precipitated
-Hydroxy-4=-(co(N-,,'tylcarbamoyl)aminophenylcopiperidine crude crystals were collected,
Washing with 20M ethyl acetate gave 3f. This was recrystallized from ethyl acetate to obtain the compound A, 741 f'.

Physical properties of l-benzyl-guhydroxy-≠-[-1(N-methylcarbamoyl)aminophenylcopiperidine Melting point: 17 uO~17 u s °C Elemental analysis value HCN calculated value 71I2% 70.77 hand 1231% actual measurement Value 7. AO Jin 70. Tata staff 1x3o Kenji/
-Benzyl-≠-Hydroxy-≠-[2-(N-methylcarbamoyl)aminophenylcopiperidine/? and 120 ml of prefectural border fj were mixed and stirred at 6≠°C for 5 hours. After adding tOml of ice water to this reaction solution, the mixture was made alkaline with a saturated aqueous sodium hydroxide solution. This was extracted with chloroform (202C×≠), and the layer was extracted with saturated saline (
Washed with OtnlX. After drying the organic layer over anhydrous sodium sulfate, the r solution was condensed to obtain an oily residue. Add 2 ml of ethyl acetate/we and n-hexane to this,
It was left at room temperature for 0 minutes. The precipitated crystals were further mixed with ethyl acetate and n-hexane (2 V/V).
) 11-benzyl-[3-methyl-J
, 4Z-dihydro-,2(/)T)-quinazolinone-Hiro-Subirou-Ki-Biberi-Jin] o, ty was obtained. This was further mixed with a mixed solvent of ethyl acetate and n-hexane (/:
The target compound of 0.4' f was crystallized from e3-crystallized from 2 v/v). -Structure of piperidine: (Method A) 11-benzyl-[
3-Methyl-3, Hiro-dihydro-,2(/H)-quinazolinone-Hiro-Subirow≠1-piperidine]/2 and 1'1
/7711A, water lO, methanol, 20rrt
And 10th gear palladium-carbon 270 pound? lf,
The mixture was combined and hydrogen gas was blown in for 4LS for 1 hour while stirring at ≠0°C. Next, after removing the nosilium-carbon,
R liquid ai! 14 to obtain an oily residue. Add water to this
After adding 1/rst of normal caustic soda water, it was extracted with chloroform (71 Ml x 4 L). This organic layer was washed with saturated brine (Jmtx, 2), dried over anhydrous sodium sulfate, and the ν liquid was concentrated to form a crystalline residue.
Got oomy. Recrystallize this from ethanol/
The target compound of 20'lfJ was obtained.

(Method B) l-benzyl-≠-hydroxy-≠-(-monoamino-J-chlorophenyl)hyvericin 3i synthesized by the method of Reference Example 1.

Ethyl λJ'Od was mixed and methyl isocyanate//rnt was added at room temperature while stirring.

After stirring overnight at room temperature, the precipitated crude crystals of l-benzyl-guhydroxy-hiro-[no(N-methylcarbamoyl)amino-j-chloro-phenylcopiperidine] were washed with 170 ml of ethyl acetate. hand,
29. Bamboo for free. This was reconstituted from a mixed solvent of ethyl acetate and n-hexane to obtain the compound with λ = 7F.

l-benzyl-≠-hydroxy-Hiroshi-[λ-(N-methylcarbamoyl)amino-! Physical properties of -chlorophenyl]piperidine Melting point: //7.0-1192℃ Elemental analysis value) i'CN Total 39 values (4H, O) tJI4 1,2.74<4
10.97% real button j riii V i, t
3< g yu2/ri6 //, 0jtl
r then l-benzyl-guhydroxy-≠-[no (N
-Methylcarbamoyl)amino-yo-chloro-phenylcopiperidine tr, z7v and 1m foot salt fig, 2.
2 yak, water 61. rat, methanol/3J, rr
Mix + efu and 10φ palladium carbon, 22, and add hydrogen gas for 10 hours and 30 minutes while stirring at 0 ° C.
After passing through this 19 reaction solution and removing the radium and carbon, the tJj solution was condensed under reduced pressure to obtain Hiro-hydroxy-t,t-(,z-(''-methylcarbamoyl) To this obtained oily residue of amino-phenylcopiperidine was added 1J+U and constant hydrochloric acid jQ- and heated at 76°C for 3 hours. After making this JV reaction solution alkaline with concentrated caustic soda aqueous solution under cooling, Chloroform (/00M
IX/#j Oml XJ).

This extract was washed with saturated saline (!Oml x 3) and then compressed with a needle. the resulting oil.

