JPS5849384A - 5,6-cis-carbapenem derivative and its preparation and use - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI[R<1> is hydrocarbon or heterocyclic group; R<2> is H or protecting group of OH; (n) is 0, 1 or 2; provided that (n) is 2 when R<1> is acetamidoethyl or acetamidoethenyl and R<2> is H or sulfonic acid] or a salt thereof. EXAMPLE:5, 6-cis-3-( 2-Aminoethylthio )-6-( 1-hydroxy-2-methylethyl )-7-oxo-1-azabicyclo[3.2.0]hept-1-ene-2-carboxylic acid. USE:An antimicrobial agent, exhibiting improved activity particularly against Gram-positive and Gram-negative bacteria, and useful as beta-lactamase inhibitors. PROCESS:A compound of formula II (R<3> is H or protecting group of the carboxyl group; X is eliminative group) or a salt thereof is reacted with a compound of the formula R<1> S(O)nH in a solvent, e.g. dichloromethane or tetrahydrofuran, at -50-+40 deg.C to give the compound of formlaI.

Description

[Detailed description of the invention]

The present invention relates to a novel 5,5-V-babenem-3-potent complex or its - having excellent anti-1 action and β-futamer (inhibitory action). A carbapenem compound having a basic skeleton represented by .
It has 1- and F-roxy-1-methylethyl groups at the 6-position, and 5
, 6th position is cis configuration 1lII! A compound with strong anti-t! It has been shown to have IA action and a false β-lactamer (for example, d@
Kaisho 55-IQ4296. Japanese Patent Publication No. 56-549@hiro). However, at the 6th position found in nature, 1-HytrolokiV-
Since the substituents at the 2-position of such compounds having a 1-methyethyl A/ group and a cis configuration* at the 5 and 6 positions were extremely limited, the stereoselectivity of these natural compounds was There was a need for the development of a compound having an exact substituent at the 2-position as well as a comprehensive and permissive synthesis method. According to the systematic nomenclature, the basic skeleton of the above carbapenem compound is 7-oxo-1,-azabi Vri aC3,2
, 0) It should be called hebut-2-ene, but in order to make it into parts, except for the next section, ★ weaving example, and d example, it is Benam, which is used in phosphorus chemistry. The resulting product shall be named "Kapabenem" as shown above. The present invention has the above power! 1-methyμethyl I4/j directly substituted with a water M group which may be held at the 6th position of pabenem
likt and a steric configuration at the 5.6-position [wherein, R1 is a hydrocarbon IA group or a divalent group, R2 is a water bulky atom or a holding group for water #1&, n indicates 0.1 or 2. 5,6-cis-carbapenem 3- The present invention relates to acid derivatives and their medicinally acceptable properties, as well as their manufacture and uses. As a result of extensive study, the present inventors found that the formula [wherein R2 is the same table as above, B3 is water 1AJ1[
Kokairi is the retention group t of the carboxy VfiI group, and X is the leaving group t.
Tes. The compound tfc represented by
8(0)nII (1) When a compound represented by the formula [symbols in the formula are as above and Table 1] is reacted, a compound represented by the formula [symbols in the formula has the same meaning as above: 1] 5゜6-
The V sukka A pabekim-3-carvone derivative or its derivative can be obtained in high yield, and the obtained compound represented by formula (I) has excellent antibacterial activity and ρ-fuctamase 1.
11i book action

[Headings based on these]
The present invention was then completed by a friend. That is, the present invention provides: (1) 5.6-cis-carbapenem-3-carboxylic acid v
14 body (I) or its fortune, greatness) Compound (I[) or someoboro and compound (1) are reversed.
5.6-cis-carbabene, characterized in that
Production of mu-3-oμ bonic acid m#4c1v>tong or its salt
Regarding the law. In the above formula, hydrogen hydride 1 represented by B1 is, for example,
For example, alkyl, cycloaμkiμ, a~kenyl, cyclo
Alkenyl, alkynyl, aryl, aralkyl I & Mine
is used. Here, 1 to kill is a straight chain
or branched lower alkyl having 1 to 6 carbon atoms,
For example, methyl, ethyl, n-7'robiμ, isopropylene
ru, n-butyl, isobutyl, di-butyl, tert-
Glythyl, ■1-pentyl, impentyl, n-hexyl
, isopequin μ, etc. are used. Cycloalkyl
It is preferable to have 3 to 8 carbon atoms, for example, cyclo
10 Bi~, V clobutyl, cyclopentyl, V clohexyl
Vfi/, S/Kurohe 1 chill, Adaman f, 4/ etc.
used. As Arkenji~, I'm a direct tfic younger sister.
Is it a lower alkenyl with 2 to 6 carbon atoms in the technical description?
ltf vinyl, ali〃, iso10beny, 2-metali~
, 2-butenyl, 3-guthynyl, etc. are used. Al
As a guinea, linear or branched O#II prime number 2 etc.
(Lower arginine μ of 76 is good, for example Echini,
l-7'roviniμ, 2-propynyl, etc. are used. Examples of cycloalkenyl include friends such as 1-p chloroprope
Nyl, l-V clobutenyl, 1-cyclopentenyl, 2
-cyclopentenyl, 3-cyclopentenyl, irises
lohexenyl, 2-cyclohexenyl A/, 3-cyclohexenyl
xenyl, 1-cyclo to 1-71z, l, 4-V cyclo
A return element Ik 3 to 8 such as hexagenyl is used,
Particularly preferred are those having an Iwa prime number of 4 to 6. As aryl
For example, phenyl, α-su7tyl, β-naphthyl μ
, Bifueni ~, Antriμ, etc. are used, but especially
Kephenyl, naphthi, etc. are frequently used. With Acylkil
Tesha, 7'? ,! :,tt;j' pen! //I/, F
Phenethyl, phenylpropyl, naphthylmethyl, etc. are used.
I can stay. In addition, the heterocyclic group represented by R1 is
For example, the phoneme atom (which may be oxidized), the # element
5 to 8 containing one to several heteroatoms such as atoms and sulfur atoms
＠Tamaki is a friend of Kuriahara Sen at Yokuai Castle and other places.
For example, 2-1, 3-pylori, 2-1
- or 3-Frill, 2-1Fi3-Thiedi~, 2-
or 3-pyrrolidinyl, 2-13-1, 4-bi9E
Ifil, M-oxyF-2-13-1Fi4-pyri
Jill, 2-13-See you again 4-Beverijini~, 2-13
- or 4-pyranyl, 2-13- or 4-thiovira
Ni A/% Pifuji〃, 2-14- or 5-thiashly~
, 2-14- or 5-oxasilyl, 3-14- or
is 5-isothiacyly*, 3-14-1 or 5-isooxy
Sashiri μ, 2-14-1 or 5-imidazoly, 3-1
4-1 or 5-bifuzoly, 3- or 4-pyrida V2
~, N-oxide-3-1 or 4-pyridare di, la'
, 2-. 4- or 5-birimishini v1fuki-oxyF-
2-14-Maji is 5-pyrimidinyl, bibefujini~, 4
- or 5-(+, 2.3-thiasiasiliμ), a-t
Tat! 5-(1,2°4-thiadiazolyl), 1,3.
4-thiadiazolyl, 1,2.5-thiacyasily, 4
-Case 7C#15-(1,2,3-oxacacyiliμ),
3-Kenji is 5-(1,2,4-oxadiazolyl), 1
゜3.4-Oxacyasily”'-1s 2-5-Oxa
Shiashiri μ, l, 2, 3. -or 1,2,4-
Triacyly〃, IH or 2M-tetrazolyl, Bi! j
t'(2,3-d)pyrimidyl, benzobifni~, 1.
8-. 1,5-. 1,6-. 1.7-. 2゜1-ma11
2,6-naphthalene~, quinoli〃, cheno(2,3-b
', ) pyridyl etc. are used for IIE. These hydrogenated hydrogen groups and heterocyclic groups represented by Bl are 1 to several.
may have multiple identical or different substitutions, such as
For example, among the expanded hydrogen groups represented by R1, alkyl
, Alkaniμ, Arginiμ, and Evacycloalkhi~
, cycloaρga2N, ary-μ, hetero-group, alkoxy
Power Boni N, acyl, oxo, halogen, cyano, hydro
Roxy, Akoki V1 aryloxy, acyluoquine,
Power ~ Bamoi〃oxy, hydroxysulfonyloxy, a
μkiss〃Honyloki V1 Arylsulfonyloki V1
Nitro, amino, carboquine 1 aminocarboxy, a μ
Kylthiocarboniμ, mercapto, alkylthio, amino
Noah Kichio, AVN aminoalkylthio, Afuruki
~thio, arylthio, heterocyclic thio, quaternary annine
1 to 3 may be substituted. specifically
Substituted alkyl/I' groups include, for example, those of the formula B4 0 [wherein m is 0, 1, 2 or 3], R%R are the same
hydrogen atom, r/%/kyl, cycloalkyl 1
A~kenyl, acylkyl, aryl, heterocycle, a! Ko
Oxycarbony~, acyl 1 friend is R' and R together.
