JPS58140083A - Preparation of tetrazole compound - Google Patents

Abstract

PURPOSE:To prepare 2-substituted-5-trialkylsilyl tetrazole useful as an intermediate of pharmaceuticals, etc., safely, in high yield, under mild conditions, compared with the conventional process, by reacting lithium trialkylsilyl diazomethanide with an ester. CONSTITUTION:The 2-substituted-5-trialkylsilyl tetrazole of formula III is prepared by reacting the lithium trialkylsilyl diazomethanide of formulaI(R is <=4C alkyl, preferably CH3) with the ester of formula II (R' is residue of an acid preferably aliphatic, aromatic or heterocyclic carboxylic acid residue; R'' is residue of an alcohol, preferably lower alcohol). If necessary, the product is treated with an acid to obtain the 2-substituted-tetrazole compound of formula IV. The compound of formulaIcan be prepared by the reaction of the compound of formula V with a strong base such as n-butyl lithium, etc. in diethyl ether at or below room temperature, and the obtained compound can be used as the raw material of the above reaction without separating from the reaction mixture.

Description

[Detailed description of the invention] The present invention relates to a method for producing tetrazoles.

Tetrazoles are biochemically considered to be carbonic acid equivalents, and are pharmacologically interesting, and there are actually important pharmaceuticals in which a tetrazole skeleton is incorporated into the molecule. For example, cefazolin, cefamandole, cefothiam, cefoperazone.

These include cefmetazole and moxalactam.

However, tetrazoles have traditionally been synthesized by reacting explosive azides with nitriles.

The object of the present invention is to provide a novel method for producing tetrazoles that is free from such risks.

The present invention produces a 2-substituted 5-trialkylsilyl tetrazole by reacting lithium trialkylsilyl diazometanide with an ester, and optionally treats it with an acid to produce a 2-substituted - The purpose is to produce tetrazoles.

The alkyl group of lithium trialkylsilyl diazometanide, which is a reaction raw material in the present invention, has 1 to 4 carbon atoms;
Preferably, it is a methyl group, and it may be the same type or a different type within the same molecule. This raw material is added to trialkylsilyldiazomethane with a strong hydroxide such as n-butyllithium (hereinafter abbreviated as n-BuLiJ) or lithium diisopropylamide (hereinafter abbreviated as "LDA") in diethyl ether at room temperature or lower. It can be easily obtained by reacting with a base. The obtained lithium trialkylsilyldiazometanide can be used as it is in the reaction of the present invention without being isolated.

In the present invention, the ester is not particularly limited, but preferably esters of aliphatic, aromatic and cyclic carboxylic acids can be used.

The alcohol moiety in these esters is preferably derived from a lower alcohol because of its ease of reaction.

The reaction of the pre-distributed thium trialkylsilyl diazometanide with the ester is carried out at a temperature of about -78°C to 40'C1, preferably -80°C.
It can be carried out at a temperature of 5°C to 5°C. t-1 as reaction time
0.5 to 10 hours can be adopted.

As the reaction solvent in the present invention, diethyl ether,
Ether solvents such as di-n-butyl ether can be used. After the reaction is completed, the reaction solution is treated with ice water, the ether layer is separated, washed with water, dried, and distilled off to obtain crude tetrazole, which is purified by preparative thin layer chromatography, column chromatography, or recrystallization. 2-substitution-6
- Trimethylsilylnadrazole The triple r lolyl group of lunatrazoles can be easily removed by acid treatment with hydrochloric acid-methanol or the like.

Next, a typical reaction formula of the reaction related to the present invention is shown below.

-BuLi The characteristics of the present invention are that it is safer than conventional methods and that 2-substituted tetrazoles can be obtained in high yield under mild conditions.

Examples of the present invention are shown below, but the present invention is not limited thereto.

The trimethylsilyldiazomethane used below is a mixture of trimethylsilyldiazomethane (65W/W%) and hexamethyldisiloxane (85W/W%) or 2.2
n-butyllithium was used as a 15% hexane solution. Example 1 2-7 enacyl-5-trimethylsilylnadrazole (
) and 2-7enaflutetrazole (■) (1) (Me represents CH3-) Trimethylsilyldiazomethane (422jV.