1Od of methanol was added to the residue, and the mixture was again concentrated under reduced pressure.

3-methyl-J, II-dihydro, z(/
The crude crystals of H)-quinazolinone-≠-spiro≠1-piperidine were triturated with 10ynl of ethyl acetate, taken out, and further washed with 10ml of ethyl acetate to obtain xto. By further performing the same treatment from the P solution, 0. j
The target compounds l and f were obtained. This showed the same physical property values as the compound of Method A.

From Example 1 I-benzyl-(,2-oxo-3,≠-dihydroλ)! −/, J-Penzoxazine-Game Pillow ρ-
Production of l-benzyl-hydroxy-≠-(no-aminophenyl)piperidine 3 synthesized by the method of Reference Example 1
9 and acetonitrile≠θM were mixed, and /,/1-carbonyldiimidazole 1A34't was added while stirring at room temperature. After stirring at room temperature for 3 hours, further 41'-carbonyldiimidazole f was added and stirring was continued for 2 hours.

The precipitated crude crystals of the target product were collected as F1, and then washed with 10 at of acetonitrile to obtain crude crystals of the target product Utah 02.

On the other hand, the filtrate was concentrated under pressure, and water (λQ mtX) was added to the residue.
After tridulation, 10 atm of methanol was added for crystallization. Take this P and get 0. J I f
A crude crystal of the target product was obtained. Both crystals were combined and recrystallized from ethanol to obtain the desired product 2.7.2f.

Example 7 6°λ-oxo 3. ! A-dihydro2)1-/,
fA construction of J -penzoxazine≠-spiro-l-piperidine hydrochloride: 11-benzyl=(λ-oxo≠-dihydro 2H-1,J-
Benzoxazine-≠-spiro41. '-piperidine) 7J4vrQ, 10% palladium on carbon
9. Water z/4(d,/, II constant fljJLJr-) and methanol/1A21al were mixed, and hydrogen gas was blown into the mixture for 30 minutes while stirring at 0°C.

Next, this reaction solution was filtered to remove palladium and carbon, and then solution F was concentrated under reduced pressure to obtain a crystalline residue≠74n. This was recrystallized from methanol to obtain its target compound.
Production of dihydro-2H-/, J-benzoxazine-Hiroshi-Subirow ρ-piperidine): # Synthesized l-benzyl-t-hydroxyda-(,2-
Amino! -chlorophenyl)piperidine J, /
7 f and acetonitrile JOwt1 were mixed, and while stirring at room temperature, 411-carbonyldiimidazole f, /
/f was added and stirred overnight. Next, collect the precipitated crystals and wash with water IO Go to obtain the desired product! I got f.

This was recrystallized from a mixed solvent of dimethylformamide and methanol to obtain the target compound i and rtt.

Example 1t 7-chloro-okine-31 μm dihydro-2H-/
, Production of j-benzoxazine-Hiro-spiro p+-piperidi/l-benzyl-(6-chloro-λ-oxo, 4'-dihydro-,
2H-/, J-be/Zoxazine≠-Subirou≠1
-piperidine) j f,! : /, J-dichloroethane y j Oml f, while mixing and stirring at room temperature.
Two volumes of 7M vinyl carbonate/ether solution were added. After further stirring at room temperature for 1 hour, the mixture was heated under reflux for μ hours. Furthermore, 7M chlorovinyl carbonate/ether solution -λ5-
was added and refluxed for 1 hour. After the reaction solution was cooled to room temperature, the precipitated hydrochloride of the raw material was removed with F' and further washed with 4-codichloroethane JOyd. This p liquid was concentrated under reduced pressure, and the resulting crystalline residue was converted into n-hexane 7 (10*
After trituration with tX Hiroshi), the furnace was removed and
Washed with hexane lOag.

By drying the obtained crystals, /'-vinyloxycarbonyl(,4-chloro-2-okino J, ≠-
Dihydro-J H-/, J-benzoxazine-≠-
Spiro C-piperidine) j, 7 j2 was obtained.

This compound /, I 4' f and Dm methylene uO
mixed with ysl. A 71N hydrogen chloride-ethyl acetate solution was added to this solution and allowed to stand at room temperature for 1 hour. This was concentrated under reduced pressure, and the resulting residue contained ethanol≠0117
The resulting crystalline residues were triturated and decanted with ether (lad) and ethanol (10 at), and then 10 ml of ethanol was added and filtered. The resulting crystals were further washed with 10 ml of ethanol and dried to obtain crude crystals i, or of the target compound.This was recrystallized from ethanol to obtain the target compound with 0.≠f.