Oxo t, nO are Kimoto atoms, Alki μ, V Cloa μ Ki p
1 ary~゛, bale 111M, halogen, anno, hydro
oxy, alkoxy V, ary~oxy, ash μ oxy, ka
Ruba Sevenai ~ Oki V1 Hydroxys ~ Honi ~ Okin, Al
Kiss Honi I Oxy, Alley Honi Oki V1 Ni
Toro, Amino, Power Boxy, Alkoxyca Boniμ, A
Mitsukaμ Bonil, 1μki/4/f, Oka~Boniμ, AV
J4/, Memucapto, Alkylthio, Aminoacypthi
O, Ashiμaminoa〃ki~thio, afuruki pthio, ant
Indicates ruthio, compound thio, and quaternary ammonia. ]
Those represented by are also used. Also, denoted by R1
or key key a μkyl, alkenyl, alkynyl
Cycloalkyl~, Vchlor~ shown as a substituent of
2~, afurky, aryl, heterocyclic group, 4th @an
Substituents for monium include 9, for example, alkyl~, alkyl
Kin, A~keni~, Ariel, Afuruki~, 1 power
, alkylthio, arylthio, ara〃kiμthio, al
Kiss〃Ho2μ, Arylsulfonyμ, Ab〃Kiss~
Honi~, trihalogenoalkyl, y1 hydroxy, oxo
, thioquine, halogen, nitro, amino, V-ano, cal
batoi μ, force ~ boxy, ashi〃, a Vlv OK y1 a V
lv amino, Hi V loki V a〃ki~, carboxyalky~
, halogenoalkyl, mono- or cyaminoalkyl
Keys etc. can be heard. Here, as Alcoki V
For example, a lower grade Ako with a number of 1 to 6 characters in the form of a
KiV is preferred, such as meth. xy, ethoxy V% n-f ropoxy, iso10 poxy, n
-butoxy, isobutoxy, especially -butoxy V1tart-
gutkin, n-pentyloxy, isopentyloxy,
n-hexyl oxine, isohexyl oxine V, etc. are used.
Examples of halogens include fluorine, chlorine, bromine, and
is used. As a polyammonium group, even if
Viridinylaf, quinolinium, etc. are used. Ann
As a base, nine examples are Hoμmi~, Ah! Gimu Calpo Ni~
, Ally tvtipvbonil, afuμki~kalhoni~,
I don't need a V14/group such as the complex ring group acetiμ,
For example, acetyp, gropionil, Ω-petite.
71/, 11-pentanoyl, n-he
Xanoiμ, benzoyl, 4-hiroki/benshii~,
4-methoxybency~, phenylacety~, 4-hydro
Roxyphenylacenal, 4-methoxyVphenylacenal
〃, 2-Cheni~Carboni μ, 2-Fri μ force μ Poni μ,
2-14-mak is 5-thiacylylacetitv, 2-also
t-3-chenylaceti~, 2- or 3-furiruryu
methyl, 2-amino-4 or 5-thiacylylacetyl
Which is used. Archipi, syktaroar~, a〃
Keyoμ, cycloa〃Ke2p1ari~, hot~kiμ, compound
As the elementary ring group, those mentioned above are used. Substituent of the swollen hydrogen group or heterocyclic group represented by R1
If there is an amino group in the
may have a protective pupil, and may have a power group or a hydroxyl group.
If so, keep these too! may have been done. amino
As a substituent of the group, AV~, alkyl, hydroxya
~kyl, acylkyl, ary~, heterocyclic group, amidino group
, aminomethylene group, carbamoy μ group, sulfonic acid group,
Alkylsulfoni μ, afuruki fi/:jI-ruhoni~
, arylsulfonyμ, alkoxycarbony~, able
Ki~oxycarbonyl, aryloxycarbo=μ, etc.
is used (here, ypy, alkyl, alkyl)
Coquine, acylkyl, ary-, heterocyclic groups are as above.
Kimono is used). Amino group. with such substituents, e.g. pyrrolidino, pipepet
Cyclic amino groups such as lysino, 7-horino, bibefusino, etc.
It may be formed. As a film-retaining group for amino groups,
It is used for this purpose in the Quantum and Beichi F composition fractions.
The one that is used is adopted as a matter of convenience. For example, phthaloyl, p-
Nitrobenzo, p-tert-butylpency
, p-tert-glybenzenesulfonyl, p-tert-glybenzenesulfonyl
yi group acyl' such as sulfonyl, toluenesulfony μ, etc.
v, &, such as formyl, acetyl, globionyl,
Monochloroacetyl, dichloroacetyl, trichloroacetyl
Ceti~, methanesulfonyl, ethane μhonyl, trif
luoroacetyl, maleyl, succinifi/fathom afd
ti67VA'li, for example, ethoxycarbonyl,
Ethoxycarbonyl, t-1 Toki V: J/I/Ponino V
1 Isoglopokinkay Boni~, 2-Cyanoe) Ki-7ka
luponyl, 2,2.2-)ritaloloethoxolbonyl
, 2-trimethi! Silylethokizoca #bonyl, benzyμ
Oki ν carboni μ, 2-methylsul small engineering Fki V′ force
p-boniμ, p-nitrobendi~okiViI/L/boniμ
, p-methoxy, shibendi μoxyka pboni~, dipheny
methyloxycarbonyl, methoxyV methyloxycarbonyl
Boniμ, acef/L'methyloxycarboni~, isobo
lunyloxy JFA/bonyl, phenyloxinecarbony
Esterified carboxy groups such as
For example, trityl, 2-nitrophenylthio, penzolidene
, 4-nitrobene ν-lidene, or trialkylsilyl
7VA/groups such as μ, benzy%p-nitrobendi/L'
Other amino group-protecting groups are used. -Proper translation of protecting groups
is not particularly limited in the present invention. Ma
In addition, as a protecting group for 'jJ~poxy A/ group, -1
Protection of the carboxy Vμ group commonly used in the field of Tam and organic chemistry
Anything that can be used as a base can be used, e.g.
thyl, ethyl, n-propy~, iso-10vir, tert
-buti〃, tart-ami〃, benji~, p-nitrobe
ndiA/, 6-nitrobendiμ, p-methoxybendi
le, benzhydry-1, phenacyl, phenyl, p-
Nitrophenyl, ethoxymethyl, ethoxymethyl, base
ndyloxymethymu, acetoxymethyl, pivaloyl
Kisimethi μ, 2-methyμ, 4/2-ethyl, 2-t
Limethi A/ $/ 9 A/Efμ, Methylthiomethyl
, trichi〃, 2.2.2-) litaroroech~, 2-ko
Doethyl, Trimethi μVIJ~, Dimethy A/V Lil,
acetylmethy~, p-nitropencyμmethyμ, p-methy
Di~benzoylmethymu, phthalimidomethyl, propio
Niyokynemethyl, 1,1-methyl 10biru, 3-methyl
ThiA/-3-butenyl, succinimi F-methyl, 3,5
-di-tert-guti--4-hydroxybenzyl, men
y methyl, benzenesulfonylmethy~, phenylthiome
Chil-1-dimethyl-aminoethyl, pyridine-1-oxai
F-2-methyl, methylsulfinylmethy~, bis(p
-methoxyphenyl)methyμ,2-cyano-1,1-di
Este A/residues such as Menalech μ, Sili A/groups, etc. are used.
I can stay. Furthermore, as a protecting group for hydroxyl group, β-fuku
Tam and as a protecting group for hydroxyl groups commonly used in the field of organic chemistry
Everything that could be used was available, and Evacetiμ,
Ester MM such as chloroacetyl N, 2.2.2-)
Taloroe [ki7calhoni~, 2-trimethylsilyletho]
Esterified forces such as xycarbonyl
11&, tert-butyl, benzyl, p-nitrobene
di~, trithi〃, methoxymethyl, methylthiomethyl,
Ethe A/residues such as β-methkin ethoxymethy/l'
, trimethy~Vril, tert-guchiy dimethy~Vril
V-lyl ether residues such as
, 4-methoxy-4-tetophhydrobifnyl, etc.
Tar residues, sulfonic acid groups, etc. are used. vmt
In the present invention, the selection of the aw group is an amino group, a carpo group, etc.