2,477! mol ) of anhydrous diethyl ether (10
n-butyllithium-hexane solution (1.52, ml, 2.4 Fffmol) was added dropwise to the solution at 0°C, and the mixture was stirred for 20 minutes. Then benzoic acid methyl ester (1g611v, 1#fmol) in anhydrous diethyl ether (5ml) I! The solution was added dropwise at 0'C and stirred for 8 hours. Add ice water to the reaction solution and extract with diethyl ether. After washing diethyl ether with water and saturated saline, dry (anhydrous magnesium sulfate). The solvent was distilled off to obtain a 262 Da yellow oil. Preparative thin layer silica gel chromatography (development #: benzene:jether ether-52 1) 'till system 1) 18811
g (70,8%) and (1) 8 capes (1,6%) are obtained.

(10-Pale yellow oil IR (Film): 1705 (CmO); 12
50.850 (siMe) NMR (CDC13):
0.44 (9H,s, SiMe), 6.20
(2H.

s, CH2) 17.44-8.12 (5H, m+ a
romaticH) Mass m/e: 260 (
M+) CI2 HI6N40 Elemental analysis value knee theoretical value for Si: C: 55.86in: 6.19iN:
21.62 (%) Actual value: C: 55.281: 6.10
; N: 21.45 (%) (1) Knee mp: 99-100"C (recrystallized from benzene-hexane) IR (Nujol): 1710 (Cm0) NM
R(CDC13): 6.18 (2H,a,C
m2), 7.44-8.16 (5H, m, arom
atic H), 8.68(1)it st cH-
N) Elemental analysis value knee theoretical value for C static kimNaO:
C:57.44+H:4.29iN:29.77(%
) Fruit #I: C: 57.6bi) l: 4.11, N:
29.88 (%) Example 2 Synthesis of 2-7enacyl-5-trimethylsilyltetrazole and 2-7enacyltetrazole 1) Same procedure as in Example 1 except that n-butyllithium was replaced with lithium diisopropylamide. Synthesis of tetrazole is carried out.

Diisopropylamine (248”f + 2.4 mm
ol ) in anhydrous diethyl ether (5 g/) solution
n-butyllithium-hexane solution (1,52 m
.

2,4 #gmol) was added dropwise, and the mixture was stirred for 20 minutes.

Trimethylsilyldiazomethane (4221III.

The ether solution of lithium diisopropylamide prepared above was added dropwise to an anhydrous diethyl ether (511) solution of L4 mmol), and the mixture was stirred for 20 minutes. Then benzoic acid methyl ester (186 da 1 IFF
JylQl) in anhydrous diethyl ether (8 resistance) solution.
Add dropwise at °C and stir for 8 hours. Post-treatment and purification methods were the same as in Example 1. (1) 28511v (90
, 4%) and (1)6q (8,2%).

Comparing this example with Example 1, it is clear that the yield of tetrazole is better when lithium diisopropylamide is used than when n-butyllithium is used.

Example 8 Synthesis of 2-(p-methylphenacyl)-5-)limethylsilyltetrazole (2) and 2-(p-methyl7enacyl)tetrazole 0 (1)
(lv) In Example 2, benzoic acid methyl ester was converted to p-)ruylic acid methyl ester (1501v).

Reaction conditions and post-treatment except for changing to 1311 mol).

The purification method is the same. (1) 2411#I (87.8%
) and (If) 6"f (2,5%)'km; 6° (2
) Knee mp: 72-78.6°C (e-crystal from benzene-hexane) IR (Nujol): 1696 (CmO
); 1260.846 (SiMe) NMR (CDCI
g): 0.44 (9H,s, SiMe), 2.45 (
8H.

it, Me), 6.12 (2H*l+CH2)
97.84C2H9dlJ■8Hz* aromati
cH), 7.90 (2L do J-8Hz+aro
matic H) Elemental analysis value knee theoretical value for C1sHxsN40Si: C: 66.90tH: 6.61; N: 20.42 (%
) Actual value: C: 56.54! H: 6.82; N: 20
．． 88 (%) @ Ni mp-: 1g 6-187°C (recrystallized from benzene-hexane) IR (Nujol): 17GG(CmO)N
MR (CDC1m): 2.47 (8H, m, Me),
6.07 (2H.

l CHx), 7.88 (2L do J-8Hz+
aromaticH)-7,90(2H,d, J-
8Hz+ aromatic H), 8.57 (IH
, Yi, CH■N) Six element analysis for C1eHtoNaO (tE knee theoretical value: C: 59.40; H: 4.98; N: 27.71e
/Q actual value: C: 59.48; H: 4.71 N: 27.
96-ring Example 4 Synthesis of 2-(p-methoxyphenacyl)-5-trimethylsilyltetrazole α) and 2-(p-methoxy7-enacyl)tetrazole (Ma) @ In the experiment cap, benzoic acid methyl ester □Reaction conditions, post-treatment, and purification method were the same except that p-7 dinic acid methyl ester (166#, 1 mol of 11F) was used.