Example 1z /1-methyl-(6-chlorochoquine-3,4A-
dihydro-J H-/, j-benzoxazine-≠-
H of spiro≠1-piperidine: a: l-methyl-≠-hydroxy-≠-(,2
-Amino-! -Riro-phenyl)piperidinetΔ5i'
2 was treated in the same manner as in Example/j to obtain the hydrochloride tλj of the target product.
I got 2. This was recrystallized from methanol and 0.37f
The hydrochloride of the target product was obtained.

Example-〇.

lI-Methyl-[3-methyl-6-chloro-3,4t-
Production of /-methyl-t-hydroxy-+-(,z-amino-j- Chloro-phenyl)biperisinyu 4A''C Treated in the same manner as in Example/3, /-
Methyl-guhydroxy-≠-[rho(N-methylcarbamoyl)ami)-3-chloro-phenyl]hyvericin2. j, 2p was obtained. This was used directly in the next reaction.

For analytical data, 200 mg of this was recrystallized from ethyl acetate to obtain pure lσ Otsu 2.

/-Methyl-guhydroxy-Hiroshi-[-1(N-methylcarbamoyl)amino-! Physical property values of -chlorophenyl]piperidine Melting point: / J /, - ~ / A J, / 'C cumulative analysis value HCN calculated value (-)) iJo) 4. Ri04! lAr/4
/J, 70tlt actual measurement [t, 7J% J-447
4c91+ /J, 18 then 7-methyl-Hiro-hydroxy-Hiro-(J-(N-methylcarbamoyl)amino-
j-chloro-phenylcopiperidine2. ! f was further treated in the same manner as in Example 1 to obtain the target product λ hydrochloride /, /7
I got V. This was recrystallized from methanol to give o, 4t
The target product λ hydrochloride was obtained.

Example-2t lI-Methyl-[3-ethyl-6-ripro≠-dihydro-J(/H)-quinazolinone-≠-spirot°-
Production of methyl-V-hydroxy-hiro-(roami/-j-ri) synthesized by the method of Reference 91J3.

l-methyl-≠-hydroxy-w[λ-(N-ethylcarbamoyl)amino-! -Chlorophenyl]piperidine 1
ytq<+, this was used as is in the next reaction. For analytical data, this /9Jv+g was extracted from ethyl acetate by 2
Recrystallized once and received 3 hits.

Physical properties of l-methyl-guhydroxy-hiro-[-1(N-ethylcarbamoyl)amino-yo-chloro-phenylcopiperidine a, t1f? , aa, :/770~/71.
3℃ elemental analysis Tsukuda HCN f14i value 7. //も 3771 Section 13゜ Vl Section'
4 g+1 g, 722 width t7. ff6% /
3-8rKVc/-methyl-V-hydroxy-Hiroshi-[co-(N-ethylcarbamoyl)amino-! -chlorophenyl]piperidine 3. /coV was further treated in the same manner as in Example 1 to obtain the target product, λ hydrochloride t,22. This was recrystallized from a mixed solvent of methanol and ethyl acetate.
Obtained the object f.

Example, 22 /l-methyl-[3-phenyl-6-chloro-j4L-
Dihydroco(/H)-quinazolinone-p-(2-amino-!-chlorophenyl)piperidine O1 AF and 6 ye of ethyl acetate were mixed, and X4. ? Phenyl incyanate O3≠3yrt was added over 3 hours while stirring in A. After stirring the mixture for a while, the precipitated crude crystals of l-methyl-≠-hydroxy≠-[λ-(N-phenylcarbamoyl)ami/-3-chloro-phenylcopiperidine were collected and diluted with ethyl acetate. Wash with 10vtl/
, Jf was obtained. This was used directly in the next reaction. For analysis data, this! 70yQ was recrystallized from a mixed bath S of acidic acid and methanol to obtain a pure product /10.

Physical property value of /-methyl-≠-hydroxy-4Z-(,2-(N-phenylcarbamoyl)amino- □rollophenyl]piperidine 18 (imaginary, : / 79 J ~ / J' 0.I℃
Elemental analysis value HCN Ft+7>(fA 7./A=1 63.
lI8 //, tt'1 real n1 an1? j i
z;, 746% 63. j/'A et al.//
, & Hiro% then l-methyl-Hiro-hydroxy-+-(,2
-(N-phenylcarbamoyl)amino-! -Chlorophenyl]piperidine/, 10ff was processed as in Examples 13 and 1Y1 to obtain crude crystals of the desired product.

The mixture was recrystallized from methanol and then statically re-crystallized.
The target compound was obtained after a try.