Ki￥μ base protection I! As well as based on, there are no particular limitations.
do not have. In the formula of Ranji, R2 is a hydrogen atom or a hydroxyl group protecting group [indicated]
vinegar. As the protecting group for the water group represented by R2, for example,
Those mentioned above are used. For example, β-methoxyethynemethyl, ethyl
Ether bonds such as oxymethyl and methylthiomethyl groups @
[Form *si etc. are often used. In the above formula, R3 is a hydrogen atom or a
The power shown by YuR3 which indicates & - Boki! Protecting group for /A/ group
For example, the ones mentioned above can be used. In particular, for example p-2) Lopendi μ, O-Nitrobe
and p-methoxybenziN, etc. are used as Il. In the formula (IN), the leaving group represented by X is R''
8 (Q)n-4(B”, n agrees with Mil.
Any substitute can be used as long as it can be replaced with ('
h3tjtldp-toluenesulfonyloxy, p-
Nitrophenyls Mhonyloxy, p-promophenyl
Such as sulfonyoxy, methanesulfonyloxy, etc.
Substituted sulfony~oxyS/ group, chloro, bromnato
Halogens such as diphenylphosphoryloxy,
Disubstituted phosphoryl such as μphosphory~oxy group, etc.
A xy group is used. In the above formula, n represents 0.1 or FiZ. - Among the above, R1 is preferably cycloakenyl. ■Arry〃,■5-8 membered containing 1-4m heteroatoms
11131 ring group, (5) Acoxycarbonyl, ■A V
μ, ■Oxo, ■Halogen, (ji)￥Ano, Hydro
Kishi, @Alkoxy, G) Ally Oxyhal Ashio
xy, ■carbamoyloxy, (J5 hydroxysulfo
Niruoki V, [phase] Alkis μs~honi poxy, @Ali
- ~ Sulfoni μoxy J nitro, σ liamino, ni) force
~ Boki V, o Amitsuka ~ Boni 14/Kill Kill Chio Power Report
Nimu, Tome-Kaputo, [Amu Kirthio Co., Ltd.], [Ami Co., Ltd.]
noalkylthio, o acylamino 7μ kylthio, [stock]
Araμ Kirthio, [Phase] Arylthio, Q-type Bet-
b; M; (wherein, Het represents 1 to 4 hete
(represents a 5- to 8-membered heterocyclic group containing a 4 atom) or 4
alkyl which may be substituted 1 to 3 times with
Kifi/l or alkynyl; then ■aρkiμ, ■al
Koki V, ■Aμkeni N, ■Aryl, ■Afuruki~, (
Grain mercapto. ■Alkithio, ■Arylthio, ■Ashiki~thio,
@Alkylsulfonyl, ■Aryls μ Honi μ, Oara
Luki μs~honiμ, 0 trihalogeno μki μ, 0 hydro
oxy, [phase] oxo, [phase] thioxo. Φ) Halogen, [Phase] Nitro, qφ Amino, [Na Co., Ltd.]
No, @Kalba 屹IL, @Karbokin, [phase] Asil, [
Stock] Acyl Oki V1sec Acylamino, ■HiF Roxyal
Kill, Wa Power ~ Bossialuki〃, ■ Halogenoarchy bill @ hair
No or di-alkylaminoalkyl A/, 1 to 3
V-chloroalkyl optionally substituted with orchid. V Croix~Kenji~, Allie/&/, Afyki A/or
5- to 8-membered heterocycle g, R2 is a water bulky atom: n is Ot-
This is the case. Most preferably, R is
Alkylamino, ■ 1 to 3 pieces of 5- to 6-membered amino acids
It is an alkyl of 1 to 6 which may be substituted. The present compound (I) has a carboxyl group at the 3-position or
If B1 contains a force μ and V group, then
It may be used as is, or it may be used as it is, or it may be
! The moon can also be shaped like F valley salt. parable
Non-toxic cations of potassium sodium, e.g.
Bases such as arginine, ornithine, lysine, histidine, etc.
amino acids, such as methylglyamine, jetta
Nolamine, triethanol-μamine, trishydroxide
Polyhydroxyalkyl acetate such as dimethylaminomethane
It may also be used by forming a woodcutter with Min etc. Also, in R1
For example, #ItII contains a basic group.
% maple with organic acids such as tartaric acid, methanesulfonic acid, and
For example, salts with A acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid,
For example, arginine, aspartic acid, and glutamic acid.
It may be used by forming a salt with any acidic acid.
. Compound (I) of the present invention is similar to starting compound (11).
It may exist in racemic form (di form);
Also included in the present invention is a mi-body. racemic form, tt, or
The racemic body is kept in public stock, and the four bodies are used as one body as a medicine.
can be used. As a specific example of this object (I), for example, it can be expressed by the following formula:
There are compounds that are 5.6-V suca μ pervenem compound (I) of the target in the lower margin of the response.
or its salt is used for Guhumu-positive and Guhumu-negative samples.
It is a valuable antibiotic active against human and domestic animals.
It is used as a medicine for people who are classified as Guhumu-positive or Guhumu-positive.
Humu negative Maili e.g. 2-J'7A" 3 lili b
7- ji-Vmumu, Tamashi Gokami 1-Toji L2, Taredeji
12. Infections caused by soybean virus, etc.
It is safely used as an anti-III agent. of the present invention
Anti-cocooning agents can also be used as fungicides, for example to preserve feed.
added to animal feed. For example, medical and dental
In order to break and prevent the harmful is+m life on the
Paints and vapors based on water, etc.
- Prevents the growth of harmful #1- in white water of the mill
As WIM killer, 0.1 antibiotic per 1 million parts of #liquid
It can be added to an aqueous composition at a concentration ranging from ~100 parts.
can. The object (I) of the present invention or a salt thereof
T! alone or with other active ingredients in any formulation of the drug.
can be used in combination with, for example, i11
~, tablet, powder or solution, suspension or eliqui V~
It can be used as These can be taken orally, intravenously or
Can be administered intramuscularly. Tablets used for oral administration include a capped excipient such as Keikai A1.
11 For example, Shirotsu 1, Abbia gum, Gelatin, Sorbi
Thor, gum tragacanth or polyvinylpyrrolidone,
4 supplements such as fuctose, sugar, corn starch
, carunium phosphate, so-pitou-mata-shigri-vn, clear
fusing agents such as magnesium stearate, talc, polyether
Tylene glycol, silica, disintegrants such as potato starch
or uses such as sodium furyl sulfate
May contain superior wet shavings. Tablets are well known in the art.
It can be coated by the method described. oralliquid
mM is an aqueous or oily suspension, bath solution, emulsion, V lotion.
Water is used to submerge or use water without formal use, such as elixirs.
or even dry products that dissolve in other suitable solvents
good. Such liquid formulations may contain suspending agents such as Tulpitot 14/
V lot 1, methylcellulose, glucose course/-ship syrup
gelatin, hydroquine f1+7 cellulose, force μ
Boximethi rose, stearic acid microkumuge
oil or hydrogenated responsable oil such as almond oil, coconut oil
oil, oily ester, 10 helene glycol A/or ethyl
Alcohol, preservatives such as Methiμmayu is propylene/L/
Contains p-hydroxy V benzoate or sobic acid
You can also Suppositories are made of suppository substrates such as coco
Avatar or other glycephids can be used
Ru. Injectable compositions can be prepared in containers containing 1 to 1 or preservatives.
It can be provided in unit convenient form 1. The composition may be oil-based or
Forms such as suspensions, solutions or emulsions in aqueous IB medium -
May be, Kake+1A11, stabilizer and (Mayuha)
Auxiliary agents such as dispersants may also be included. In addition, the viscous component may be removed by using excessive solvents such as
Available in powder form for reconstitution with pyrogen-free water
It can be done. It may also be caused by dryness of the nose and throat or by bronchial tissue.
Excessive forms of absorption, e.g. powders, liquid sprays
Or formulations such as inhalants, roseine, throat paints, etc.
For eye or ear @S administration, which can also be
, liquid or semi-solid form of sardines, or as drops.
It can be used as a box. In addition, we also have a variety of products such as kimto, cream, loci, paint, and powder.
External preparations using hydrophobic or water-resistant drugs such as
You can also use it as In addition to carriers, stabilizers, condensing agents, antioxidants,
4A41. Lubricant agent, suspension agent, thickening agent or flavoring agent, etc.
Contains other ingredients such as Additionally, the composition may contain other activities.
Active ingredient [contains a broader spectrum of anti-activity]
You can also give. For livestock, the *<acting friend will quickly release 1C.