(V)285 da (80,9%) and (VD61q (2
, 7%).

(Ma) -- mp, near 8-74°C (recrystallized from benzene-hexane) IR (Nujol): 1696 (C=0), 12
46.855 (SiMe) NMR (CDCIg):
0.44 (9L SiMe), 8.92 (8H.

IsOMe), 6.12 (2L so CHz), 7.
02 (2H+ cLJ-8Hz+ aromaticH
) @ 7.96 (2HI d, Jwx8kb.

aromatic H) Elemental analysis value knee theoretical value for C1ant and Na0m5k: C: 58.77 + H: 6.25; N: 19.29
(to) Actual value: C: 54.05i) 1:6.82iN:
19.49 (to) @ knee mp: 96-98°C (recrystallized from benzene-hexane) IR (Nujol): 1692 (C=O) NMR
(CDCIg): 8.90 (8H,s, OMe), 6
．． 10 (gH.

i CHs)+7.08(2He do J-9Hz
+ aromaticH).

7.98 (2He do J-9Hz aromat
ic H) + 8.68 (In2 Hatake, C) l-N) □ C + oHt・N4 (elemental analysis value knee theoretical value for h:
C: 66.04; H: 4.62; N: 26.67C%)
Actual value: C: 65.84iH: 4.86iN: 25.7
9 (%) Example 5 Synthesis of 2-(8-phenylacetonyl)-5-)limethylsilyltetrazole surface ■ In Example 2, benzoic acid methyl ester was changed to phenylacetic acid methyl ester (150#, 1 ssmol) Other than that, the reaction conditions and post-treatment were as follows:
Chloroform:diethyl ether concentration 10:1)
I made it and got 185 Da (49.2%).

#I#J knee mp: 100-101'C (recrystallized from benzene-hexane) IR (Nujol): 1780 (C=O)
, 1260.850 (SiMe) NMR (CDC1i)
: 0. Mouth (9H,s, SiMe), 8.
80 (2) 1゜hatake, cocyojlPh), 5.62
(2H,s,C0CHxN)-7,20~7.62(6
L nll aromatic H)C+5HtaN4
Brother analysis f= for 0Si: -Theoretical value: C: 66
．． 90tH: 6.61; N: 20.42 (%)! 111
J value: C: 56.97; H: 6.65; N: 20.66
(%) Example 6 2-7 enacyltetrazole value) during synthesis
(1) (1) (memory "f + O-4 mmol), salt production # (2
(drops) and methanol (10 ml) is stirred at high speed for 1 hour. After distilling off the solvent under reduced pressure, 101 tt of water was added to the residue.
In addition, after making it alkaline with 5% caustic soda water bath solution,
Extract with benzene. After washing the benzene layer with water and drying (anhydrous magnesium sulfate), the solvent iIN was used to give colorless crystals (1) 6
Obtaining 7Iv (89,0%).

Example 7 Synthetic surface (ID (69Mf, 0.25 Fl+fmol) of 2-Cp-methylphenacyl)tetrasol α)
, concentrated hydrochloric acid (27%) and methanol (6 ml) was refluxed and stirred for 8 hours. Post-processing is the same as in Example 6.

The crude product was recrystallized from benzene-hexane and 0f34
11F (81.2%) is obtained.

Example 8 Synthesis of 2-(p-methoxyphenacyl)tetrasol (2) A solution of ff) (16711f1.0.5411!mol), concentrated hydrochloric acid (2 drops) and methanol (lamt/) Reflux and stir for an hour. Post-process #i Same as Example 6.

Recrystallize the crude product from benzene-hexane) 88
We obtain q (74,7%).

Example 9 Synthesis of 2-(p-chlorophenacyl)-5-)limethylsilyltetrazole (vlIl) and 2-(p-chloro7enacyl)tetrazole (IX) (Vl) (IK) Example 2
methyl benzoate was converted into methyl p-chlorobenzoate (
The reaction conditions and post-treatment were the same except that K was changed to 17011f (1.1 mmol) and trimethylsilyldiazomethane (f 2.2 mmol/ml) in hexane solution (1.09ml (1.2.4 mmol)). The crude product was purified by decentralized thin-layer silica gel column chromatography (-(MIK:chloroform:ethanol 20:1)) 2
60 Iv (88,2%), ([)8 Jv (1,8%) are obtained.