Example/Production of 1-methyl-3'-bromo-[3-methyl-6-chloro-3, dihydro-J(/H)-quinazolinone-Hiro-spiro ψ-piperidine]: Reference example Hiro's method l-methyl-cou (λ-
Amino! -Chlorophenyl)-/, J JΔ-tetrahydropyridine/l/, immediately mixed with 6 ml of ethyl acetate, and while stirring at room temperature, 0.0 ml of methyl isocyanate was added. ．． 2
After further stirring in the room for 2 hours, /-methyl-μm[λ-(N-methylcarbamoyl)amino-! The crude crystals of t-tetrahydropyridine (-chlorophenyl)-/, 2-t-tetrahydropyridine were collected in a furnace and ethyl acetate r
Wash with AT and dry! 6 On the other hand, the crystalline residue obtained by condensing solution F under reduced pressure was triturated with ethyl acetate/ml to collect P, washed with ethyl acetate/stj,
After drying, additional /lOrg was obtained. These crude crystals were recrystallized from ethyl acetate to obtain a pure product, 71η.

/-Methyl-≠-[λ-(N-methylcarbamoyl)amino-! -Chlorophenyl]-/, J to Physical properties of A-tetrahydropyridine Melting point 1tZo-tt
r, r”c Elemental analysis value CHN Total a-value to, ios t, ayqb is,
Actual measurement of ox coefficient j5! rigs +, t+*
1 atsa) then 7-methyl-≠-[λ-(N-methylcarbamoyl)amino-yo-chloro-phenyl]-4
2-6-Tetrahydropyridine J 00 After the immediate dissolution, the mixture was stirred for 3 hours at this temperature, and the reaction solution was poured into 0 ml of ice water. After adding sodium hydrogen carbonate to this aqueous solution and adjusting it to pHI, ethyl acetate (λ0ylXJ
) was extracted. After washing this J1- with water, drying with anhydrous sodium sulfate and concentrating it, a crude crystal residue of the target product J1.
I got 2sp.

This was recrystallized from 1J & ethyl to obtain 10 pg of pure product.

Example 24 1'-(1-(3,4-dimethoxybenzoyl)ethyl]-(2-oxo-3,4-dihydro-2H-1,3-
3. Production of benzoxazine (4-spiro-4'-piperidine) 3. 4-dimethoxy-α-bromopropiophenone 2.
73 g, 2.55 g of 2-oxo-3,4-dihydro-2H-1,3-benzoxazine-4-spiro-4'-piperidine hydrochloride obtained by the method described in Example 16,
Sodium iodide 1.50 g + ethanol 50
ml and 6.16 ml of triethylamine were mixed and stirred at room temperature for 6 days. The precipitated crystals were collected by filtration, washed with ethanol and water, and dried to obtain 2.77 g of the desired product. Of these, 200 μm was recrystallized from ethanol to obtain a pure product of 94 μm.

Example 25 Threo-1” (2-(3,4-dimethoxyphenyl)
-2-Hydroxy-1-methylethyl]=(2-oxo-3,4-dihydro-2H-], ]3-benzoxazine-4-spiro4'-piperidine) 1'-(1-(3 ,4-dimethoxybenzoyl)ethyl]-(2-oxo-3,4-dihydro-2H-1,3
-benzoxazine-4-spiro-4'-piperidine)
1.23 g and anhydrous tetrahydrofuran ('I'll
F) Mix 60 ml and IM while stirring at room temperature.
Nine liters of L-selectride-THFHF solution was obtained. After 1 hour, 2 ml of water was added to the two reaction solutions, and then concentrated under reduced pressure.

25 ml of water was added to the residue, and the precipitated crystals were collected by filtration. This was recrystallized from ethanol to obtain 1.10 g of the target product (
88.8%) was obtained.

Example 26 Erythro 1′-(2-(3,4-dimethoxyphenyl)-2-human fuxy 1-methylethyl]-(2-
1'-C1-(3,4-dimethoxybenzoyl)ethyl]-(2-oxo-3 ,4-dihydro-211i,3
-benzoxazine-4-spiro-4'~piperidine)
1.23g, 1N hydrochloric acid 31I11. Water 7.5ml1. Methanol 15ml 1. and 10% pd-C200 were mixed, and hydrogen gas was passed through the mixture for 26 hours while stirring at 40°C. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. The crystal residue was dissolved in a small amount of methanol, made alkaline by adding an aqueous sodium hydroxide solution, and then extracted with chloroform.