The compound (I) of the present invention can be formulated as an intramammary preparation in a matrix containing
For example, mammalian respiratory tract infections, urinary tract infections, and purulent diseases.
, biliary tract infection, intravomeral infection, noodle gynecological infection, surgical infection
Cure for diseases etc.! It can be used for. Its daily administration
Otori is the foreshadowing of the patient who is being treated, the power outage of the host, and the administration.
Methods and Frequency -6 Preferred Parenteral Methods for Infections
and oral methods for intestinal infections. In general, the oral dosage of
For older pigeons, t6 per patient's power outage.
The component is approximately 15 to ε00 and consists of a cape. to adults' opinions
The amount of active ingredients per day is calculated as follows:
about 10 to about 200q], and 2 to 4 talK minutes every day.
Parenterally at a dose of about 2.5 to about 100 V/pass once.
One dose is given to the patient. Compositions containing compound (I) can be prepared, for example, in solid or liquid form.
Administered in a unitary form 1 that can be taken orally.
Persistent 90 compositions per liquid or solid unit use
Contains 0.5-99%1 of the substance. A preferred range is about 10
~60 whispers. The compositions generally contain between about 15 and 15 active ingredients.
Contains 15,001ft. However, in general,
It is possible to use the usage amount to2 in the range of about 250 to 1000”F.
is preferable. The bottle containing the compound (I) of the present invention is as described above.
It also has a β-phuctamai inhibitory effect.
Therefore, it may be used in combination with β-fuctum antibiotics. This way
Examples of β-fuctam antibiotics include
Nji Beni V! #n, fenoki V mechi〃penicillin, power
〃Veni V phosphorus, Ampi V 9 phosphorus, Acexy V phosphorus, Surve
Beninlin antibiotics such as NiVrin, and
Cephaloridine, cephalothin, cefazolin, cepha
Reki V-n, Shichihoki V-chin, Cefasetori~, Sefaman
F-μ, cefmetuxime, cefsulcin, cefothiam
, cefotaki V, cefaviline, ceftizoki V, se
Cephalos such as furazine and cephaloglylin are phosphorus-based
Antibiotics and the like can be used. 5, 6-5' Sukarupabene F-3-ka of the object of the present application
Rubonic acid-conductor (I) or its salt is compound (If)
Mayu reacts the compound (Ml) with the woodcutter)
Can be manufactured. Examples of the salt of compound (1) include those mentioned above for the salt of (I).
Tokimono is used. Compound (ml) remains free
For example, a woodcutter who is not involved in the reaction may be used.
alkali metal salt loadings such as aluminum, sodium, potassium, etc.
Alkaline earths such as , force μ silaf, magnesium etc.
It may be used in the reaction as a metal salt or the like. Compound (n)
or Compound (1) or its 11 to 1c*
10 mμ, preferably 1 to 5 cA/l. Aburajo
, the reaction is carried out in a solvent, 7t for 3m silver,!
:, t-halogenated chloromethane, chloroform, etc.
Hydrogens, nitric μ such as acetonitrile μ, dimethoxy
Ete A/I 11% such as V ethane, Tetotsuhi F Rofuran etc.
Shimechip*〃muamide, dimethylsulfoxide V-do, hexa
Methylphos holamide and the like are preferably used. base
The addition favorably advances the reaction. As such a base
For example, sodium bicarbonate, potassium bicarbonate,
Sodium malate, potassium carbonate, sodium hydride, water
potassium, sodium amine, F, sodium methoxychloride
Sid, F ethyl amine, diisoglobi-ethyl amine
, Piggin, etc. are suitable. , Mayu, in this reaction the base
12 Instead of using compound (1), for example, as above
Convert to alkali metal salts, alkaline earth metal blocks, etc.
It may also be reacted with compound (1) or its compound. for
The amount of base present is determined by the amount of base used for compound CI), (11
) and the type of solvent and reaction conditions of the pond).
, usually preferably 1 to 10 mol per 1 basket of compound (I)
is from 1 to 54. Reaction temperature is approximately -50℃ to 40℃
It is preferably carried out in a field at -30℃ to 20℃, so there is no
The reaction time depends on the type of compound (1) or its salt, the type of compound (1)
) or depending on the type of salt, reaction temperature, etc.
, 1 to 72 hours, preferably 1 to 24 hours. belittled
The desired product (I) can be obtained by methods known per se, such as concentration, liquid
conversion, dissolution, solvent extraction, crystallization, recrystallization, fractional distillation, chromatography
It can be isolated and purified using Matogutshufi etc. Ta
For example, when mixed with water, such as ethyl acetate in the reaction mixture.
Add organic solvent and water, separate the organic solvent layer, and add water.
After washing with water and drying with desiccant, the solvent was distilled off.
Therefore, it can be obtained. The compound obtained by K in this way
Product (I) can be prepared by conventional methods, such as preparative thin layer chromatography, if necessary.
matogutphy, column chromatography, recrystallization method
It can be further purified by When the target compound (I) thus obtained has a protecting group,
can be removed if necessary
. The protecting group
llllK Depending on the acid method, - group method,
F fusin method, reduction method, iminohalogen
as required after the action of the etherification agent and then the iminoetherification agent.
Depending on the method, commonly used methods such as hydrolyzing
It can be carried out. In the case of the acid method,
Although it depends on the protecting group @leprosy and other conditions, examples of acid
For example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid,
fluoro1H[,10pionic acid, pen(sulfonic acid,
In addition to organic acids such as p-to-μ engineering and fonic acid, acidic ion exchangers
It is used for exchanging wMm, etc. , in the case of the base method
, depending on the bridge shrinkage and other conditions, or salt
Alkali metals such as sodium and potassium as bases
Or power ~ alkaline earth metals such as Sium, Madane Vum, etc.
hydroxides of the genus, inorganic bases such as hydroxide, metal alcohols
oxides, organic amines, quaternary anthenium
In addition to wt bases, basic ion exchange resins etc. are used.
. In the case of the above acid or base methods, solvents are not used.
When using a water-based organic l# medium, a mixed solvent is used for water bottles.
glI! It is rarely used. Where the method is based on reduction
Although it varies depending on the conditions such as the forest of the forest, the forest of the forest and other conditions, examples
For example, soot, metals such as noodle lead, or dichotomous combustibles, acid salts, etc.
Metal compounds in romu tatami and acetic acid, propionic acid, hydrochloric acid, etc.
Methods of using organic and inorganic acid cape acids for catalytic reduction of gold
Examples include a method of reduction in the presence of a metal catalyst.
Catalysts used in catalytic reduction methods include, for example, white
Gold wire, platinum sponge, platinum black, platinum oxide, colloidal platinum, etc.
Platinum catalyst, Pufficum sponge, Pufficum black, Oxidized buff ν
rim, palladium barium sulfate, palladium barium sulfate
mu, palladium envy, palladium silicage mu, colloid
Buff catalyst such as Buff Vum, reduced nickel μ, nitric oxide
Examples include nikkeμ, fune 12tsuke~, rich nikkeμ, etc.
. In the case of the reduction method using nine metals and acids, iron,
Metal compounds such as ROM, inorganic acids such as hydrochloric acid, and formic acid and acetic acid
, organic acids such as propionic acid are used. By reduction
The method is carried out in a remote medium, for example by catalytic reduction.
In the case of methano-11 ethanol, propylene alcohol
1 isopropyl alcohol, etc., II/1m%
Ethyl acetate etc. are frequently used. 1f:. Water and acetone are commonly used in metal and acid methods.
However, when the acid is liquid, the acid itself is used as an r# medium.
You can also do that. Acid method, base method, reduction
The reaction temperature in this method is usually under cooling or under heating.
It is done in degrees. In addition, iminohalogenating agents,
After applying the etherification agent, hydrolyze as necessary.
used in the case of a method for removing a protecting group
Examples of the iminohalogenating agent used include phosphorus trichloride, 5
Filled phosphorus, tribromide, phosphorus oxychloride, thioni chloride μ, phosphorus
Gen force is used. This reaction temperature is not particularly determined.
However, it is usually carried out at room temperature or under cooling. Imino acids that act on the reaction product obtained in this way
As the etherification agent, alcohol or metal
Coxides are used as alcohol, methanol as alcohol
, ethano-μ, 112 bano-μ, iso-1a panol, n
-Butano-voice, t@rt-Butano-N etc. A/iIno
-*Jlt or these alki μ parts are metki V, etho
Al such as Ki V1 Zorol Ki V1 Iso 101 Ki, Gutki Y, etc.
Compounds substituted with coki V groups etc. are used, and metal alkyl
Kisai) Im as for the above-mentioned place.
Sodium alkoxide, potassium alkoxide
Alkali metal alkoxylic acid F and force fi/V such as id, etc.