(Vl): - mp,: 101-102°C (recrystallized from benzene-hexane) IR (Nujol): 1695 (C=0
), 1245.850 (SiMe) NMR (CDCb)
: 0.44 (9H, s, SiMe), 6-06 (2H
.

s, CH2), 7.44 (2H1cL J-8Hz
, aromatic H) S7.82 (2H, do
J-8Hz, aromaticH)C+zH+5CtN
Elemental analysis value knee theoretical value for aO8i: C: 48.8
9 o H: 6.18iN: 19.00 (%) Actual value: C
:48.74iH:4.99iN:1128(%)(W
): - mp-: 144-145.5°C (recrystallized from benzene-hexene) IR (Nujol): 1705 (C=0
) NMR (CDCIg): 6.1G (2H,s, CH
z), 7.57 (21°d, Jm8Hz, aromat
icH), 7.96 (2H, d.

J=8Hz, aromatic H)+8.60(I
H, a, CHsgN) C@Hy Elemental analysis value knee theoretical value for C1N40: C: 4g, 66:H: 8. S7;
N:25.1? (%) Actual value: C: 48.66iH:
2.99; N: 25.47 (%) Example 10 2-(2-ocymptyl)-6-drimethylsilyltetrazole α) ■ In Example 2, methyl benzoate was changed to methyl propionate (881f, ljllmol), except that trimethylsilyldiazomethane was changed to a 2.2 mmol/g/hexane solution (1,09d, 2.4 mmol).
The reaction conditions and treatments are the same. The crude product was purified by decentralized thin-layer silica gel chromatography (developing solution: chloroform:diethyl ether-20:1) to obtain α) 1811v (61.7%) as a pale yellow oil.

■Knee IR (Film): 1785 (C=O), 125
0.850 (StMe) NMR (CDCb): 0.
41 (9H, s, SiMe), 1.10 (8H.

t, J=7Hz, CH*Cdanj) 12.48 (2H
1q* J-7Hz+Cji7CHa), 5.42
(2H, a, CH2)CsH+aN40Si V
Elemental analysis value knee theoretical value for layer: C: 45.25; H
Near, 60; N: 26.89 (%) Actual value: C: 46.
0OiH near, 60iN: 26.44 (%) Example 11 2-nicotinylmethyltetrazole (To) In Example 2, methyl benzoate was replaced with methyl nicotinate (187Mf,
1 mmol), trimethylsilyldiazomethane was added to 2.2 mmol/s/ of hexane bath solution (1.09 mmol).
The reaction conditions were the same except that the reaction conditions were changed to 1 + 2.4 mrnol). Add ice water to the reaction solution and extract with diethyl ether. Add saturated ammonium chloride aqueous solution to the aqueous layer and extract with diethyl ether. Both diethyl ether extracts were combined, washed with water, and dried (anhydrous magnesium sulfate). The solvent was distilled off, and the residue was subjected to partial thin-layer silica gel chromatography to obtain N.@51jv (27%).

mp,: 100-101.5°C (recrystallized from Penzen-Hekibun) IR (Nujol): 1695 (C=
0) NMR (CDCIg): 6.14 (2H,s,
CH2), 7.40-9.20 (4H+ n1+
aromatic H), 8.60 (2I-1
,s, CHz-N) Elemental analysis value for CsHy NsO - theoretical value: C: 50.79; H: 8.78;
N: 87.02 (%) Actual value: C: 51.01iH:
8.52iN: 86.85 (', G) Example 12 2-(p-chlorophenacyl)tetrazole (V layer)

(■) (VID (14'?”V, Of71mol
), (lk hydrochloric acid (2 drops) and methanol (10 resistant)
Stir the bath solution for 4.5 hours. Post-processing is the same as in Example 6. The crude product was recrystallized from benzene-hexane to obtain ω92 da (82.9%).

that's all

Claims (2)

[Claims] (1) Lithium trialkylsilyl diazometanide (here, the alkyl group has 4 or less carbon atoms, and even if the 8 alkyl groups in the same molecule are of the same type, they are different from each other) A method for producing a 2-substituted-6-trialkylsilyltetra sol Liqin*, which is characterized by reacting a 2-substituted-6-trialkylsilyltetra sol with an ester. (2) Lithium trialkylsilyl diazometanide (here, the alkyl group has 4 or less carbon atoms, and the 8 alkyl groups in the same molecule are of the same type but different from each other) 1. A method for producing 2-substituted tetrazoles, which comprises treating a 2-substituted tetrazole with an acid.