By concentrating the extract under reduced pressure, crystals of the target product 820
I got ■. This was recrystallized twice from ethanol to obtain pure product 6.
I got 20■.

Example 27 1'-(1-(3,4,5-trimethoxybenzoyl)
ethyl)-(2-oxo-3,4-dihydro-2H-1
, 3-Benzo-xazine-4-subirou-4'-piperidine) In the same manner as in Example 24, 3.4.5-trimethoxy-α-bromopropiophenone and 2-oxo-3,4
The desired product was obtained from -dihydro-28-1,3-benzoxazine-4-spiro-4'-piperidine hydrochloride.

Example 28 Threo-1'-(2-(3,4,5-trimethoxyphenyl)-2-hydroxy-1-methylethyl)=(2-
1'-[1-(3,4,5-)dimethoxybenzoyl)ethyl)-(2 -oxo-3,4-dihydro-28-
1.32 g of 1,3-benzoxazine-4-spiro-4'-piperidine) was treated in the same manner as in Example 25 to obtain 975 ml (73.5%) of the desired product.

Example 29 1'-(1(3,4,6-)dimethoxybenzoyl)ethyl) -(2-oxo-3,4-dihydro-'21(
Production of 3.4.6-trimethoxy-α-bromopropiophenone and 2-oxo-3,4
The desired product was obtained from -dihydro-2H-1,3-benzoxazine-4-spiro-4'-piperidine hydrochloride.

Example 30 Threo-1" (2-(3,4,6-drimethoxyphenyl)-(2-oxo-3,4-dididraw 2H-1.

Production of 3-benzoxazine-4-spiro-4'-piperidine) 1'-(1-(3.4.6-)rimethoxybenzoyl)ethyl)-(2-oxo-3,4-dihydro-
2Ir-1,3-benzoxazine-4-spiro-4'
-Piperidine) was treated in the same manner as in Example 25 to obtain 838 g (63.2%) of the desired product.

Example 31 Erythro 1'' (2-(3.4.6-)dimethoxyphenyl)-2-hydroxy-1-methylethyl]-(
Production of 2-oxo-3,4-dihydro-2H-1,3-benzoxazine-4-spiro-4'-piperidine) 1'-(1-(3,4.6-)dimethoxybenzoyl),ethyl] =(2-oxo-3.4-dihydro-2H-1.3-benzoxazine-4-spiro-4
'-pyheridine) and 30 ml of EtOH, and while stirring at room temperature, N a B H 4945
．． 8■ has been added. - After stirring at room temperature overnight, the reaction solution was concentrated under reduced pressure and water was added. Extracted with chloroform. After concentrating the extract under reduced pressure, the resulting residue was subjected to silica gel column chromatography (Wakogel C-200, AcoEt).
The desired products (erythro form) 257nvr and threo form 661. The target product was recrystallized from ethanol to obtain 200 ml of pure product.

Example 32 1'-[2-(3.4.5-trimethoxyphenyl)-2-hydroxyethyl)-(2-oxo-3,4-
Method for producing dihydro-2H-1,3-benzoxazine-4-spiro-41-piperidine) 3, 4. 5-)
Liftoxy-ω-bromoacetophenone 867■ (3m
mol), 2-oxo-3.

4-dihydro-28-1.3-penzoxazine-4-spiro-4'-piperidine hydrochloride 764■.

Trimethylamine 0.84ml and ethanol 20ml
were mixed and stirred overnight at room temperature. This reaction solution contains NaB
After adding 41 g of H, the mixture was further stirred overnight at room temperature. The precipitated crystals were collected by filtration and washed with methanol and water to obtain 482 mg of crude crystals of the desired product. On the other hand.

The mother liquor was concentrated, and the residue was dissolved in chloroform and washed with water. This was concentrated under reduced pressure and the resulting oily residue was subjected to silica gel chromatography (Wakogel C-・200°AcoEt).
An additional 93 ■ was obtained. These were recrystallized from foam and ethanol to give 465 cm (1,100 m).

Example 33 1'-(2-(3-hydroxy-4-methoxyphenyl)-2-hydroxyethyl)-(2-oxo-3,4-
3-acetoxy-4-methoxy-ω-bromoacetophenone 1.82 g (6
,3mmo I), 2-oxo-3,4-dihydro-2H-,1,3-benzoxazine hydrochloride 1.5
3g, triethylamine 1.68ml and ethanol 3
0 ml was stirred overnight at room temperature.