Al such as Umua ~ Kokisai F, Bariuma ~ Koki f I F, etc.
Potassic earth metal AμKOKINAI F and the like are used. Also,
For example, if the protecting group is the residue of an organic acid, the force μ
a free amino group adjacent to the bonyl group,
Vμ group, mercapto group, μFoxyl group, sulfonic acid
When there are substituents for the group ◆, the adjacent effect of these groups t
``A treatment to increase the reactivity of the p-bonyl group is increased.
Removal of the protecting group first gives favorable results and is advantageous.
be. As an example of such a case, for example, the carbo
The substituent on the strand adjacent to the niμ group is a free amino group.
For example, when the free amino group is
How to deacylate # converted to uret'J& etc.
1 A known method used to decompose a tied bond is
An example of this method is to apply it and exhort the base. This anti
The reaction temperature is not particularly determined, and depends on the am of the holding group, the method of elimination, etc.
Depending on the type of
It is preferable to carry out the process under mild conditions. Specifically, the retention of the p-phoxyl group in the target product (I)K
- group is halogenoalkyl group, afurkyl group, penmehi F
In the case of 9A' group etc., contact with 1lyclA.
Therefore, it is achieved. The reducing agent used in this reaction is
For example, if the carrier group of μ phoxyl group is 2.2-$' Gromme
Chill, 2,2.2-) Halogeno such as Ritarolechi μ
Zinc and acetic acid are preferred in the case of alkyl groups)
, the carrier group is, for example, benzyμ, p-=)lopenzyl.
When it is an isophonic group or a penzuhi Fsp group,
Water bulk and saponified platinum, platinum black, platinum sponge, puff V
Kazuhiro Tsufu, palladium puftsuku, palladium-sulfuric acid
Barium, buff V cum barium marate, reduced nickel β,
Fune 12 Tsuke~, Urushibara Nickel Like & Catalytic Reduction Catalyst II
＆Also sulfuric acid) like rum or potassium sulfide
Alkali metal sulfides are preferred. Also, O-nito-be
In the case of di-μ group, p-methoxyben V is removed by photodistance.
~ In the case of the morning, it can be removed by electrolytic reduction.
. The reaction is carried out in the presence of a solvent and is used as a solvent.
is not particularly limited as long as it is not involved in this reaction, but
Methano-mu, aco-coagulant like ethanol, teflon
Ethers such as hydrofufuran, dioxane, acetic acid
The combination of fatty acids such as these and these organic fIIIla with water
Mixed solvents are preferred. The reaction temperature is usually around 0° to 4C, and the reaction time is
Varies depending on raw material compound and reducing agent 111111
However, the period is usually from 5 minutes to 12 hours. In addition, the target object (
The protecting group for the amino group in K is, for example, p-=)a.
sFIIM/O*y**#2*&, 0-nitriveny
tv oki V capboni p group, p-methoxy V pen vk oki V
Kaboni A4, Benji! Oki V-11 ~ Boe p group etc.
In some cases, the said Karuhoki S/, #'! ! -1 deduction
Removed unreacted. First, in the target compound (I), hydroxy acid
The protective group of the group is lower aliphatic aVA/O such as acetoxyV
When it is a xyl group, it is externally formed as a ring group in the aqueous layer agent.
It can be removed by The solvent used is normal
There are no particular limitations as long as the solvent is used for the hydrolysis reaction Km.
-is, water and methanol, ethanol-μ
Roku Akko 1@/lII or Tetofhydrofufun,
With organic solvents such as ether A/Ill like dioxane
A mixed solvent of is suitable. Also, as a conveniently used base,
It is carried out with something that does not affect the β-fucta cycle.
. The reaction temperature is 0℃ or li! It is done warm. reaction
The time varies depending on the species of raw material compound and reaction temperature.
It usually takes 1 to 6 hours. In addition, the retention of hydroxyl groups a
m as tart-buti~VmechiμVsu~
Lower Alki 11. / When the Fyl group is used,
For example, fluoride det-μ ammonium or fluoride
It is removed by treatment with fluoride ions such as potassium.
It will be done. Solvents used include teFrahydrofuran and dioxa.
Ethers such as ethers are preferred. The reaction takes place around room temperature.
This is done by treating for 10 to 18 hours. In the above protecting group removal reaction, R1 is capacitated VA/
In the case of a group with a group its induction at carboxy #&
There are times when the body turns into force, but of course
This case is also included in scope 8 of this invention. The thus obtained compound (I
) can also lead you to the desired woodcutter in the usual way. Since compound (I) has a force μ boxy μ group, generally
, interacts with bases to form and despise woodcutter. Friends, Compound
(I) is sometimes collected as a woodcutter), and is obtained as a woodcutter.
It is easy to stutter in the free form and can also be used as other salts.
stomach. Furthermore, compound (I) tj obtained in ml1ll form
J
Examples of methods for releasing the mold include methods using acids, etc.
is used. The acid used depends on the type of holding group and other conditions.
However, acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc.
organic acid, formic acid, acetic acid, p-) μ ence μ fonic acid cape
is frequently used. In addition, acidic ion exchange resins, etc. are used.
It will be done. In addition, examples of the II# medium include acetone, tetof
hydrofufun, methano-μ, ethano-A/,-dioxa
Hydrophilic organic lII media such as water, water or mixed media are used.
Often. This method is usually carried out at room temperature, but may be carried out under cooling or heating.
Go down and do 4. Reaction time, types of acids and solvents
Although it varies depending on the temperature, it is generally preferable to finish in a short time.
The preferable free form of compound (I) obtained is as described above.
The kernels to be isolated can be prepared by known means. The target compound (I) thus obtained has a substituent represented by B1.
If there is a free amino group in the
Converted to amide, clay F1 amidino, guanidino groups, etc.
and when it has a hydroxyl group, its water e
Converting a group to an acyloxy group, a hapgen atom, or an azide F group
In addition, if Kn is 0 or 1, Sulfur
It can also oxidize children. Amino group, amide group, ureido group, amidino group, guani
Conversion to a dino group is achieved by various methods known to the reaction company.
be done. The conversion reaction to an amide group is carried out in the presence of a solvent.
This can be carried out by contacting with a layering agent. There are no particular limitations on the layering agent used, but chlorophore μ
halogenated hydrogen chains such as methylene chloride,
Ether chains such as tetofhydrofufun and dioxane
suitable. The reed μ layer agent used is ordinary amino acid.
There is no particular limitation as long as the compound can be made into a Vfi/.
However, 1W fatty acid anhydride such as acetic anhydride and propionic anhydride
substance, acetyl chloride, globioni chloride, n-butyl
Chili μ Promide F2 Isobutyri μ Promide, Methoxali μ
To give fatty acids (such as chloride) II conductors
I can do it. This reaction is preferably carried out* in the presence of a base.
, te bases used include triethyl μamine, pyridine
organic bases such as sodium acetate, potassium acetate, etc.
Fatty acid alkali metals such as aluminum are preferred. There is no particular limitation on the reaction temperature, but it is preferably between 0 and 4 degrees.
It is. The time required for the reaction depends on the type of acyl layer agent and the reaction time.
It varies depending on the reaction temperature, etc., but usually (15 to 5 hours)
It is. The conversion reaction to ureido group is similar to the conversion reaction to amide group.
Substituted isoleanes in the presence of solvents such as those used in
and substituted isothio V achitos [by stirring the reaction]
It is done. Substituted isoleanates include, for example, methyl-isoV a
nate, Echi μ iso V anate, Fenii yv ane
, p-gromophenyl μiso V anate, etc. are used.
It can be used as a substituted isothiorianate.
BAMETHIμISOTHIO V ANNEE F1 FUENIMUTHIOISOTHIOSY
Anate and the like can be used. The reaction temperature is
to around 40°C, and the reaction time is usually 0.5 to 5 hours.
Ru. Conversion to ami v) group is performed using dioxane, tetofhydrofura
N, dimethymu formamide, chloroform, amethane,
In layering agents such as acetonitrile and water, e.g.
This is done by reacting with TeA/Jllill.
. As an imidoesthetic, for example, ethylformimide
date, ethylformimidate, ethyl acetimide
aceto, ethyl acetimidate, methi-phenylaceto
Imidate, Echi μ Summer-Methi/L/Home μ Imidate
, methi 14/M-ethylformimidate, methi N
- Isopropyl μhomimidate etc. may be used.