After concentrating this reaction solution under reduced pressure, water was added, and the precipitated crystals were collected by filtration and dried. ,3-benzoxazine-4-spiro-4'-
1.78 g of crude crystals of piperidine) were obtained. this house,
1 g was mixed with 50=+ ethanol and 1.0 g of NaBH was added while stirring at room temperature. - After stirring overnight, the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the precipitated crystals of the target product were collected by filtration. This was recrystallized from DMF and ethanol to obtain pure product 307■.

Example 34 1′-(:2-(3,4-dimethoxyphenyl)
-Methyl]-(2-oxo-3,4-dihydro-2H-
Production of 1'-[2-(3,4-dimethoxyphenyl)-2-
hydroxyethyl]-(2-oxo-3,4-dihydro-2H-1,3-benzoxazine-4=spiro-4'
-piperidine) Ig, 20 ml of trifluoroacetic acid, and 1 g of triethylsilane were mixed and stirred overnight at room temperature. After concentrating this reaction solution under reduced pressure.

30 ml of water was added to the residue, made alkaline with sodium carbonate, and then extracted with chloroform. The extract was concentrated under reduced pressure, and the resulting crystalline residue was recrystallized from ethanol to obtain white crystals 811■, the desired product.

Reference Example 1 ■-Production of benzyl-4-hydroxy-4-(2-aminonoenyl)piperidine: l-benzyl-ψ-hydroxy≠-(coffeehaloylamino!-chloro-phenyl)piperidine JOf and 1
0tipalladium carbon J, ltf, sodium hydroxide IO? and ethanol/l were mixed, and hydrogen gas was blown into the flask for 10 hours and 30 minutes while stirring at room temperature. Here, more IO Palladium Carbon 2! f was added, and hydrogen gas was continued to be blown in for one hour. After confirming by silica gel thin layer chromatography that the raw material had disappeared, the reaction was stopped and the palladium and carbon were removed in the furnace. Add 2N @f and 73rOvd of acid to the residual liquid obtained by concentrating the p solution under reduced pressure,
The mixture was heated under reflux for 3 days. After adjusting the pH of this reaction solution to io with a concentrated aqueous sodium hydroxide solution, the precipitated insoluble matter was counted. This is 100fd of water! After washing with water, it was dissolved in 4'00 ml of chloroform. Wash this solution with water (
/ 00rd, x≠), then dried and concentrated under reduced pressure.

Ethyl acetate was added to the obtained oily residue (J/, It), and the mixture was again concentrated under reduced pressure. The target product was crystallized by adding 30 g of n-hexane to this residue.

Divide this into n-hexane/! It was washed with O1d and dried to obtain crude crystals of the target product, lIA≠2. This was recrystallized from a mixed bath of n-hexane and ethyl acetate 6v (j:/v/v) to obtain the target compound 70.4'f.

Melting point /C1. θ~/, 2Jj”C Elemental analysis value HC'N 1t3iILllk7.Ijalr 7t, 16%
51.1% Actual value Zrijchi 76.1,09
1+9! Reference Example 2 I-benzyl-Hiro-hydroxy-V-(2-l-benzyl-Hiro-hydroxy-4C-(,2-hybaloylamino-!-chlorophenyl)piperidine 10f and co-defined @
ff23θ01 was mixed and heated under reflux for at hours. This reaction solution was poured into 200 ml of ice water, and the pH was adjusted to 10 with a concentrated aqueous sodium hydroxide solution, and then the precipitated insoluble matter was collected. After washing this with water JOOyil, it was dissolved in 200 ml of chloroform. This solution was washed with water (jOdX4
After drying and compressing under reduced pressure. Ethyl acetate (7!) was added to the obtained oily residue (7:jr). Resistant to n-hexane!
L! td was added. This was subjected to fJMIN under reduced pressure, and the crystallized residue was mixed with a mixed solvent of ethyl acetate and n-hexane (/:
j v/v) 4 was added, triturated, and taken out in the oven. Further, after washing with this mixed bath p#, it was dried to obtain 21rif.

This was mixed with a mixed solvent of ethyl acetate and n-hexane (/:
Recrystallization from J v/y ) gave the desired compounds of /, tf.

Melting point ioo, o-toi, o℃ Elemental analysis value (?6) HCN Calculated value A, 4♂哄 4F, λ4 coefficient r, irq Actual value t, ri, 44 tIr, lI/% 1.37
% Reference Example 3 1-Methylder-hydroxy-p-(,z-amino-j
-chloro-phenyl)piperidine dye l-methyl-≠-
Hydroxy-<Z-(U-piparoylamino-!-lylorophenyl)piperidine 21 and 2N 4tre
/j Otri were mixed and heated under reflux for an hour.