I can do it. The reaction temperature is from 0″ to around 25°C, and the reaction time is
The conversion to the yuguanidino group, which usually takes 1 to S time, is
, V methylformamide, hexamethylene fluoride
In a solvent such as F, for example O-1μ+fi/l or O-
Arylgtude urea, or 8-alkyl A/Makuha S
-By reacting with aryl-1 soidothioureas
It is done. Gusoy F ureas include O-methyA/
7'Soid urea, 8-methypsoyF urea, o-2,4
-5/taloloa z2~pseudourea, 8-p-nitroff
phenylgusoidthiourea, O-N, 1i-)
Soy F urea and the like can be used. One reaction is
The reaction time was from 0 to 40°C, and the reaction time was from 1 to 24 hours.
Ru. Compound (I) thus obtained can be prepared by a method known per se.
Single purification is possible. Changing hydroxyl group to a￥μoxy group, halogen atom, azyl F group
The conversion reaction can be accomplished by a variety of known methods. a
The conversion reaction to S/μoki V group is performed using the above amino 1 & [a
It can be carried out with the reaction of converting to MiF group and Mal.
Wear. Conversion to halogen atoms is halogenated according to the conventional method.
Achieved through kindness and compassion. Herogen layer agent used
As a company, for example, Chioniμtarovdo, Chioni〃Glomi
Oxalyl chloride
Sufuin, Four Odors (1131-) Lihueni &/Shin Sufi
7g! ! The solvent used is
Toehadetohydro7fun, ether like dioxane
A'11m1% Benin, like toluene
Hydrogens and the like are suitable. Reaction temperature is 0℃ to room temperature
The reaction time is usually 15 molecules IR1%/%
It takes 5 hours. The conversion reaction to aziF group is phosphine
In the presence of derivatives and azodicarbonate
React with hydrogen azide or diphenyl phosphate
This is achieved by The phosphine derivatives used include, for example) 17
z2~phosphine, scale-rx-7fμ phosphine is preferred
As the azo N*A/boxylic acid diester,
For example, azo 5) jhtv bonic acid V methi μ este μ, azo
Civic acid V ethyl esde μ and the like are used. used
Examples of solvents that can be used include seeded methane, chlorophore,
Fufu-like halogenated hydrocarbons, tetrahydrofufun
, ethers such as dioxane are suitable.
. The reaction temperature was O'c* to 60°C, and the reaction time was 5 minutes.
5 hours is suitable. The compound thus obtained (I
) can be purified by a method known per se. The oxidation reaction of sulfur atoms is carried out by a method known per se.
I can. For example, power is unique to the pabenum skeleton.
? ! Mild oxidizing agents that are not used, even tf perbenzoin,
Zon, Feni~V Taroro Iodai F1 Hydrogen Peroxide, Me!
For sodium peroxide-F acid, sodium hypochlorite, etc.
It is done by In particular, for example, perbenzoic acid, m-chlorobenzoic acid 111#, etc.
Which is preferable? Oxide M to compound (1) (n=0)
However, when 1 equivalent is used, it is usually
If 1) is obtained and 2 equivalents or more can be used,
Sulfone (n-2) is obtained. The reaction is usually 9 e.g. νriG2A/methane, chloro3#L
A/mu, 2! -30 or more in an inert medium such as woodcutter
The reaction was carried out under mN conditions at around 25°C, and the reaction time was
Approximately 3 minutes to 3 hours for phoxite, and approximately 3 hours for sulfone.
It takes about 1 to 9 hours. 8-Kankasei Kaimono is a well-known
Although mono-Sat can be produced in a variety of ways, sulfo-Sat
In the case of shiF, 24111I with different 8-o bond coordination
Diastereoisomers may form. these
Isomers can be obtained using known methods such as Cammu chromatography Duffy, recrystallization, etc.
It can be separated by the following method. In addition, the compound (If) in the present application is, for example, the above-mentioned compound (If).
or a similar method.
I can do that. (hereinafter referred to as Hill-Sho [in the formula, It”, BS Ha 11th! M: t41'k
, )17 Ha hydrogen atom or the protecting group of the amino F group, -
Hydrogen atom front hydroxyl group, or with B'F
18 are bonded to each other to form a rotational hydrogen group or a heterocyclic group 1
9 represents a swollen hydrogen group or a heterocyclic group. ]The above lll formula
Accordingly, the starting material is 4-(
2-Hydroxy Vethyl A/) Azethyl V-2-one (B
・V-Christensen et al., Vjarna μ op Ogre
Nick Chemistry (Journal of Org)
Anic Chemistry), Volume 45. 1130 (1980)), the amiF group and hydroxyl group are
A silver-coated compound (V) is used. B-group 1 and R8
There is nothing to be done in making this choice as long as it does not interfere with the following reactions:
- @ Not available, but for example trimethyl~V9, t-butyldi
1NllVvru & 2-tetra such as methylsiliμ
It is a cyclic ether such as hydrobifni μ, and further R
7, R8 is the following formula [where BIO2Bll is the same or different, it is a rotational hydrogen group]
] At the same time, by forming a protecting group as shown in
It is possible to unite and hate. ,M) , ,11
As the swollen hydrogen group, those mentioned in the inscription R can be used.
For example, methi~, methiμ, isopropylene.
A lower alkyl group such as μ group, and further R10 and IIn
Those that are bonded with an akyn group having 3 to 6 carbon atoms are common.
may be used. Of (river), R10 and T111 are
Compounds with both methyμ groups have already been described in the literature (
B.G.
- Ganic Chemistry, Volume 45, Page 1130 (19
80 years)). 4-(2-kF lokiVethiμ)a(thidine-2-one and
2,2-dimeFxipuripan and ttrifluoride* Uron x-
Acid catalysts such as deuterate, p-tene sulfonic acid, etc.
He reacts to his presence and is despised. (other punishment) is 2.2-$'methoxy v propane in the above reaction.
), 1 m of ketone ($/ethiN ketone, methiμech~
Ketone, V isopropyl ketone, V chlor10panone, V
Talbutanone, V-clopentanone. (V Riden hexanone, etc.)
can get. It is preferable to use (XVI) in the following reactions. 3rd place of 1st work 11 butterfly (V)
). When carrying out the reaction t* in this step, preferably (V)1
4A/1l-3c14/amount! J+'7AN4/7”
Biamide, lithium isopropyl μV talohex vfi/
such as amines, sodium amide, potassium hydride, etc.
Tetrahydrofilane (TIIF) in the presence of a strong base
, dimethoxy V ethane, ether. V Methylv*μmamide (DMj'), $'Methyμsμ
in a solvent such as Hoki V-do (D1180) at approximately -78°C.
1 mol of sphene = μ layer agent and reaction at temperature a″ct from
(1) is obtained. Expanded as sulfenyl layer agent
For example, in equation (19B), it is possible to have a ditM such as
[R9 in the formula has the same meaning as above]. As B9, expanded hydrogen as mentioned above in Bl is used.
group, heterocycle 1 is used, and for example Hue = y group
, low alkyl groups (methy~, ethyl J[,!') are replaced with
E2μ group, halogeno (chloro, pro-hair) substituted phenylene
2-pyridi μ group, 2-benzo
Heterocyclic groups such as thiazole p group, methy μ group, ethyl chloride,
Iso-10 Bibase. Lower alkyl fi/I! such as n-propyl group! &etc
Can be used frequently. (Regarding the substituent at position V113
Two diastereomers can theoretically exist. these
Isomers are column chromatographies. It can be made into single pieces by operations such as recrystallization, and each can be used for the next step reaction.
can be used for one part of the mixture without isolation.
- Can also be used in the next step reaction. The second step is (Vl) 03rd place t7A/ki/& conversion (vl)
This is the process of obtaining l). When performing the reaction t* in this step, the
o'ct from about -78℃ using the same base and solvent as
At a temperature of (■) 14fi/ at night, 1 moμ to 207~
When treated with a ketone, (■) is obtained. or more (V)
→ (Vl) → The conversion reaction of (1) is to form a single layer of (■)
Convert from (V) to (■) in the same spring mackerel (middle tube 2 in the above figure)
’ process). In this case (V)
Using the same strong base and solvent as used in the first step, -7
Temperature fft JIL tomb Lf from 8℃ to O℃t, (V) 14
Add ~1 wall of Supheni μ layer agent to A/, then add 1
by adding 207μ of acetone from 4*) (■)
Ill meet you. The amount of strong complex used is (V) 1 碌μ
For that, 2 mo μ to 3 mo A/ is 1 hit. obtained (■
) Two types of diastereomers due to the Fi 3-position substituent are understood.
Theoretically it could exist. In this reaction, these isomers are
Romatogutufi. By JIk production such as recrystallization method, each can be consumed in a single meal, and each can be transferred to the next process.