This reaction meter was adjusted to pH 10 with a concentrated sodium hydroxide water bath, and then extracted with ethyl acetate (100mt x 4t). This organic layer was washed with saturated water and then compressed under wave pressure.

? After adding n-hexane 2016 to the discharged crystal residue and trituring it, it was washed several times with 30 parts of n-hexane and dried to obtain the target crude crystals of Hiroshi 22. This was recrystallized from ethyl acetate to obtain 1 ftl of pure product.

Melting point 93 S-, 200, j℃ Elemental analysis candy CHN Calculated value 962% '10?96//JY'4 Actual value [7A* 7u/1 //, JI'ly reference example Hiro/-, ethyl -≠-(-monami/-j-po-lophenyl)-/, 2. ! 0.7f of 4-tetranohydrobiri/-methyl-≠-hydroxy-≠-(λ-pivaloylamino-monochlorophenyl)piperidine J and 300 g of 2N sulfuric acid were mixed and heated under reflux for 7.2 hours. This reaction solution was pH/OKIL with concentrated sodium hydroxide aqueous solution.
After Q4 adjustment, the mixture was extracted with ethyl acetate (200*t×3). This extract was added to a saturated saline solution (10 (1+/X, 2)
After washing with water, we changed the line and decompressed nine lines. Ethyl acetate (717t) was added to the residue to precipitate fC7-methyl-Hiro-
Hydro□roxy-(-monoamino-yo-chlorophenyl)
The piperidine was further washed with petroleum ether.
Next, these P solutions were collected and d-condensed. Ethyl acetate was added to the residue to dissolve it, and an appropriate amount of n-hexane was added to further dissolve the no-methyl-gu-hydroxy-(2-amino -!-Chlorophenyl)piperidine was precipitated. Take this P and make 232 q4. After dissolving the residue obtained by distilling the p solution under reduced pressure in chloroform, the internal product was added to a Japanese column. Yakusha screw〕l
A column prepared by suspending and maintaining the sample/f in chloroform was charged. The mixture eluted with chloroform 21, and further chloroform-methanol-h31 (,20:/v/v
) to isolate the fraction containing the target product.

After concentrating this fraction under reduced pressure, ethyl acetate
j), n-hexane (Jt*Q is added, and further KN pressure'f
I was in group A. After 2 hours at room temperature, the crystallized residue was
- Hexane was added and triturated to remove P.

This was washed with 2 rml of n-hexane and l-methyl-
-(2-amino-yo-chloro-phenyl)-4λyo6
- Citrahydroviridine Hiroki &f was obtained. This product had a purity that could be used for the next reaction, but -20
0 ■ with ethyl acetate (0, II!) and petroleum ether (
o, s m, t) is recrystallized from a mixed solution # of pure product l.
I got it wrong.

Melting point 7j: θ ~ 76, reference ℃ Elemental analysis value HCN Temperature, value 675% 6hi 71chi / 2j7 coefficient 8
11j i111. No:, r74 AI
A7/Riro/! 19b Reference flJ Production of l-benzyl-≠-hydroxy-gu(-monohaloylamino!-chlorophenyl)piperidine: l-pivaloylamino-≠-chlorobenzene J /,
tf and 7 ml of anhydrous tetranohydrofuran were mixed, and 3 ml of n-butyl lithium was added dropwise over 3 minutes while stirring from -j''C to 0°C under a nitrogen stream. After the completion of the above, the solution of l-benzyl-Hiro-piperitone 3θV dissolved in anhydrous tetrano\hydrofuran≠!w+lI/C was heated to 0 to 3°C after further stirring for λ hours at 0°C.
It was dripped in 1 hour.

After stirring for an additional 3 hours at 0°C, cooling was stopped and stirring was continued at room temperature overnight. The reaction solution was poured into 1 liter of ice water, and the organic layer was separated, washed with saturated brine, dried, and concentrated under reduced pressure. This residual liquid was chromatographed on silica gel (ethyl acetate: n
-Hexane=/:J followed by ethyl acetate only) to obtain crude crystals of the target product.1. /fi got it.

This was mixed with a mixed solvent of ethyl acetate and n-hexane (/It:
2 to v, /v) to obtain the target compound /
1, 7F was obtained.

Melting point 20J-0~2027℃ Elemental analysis value HCN Total rust, value 7.22% tl, YO (fb
A, Tata Temi fill (IN 7.3196
6r, t 7 % 7.0 ff % Reference Example 6 Preparation of l-methyl-≠-hydroxy-≠-(copivaloylamino!-chloro-phenyl)piperidine: CH.