Can be used in reactions, but not as a single mixture, but as a mixture
It can be used in the 4th step reaction. The third step is to reduce (■) and selectively substitute 3.4-cis
This is the process of obtaining A (tidinone (■)).
For example, organotin compounds and nickel μ compounds. Mercury compounds, T11It compounds, etc. are used, preferably
Organic compounds such as
This is done by using chemical compounds. Represented by HW
The swelling hydrogen group to be used is the turtle mentioned in R1.
For example, methi μ, ethi μ, n-pro
Pi μ, isoglobi fi/Jn-buti~, t-guchi μ, n
- leg prime number 1-ε lower alkyl μ groups such as bench μ, 9
For example, 7z two μ group, paper binding alkyl μ group (methi μ, ethi μ group)
etc.) substituted feni wl& can be used. Specifically, water bulking triphenyltin, 2
n-Butyltin, diphenyltin hydride, water 97iN
-n-butyμtin, triethytin hydride. Water bulking trinochi~tin, water bulking - n-guchi μ tin layered
among others, for example, hydrogenated truffles.
Anyfi/tin, hydrogenated) di-n-butchi voice tin etc. are preferred.
The preferred 11-element agent is (■) usually 1 ml per 1 ml fi/.
to 104*, preferably 1°2 to 54fi/ is used
be done. This reaction consists of (117μ to (154~) azobis
Isobutyronitrium or Di-t-1timber
Preferably carried out in the presence of a play*aii start lI4 such as y
be done. In addition, light irradiation was performed instead of using free radical initiation.
It's okay to be. The reaction uses the reducing agent itself as a solvent.
However, it is carried out in a solvent that does not participate in the Harutohiro reaction.
. For example, acetone, methi μ ethyl ~ ketone like ketone
oxane, more ethers of tetrahydrofuran
alcohol chains, methanol-μ, ethanol-μ chains,
Benzene, Tomuene, IF Lennoyo Una Fragrance IN#lI
Can be used as a t# section in hydrogen hydride l111
Ru. The reaction temperature is usually 0°C to 130°C. In particular, 10°C to 100°C is preferable), and nitrogen is added if necessary.
in an atmosphere of an inert gas such as argon or argon.
It can be done by The reaction time is 8 times depending on the type of raw material compound.
Approximately 1 to 2 depending on the reaction temperature, amount of reducing agent used, etc.
It is 4 hours. By this reaction, 3', *4-
It is possible to give priority to the target compound (■) that has a
However, a small amount of side effects of compounds with 3,4-tofuns configuration
accompanied by life. Isolation of (1) from the reaction mixture was carried out according to a conventional method.
Three steps are carried out, such as distilling off the solvent and recrystallizing the residue.
method or Kaff chromatography, etc.
Therefore, it is easy to
Wear. The $14 structure is newly formed with (■) and has a friendly hydroxyl group t4#.
This is a process in which rx > t*. The protective group represented by R2 is as described above.
For example, β-methoxy V etoxy V me? A/Group, Me
Ethers such as methylthiomethyμ group and methylthiomethyN group
A bond-forming group or the like is suitable. Of these
In particular, for example, ρ-methoxy V ethoxy V methoxy μ groups, etc.
(2) It is preferable as a safety measure. The reaction for introducing a protective group is
This can be achieved by known methods, such as the one mentioned above.
In the case of a binding group that forms a tel bond, β-methoxy V ethoxy
V Methyl chloride F, Methoxymethyl chloride, Methyl chloride
Tries μ such as aluminum halides such as omethi-chloride.
Thylamine, diisopropyl-ethylamine, pyridine,
Rings such as n-butyllithium, F hydride, etc.
In the presence of groups, dichloromethane, taloloform μ, i! 1 salt
carbon, 'rIr, ether, dimethoxyethane, acetate
In a solvent with Tonitri ~, DIF, DI80t, about -20
℃ to 100'C for 0.5 to 72 hours (■
) by reacting with Alkylating agent
and the amount of ring groups used depends on their type, jl [material compound
Although it varies depending on the S medium 2 reaction temperature, etc., (*) 1 wall μ
14A/ to 2omoμ, preferably 1km to 57~
It is. (IX) obtained by the following formula reaction
(X■) [Symbols in the formula have the same meanings as above] It can also be obtained from (■) via <'nx). Above formula anti
The response is to store the hydroxyl group of trench (■) and then 0■)tll, then
is reduced to obtain (IX). (■) to (X
The conversion from (■) to (IK) is similar to the conversion from (■) to (IK).
achieved by a similar method. Maji α■) to (I
The conversion to X) is qualitatively the same as the conversion from (■) to (■).
This is achieved by different methods. The fifth step is to remove the silver film groups B' and n8 of (Tx),
This is the process of obtaining <x>. Removal of f4-group B7 and P8
By applying various known de-fltS methods,
For example, (IK) is derived from (XVI).
When the compound is
for 5 minutes at a temperature between 0°C and 15°C in a solvent such as
It can also be carried out by acid hydrolysis with reaction times of up to 16 hours.
It will be done. The 6th step is the t-droxyethyl A/I oxidation reaction of (X).
Therefore, force μ is converted to Vmethy~ group, and (XI)tII becomes
It is a process. Oxidation reactions include acetone, aqueous THF, aqueous dioxane, etc.
1 in a temperature range of about -10°C to 40°C in a solvent such as
From 0 minutes to 24 hours, jeans trial, permanganate
Various known oxidation systems such as lithium oxide and AT can be used.
It can be implemented by Especially (X)t acetone.
10 in any solvent at a temperature of about -10°C to 30°C.
The oxidation reaction was carried out using a carbon dioxide reagent for a period of 8 hours to 8 hours.
It is preferable to In the conversion reaction from (X) to CM), (X)t'
The following formula () [Symbols in the formula have the same meaning as in the 1st era] 2 (and then converting to (XI).
31 such as
In the class DM80-Saccharic anhydride, Pure water chromic acid-Viridine,
V Kuroheki VA/Power ~Posimide-DM80&and-like
by oxidation with a suitable oxidizing agent at a temperature of about 0°C to 40°C.
It is done. From α■) obtained in this way, (X
The conversion to [) is similar to the conversion from (X) to (XI).
achieved by a similar method. (X[) is t, (]x)tUi[subject to oxidation reaction
(In the diagram, 3g6' construction
). For example, a friend (IX) was cast from (XVI).
in a solvent such as acetone etc.
Using Jeans reagent at a temperature of about -10℃ to 30℃
When subjected to oxidation reaction for 10 minutes to 8 hours, (XI) is obtained.
Ru. This reaction is the main bullet in the middle, and nine (X) is alive, then
The oxidation reaction progressed in ◆. (I), which is the object compound of the present application, has one compound. It includes any of the four bodies, and the optically active (V
) can also be used to prepare optically active (I)ijl from
In the case of 4 bodies, perform optical division using ()ff)l.
is a needle connoisseur. Division can be carried out using various known methods.
can. For example, use the crystallization method or (X[)
For example, quinine, protein A/F, and
Amines such as ferrin, strychnine, and self-in
Fractional crystallization of V anteleomer bottles formed by reaction with
By physical separation methods such as
be divided. The seventh step is to activate the force of (XI) Vμ group, and then
This is a process in which the vertical cable atomic region 2 is sickled (expletive) and wrapped in Vt. In conducting the reaction t-screen in this step, first (XI) is
Friends! In a solvent such as H1, dimethoxyethane, (X
I) $4fi/tomo 1 to 27μ,
1'-force μboni μ-ν imidazoN or 1, r-ka
Rubonylbis(2-methylimidazo-fi/)1
The imidazophy was reacted with a reagent such as
and then without isolating the imidazophyte (
XI) A magnesium bottle of malonic acid cast conductor and a malonic acid cast conductor magnesium bottle expressed by the following formula % formula % ([in the formula, 1 is the same as above] 1 to 3 moles per 1 mo, 4/
It is carried out by reacting at 50°C for 1 to 48 hours.
be exposed. The 8th step is the step of diazotizing (A) to give 001)
It is. The diazotization reaction can be performed using, for example, acetonitrile, Shita! μme
! (in an eil medium such as '1' HF, etc.)
Like ethylamine, diethylamine, pyridine etc.
In the presence of a base (total) of 1 to 24N for 17 to
For example, p-carpoquine acid, p-to
μ Ensulfo=〃Aji F, Melins p junior high school! Horse mackerel F etc.
This is carried out by reacting with azide F. Reaction a!
The temperature is about -10℃ to 40℃ 1 reaction time is usually 1 or 48
It's time. The ninth step is to remove the protecting group (B"l of (XI) and to remove (XF
)l, but the protecting group is removed in this step.
is not required, provided it is pharmaceutically acceptable.
may remain in the object CI), and even if necessary
For example, the protecting group can be removed in any step after this step.