/-hybaloylamino-≠-chlorobenzene 1/, 2f
and hot water tetrahydrofuran AOml were mixed, and 1 trt of ljti n-butyllithium was added dropwise over 77 minutes while stirring at -j°C to θ°C under a stream of 9 atoms. After the dropwise addition was completed, the mixture was further stirred at 0°C for 2 hours, and a solution of %, i-methyl-goupiperidone/, /JV dissolved in anhydrous tetrahydrofuran was added dropwise at around 0°C at 7 o'clock [mouth j]. 1 more
After pressing T at ℃ for a time (〕℃), the cooling was stopped and the mixture was stirred overnight at room temperature.The reaction solution was poured into ice water -〇0rJ, made ρ with ￥￥A acid, and then extracted with 100*l of ethyl acetate. The Aritoshi layer was further back-extracted with 60 trl of constant hydrochloric acid, and all the aqueous layers were combined. This was made alkaline with sodium octahydroxide, and then extracted with 100 trl of ethyl acetate.

After washing the layer with water, it was concentrated under reduced pressure to obtain crude crystals of the target product.
I got it. This was recrystallized from methanol and the pure product was 0.52
I got an F.

Patent applicant (102) Kyowa Hakko Kogyo Co., Ltd.

Claims (1)

[Claims] (11 General formula [1] (horse)n) R/θ is a group represented by the R1 carbon, a lower alkyl group having 1 to 3 A atoms, or a substituted or unsubstituted benzyl Q (l- I (. m is an integer of O or /-j. A is aqueous, hydroxyl group, ]-rogen atom, lower alkyl group, lower alkoxy group, lower alkenyloxy group, lower alkynyloxy group, low iron Alkylthio group, carboxyl group, lower alkoxycarbonyl group, nitro group, amine group, lower alkylamino group, lower acylamino group, sulfamoyl group, mono- or di(lower alkyl)aminosulfonyl group, lower alkylsulfonyl group, carbamoyl group, cyanogen group or a trifluoromethyl group.When m is 2 or more, A can be the same or different than (r), or two A's can be combined to form a lower alkylenedioxy group. X is an acid, a sulfur atom, a carbonyl group, a hydroxymethylene group, or a methylene group. Q is hydrogen, a lower alkyl group, a halogen or a hydroxyl group, or a lower fatty acid ester thereof. n is O or an integer of /-≠. R7 is a hydrogen hydroxyl group, lower alkoxy group, halogen atom, trifluoromethyl group, trifluoromethoxy group, trifluoromethylthio group, nitro group, or amine group. n is 2
In the above cases, R2 is the same or d, different groups,
Furthermore, two R1s may be combined to form a lower alkylenedioxy group. B is -NH-1-1J(8)-(
R is lower alkyl or substituted or unsubstituted enyl. ), or -〇-. ] Piperidine derivatives and acid addition salts thereof. (2) Piperidine derivatives and acid addition salts thereof represented by the general formula [I°] (wherein A, B, and D (8, R1%, X, m, and n are as defined above)). (3) General Formula [1'') (In the formula, A, , A, , As and A4 are the same or different groups and have the same meaning as A.
has the same meaning as above. ) Claim 2
Compounds described in Section. A piperidine derivative represented by the formula (wherein B%Q, R, , R, and n are as defined above) and an acid addition salt thereof. (5) A piperidine derivative represented by the general formula [XI[] C) (wherein R, o, R, , n and Q have the same meanings as above), phosgene, trichloromethyl chloroformate and an alkyl chlorocarbonate. The biverizine is produced by reacting with a carbonic acid halogenide, a carbonic diester or /, /-carbonyldiimidazole selected from the following! The piperidine conductor is cyclized by cyclizing the conductor, or by reacting the piperidine derivative with a lower alkyl isocyanate or a substituted or unsubstituted phenyl isocyanate to form a urea compound, and then treating the piperidine derivative with an acid. A method for producing a compound according to claim no. (6) Claims characterized in that a piperidine derivative represented by the general formula [XVD (where n%R, R, and Q have the same meanings as above) is cyclized by acid treatment. A method for producing the compound described in item ≠. (7) A piperidine derivative represented by the general formula CXVI[) (in the formula, 1110 and Rn have the same meanings as above) is converted into a lower alkyl (methyl, ethyl or propyl) incyanate or a substituted or non-if substituted phenyl After incyanate is reacted to form a urea compound, it is treated with an acid or a halogen selected from chlorine, bromine and iodine, or N-chlorosuccinimide (NC8), N-bromosuccinimide (NBS).
) and N-iodosuccinimide (NIS).