Wear. Removal of such protecting groups can be accomplished using various known deprotection methods.
is done by and when B2 is β-method
In the case of a methyl group, for example, chloro*
! in solvents such as silica, dichloromethane, and THF.
For example, when in contact with Lewis acids such as titanium tetrachloride, zinc bromide, etc.
It is done by touching. /L/Use of isic acid
The amount (XIN to mol) is 1 to 30 to 1, and the reaction temperature is approx.
-10℃ to 40℃ 1 reaction time is 5 minutes to 10 hours
be. Step 1a is a step to cyclize (XIV) to obtain te(MV)t-
That's about it. The wood chemical reaction is (XIV) l9 For example, benzene, ) μe
For example, sulfuric acid in IIIF#ll such as 'I'Hr.
steel. Copper powder, rhodium acetate, palladium acetate, etc.
What is done by cyclization in the presence of a catalyst?
It will be done. Reaction 1! The temperature ranges from 50℃ to 110℃. Reaction time is 1 to 5 hours, usually highly toxic or alkaline.
It is carried out in an atmosphere of an inert gas such as gas. maku
This optimization reaction converts (ff) into nine, for example, Ben f! 11F
, fijjl [chemical #i2 element, zoech 7v ete ~ etc.
Light irradiation for 0.5 to 2 hours at about -10°C to 40°C in a bath medium.
It can be done by shooting. The 11th step is activation with (XV') f activator and (
IN) is the process of obtaining t-. When X in (1) is a substituted sulfonic μoki V group, (KV)
l (1 to 37 μ for μ, e.g. anhydrous p-)μ engineering
sulfonic acid, m-water p-2F-μ sulfonic acid, anhydrous
2.4-) Lisoderobi ρ-7E=μs~Hyric acid, x water
Methanesulfonic acid, p-)
, p-fuJt7X=py; xβhoniμcoulide, etc.
Sulfonyl (tit) such as dichloroμmethane
, Kurognemu. Such as acetonitrile μ, dimethoxyvinyl alcohol, TIP, etc.
In a suitable solvent, for example, F amine,
Ethylamine, pyridine, 4-dimethymu aminopyridine
The reaction should be carried out in the presence of a filler such as usually,
From reaction temperature Fi-20'C to 40°C-2 reaction time is 0.
5 to 5 hours. When X in (1) is a halogen, the above X is a substituted sulfonyl y
Sulfonylated AIO group in the reaction with oxy group
(Halogenating agents (e.g. oxali μ chloride,
(C6H5)3 PCl3 , (06H,)3
PBr,, (C61!.o), PBr,, thionyl chloride, etc.)
Then, under the same conditions, (XV) can be converted to (1).
Wear. When X in (summer) is a di-substituted phosphonic acid group or an oxy group
, in the reaction when the above X is a substituted sulfonyloxy group
In place of the sulfony μ layer agent, Nesphori μ layer agent (e.g.
niμ) phosphoric acid chloride, y-methyl phosphoric acid chloride, jethi
fi/9-phosphate chloride etc.) under the same conditions.
can be converted from (XV) to (I). After the reaction is completed, the first compound of this step (summer is added according to the usual method)
taken from the reaction mixture. For example, acetic acid in the reaction mixture
Water-immiscible organic compounds such as Ethi~
Add water, separate the ammonium chloride layer, precipitate it with water, and remove the desiccant layer.
After drying with
be able to. Also, (1) can be done without the above single operation.
It can also be subjected to the t'-next step reaction. The above examples do not limit the starting material (II);
Any starting compound (I[) suitable for the purpose of this application
' can also be used. For a specific example,
will be shown later as a reference example. (Left below) Reference example 1 1-phenylthio-8-oxo-2,2-dimethyl m3
-oxyf-1-azabicycloC4,2゜0]octanediisopropylene #7 i in IL, 82yl (ao 1
5311 ol) of anhydrous tetrahydrofuran 140 dll
Electrical atmosphere n*y in N1, -is℃tel 5%n-riff1
yl) ff) J-/hexane 42mg (11067m
ol) Add from tka@'*4tk. in a solution of kernels
8-oxo-2,2-dimethy*-S-oxer-1-aza
Bicyclo C4,2゜0〕Occlin 4.65f (0,0
3 mol) water? ) Foot drop 730IIt
Add liquid J for 20 minutes while stirring. 10
After 6.5 minutes, this mixture contains diphenylene to disulfide 6.5
Dorofuran 30 to anhydrous tetra of 4IC0,03 O1)
Keeping the w1W solution at a temperature of -73°C or lower, the KI [
It drips. After stirring this mixture for 110 minutes, m
Pour into Wakoka ammonium water (150g?) under ice cooling,
Separate the detoxhydrofuran layer and add 11 liters of water to ethyl acetate.
Extract with Combine the organic layers and add 0.5 M MaOTl
, water and then drying (lia, 804) L solvent
to remove. Convert the residue to isopropyl ether.
When II&, the trans isomer of the title compound forms colorless crystals (
5,72f). Concentrate the crystallization mother liquor and remove the residue.
Kahum chromatography using distillate fV Rikage lJ/
- (hexane-ethyl acetate-4:1), further K
Colorless solids of IJ3F (total yield 7.051, 89.3%)
Crystals are obtained. Melting point 49-51°C. From J/"j013: 174G1n&X old i B (60M II s - CDCl5)':
L 20-1-6" or 3M. 8X2 # -CHsX2) m 1.9 < 21,
m, -CH2->. 3=4 (I II m m -> CH-N <
4177 (2H2m. -CH20-)s195 (IH, d, J-2H2゜
-8>C11CO-), 7.1-7.5 (5H, m
, arom, H) Elemental analysis value C□J□-o,s Calculated value: C63,85 + H6,51; x 5.3
2-cell measurement value: C64,OOs H6,431315,1
8 Obtained by concentrating the crystallization mother liquor of the trans isomer produced above.
NMII of oily substance (116f)? The spectrum μ is
In addition to the above absorption derived from the lance isomer, the title compound
Absorption originating from the cis form (CDCl, medium. 14, @ 0, J -5Hz, C(7)H>$11
1414. Reference example 2 7-(1-hydroxy-1-methyμethyl/%/)-7
-phenylthio-8-oxo-2,2-dimethy14/-
3-#ki t-17 Zabi S/ri t2C4,2,0) Octa
(1) T-phenylthio-8-oxo-2,2-di) f
1L/-3-oxa-1-azabicycloC4,2. 0] Manufacturing method from octane Diisopropylamine 3.16 s/ (22,5mm
ol) anhydrous tetofhydrofufun somtl # solution
Atmosphere fig, 15$n-7μ lithium/h at -78℃
Stir 15m (24,0mmol) of xane for 1k
Add. Trans-1-phenylthio is added to this fa liquid.
8-oxo-2,2-dimethylm3-oxa-1-aza
Bicyclo (4,-2,0) octane & 95f (15mm
ol) anhydrous Tetof hFa:yfun 15s/1III/
Add II at -18°C and stir for 10 minutes. Then anhydrous
After adding 5 mt of acetone and stirring for 30 minutes, reaction a
Te acid (4d) - in water (150sZ) at an internal temperature of 5℃ or less
Add while stirring and separate the organic layer. Remove the aqueous layer with acetic acid.
After extraction with water, the organic layers were combined, washed with water, and dried (N
a2804) L, distill off the solvent. M sound thing is iso
The title compound when treated with propyl ether and hexane
A substance is a mixture of isomers A and B (from MMB spectrum μ to mu
Obtained as colorless crystals (3,50f) of B-about 2.4=1)
It will be done. Concentrate the crystallization mother liquor and remove the residue by cuffing using licagel.
Fuchromatogutphy (hexane-ethyl acetate A'-4:
1,1:1), output @11 [1I4 (recovery (L16
f)>! and mark j [l substance < isomer A) 1.1 (total yield 4
．． 5Of, based on 91.2% unrecovered raw materials) are each colorless.
Obtained as crystals. Isomers. ! A part of the mixture was chromatographed using silica gel.
Goufui (hexane-ethyl acetate A/-4:1.1:1
) to obtain isomers A and B as colorless crystals. So
Their physical properties are as follows. Isomer A (main substance) 2 points 95-97℃ zi+ AINujol 31:347G, 1725
1aX IMI (100MHz, CDC13)':
1.33 * L4 G (3H, sX2.-CH each
,1$2)-1,56(611f8m-CH3X 2
) -1-70 (I K -Ken->C<a)
-130(1" am ->C<x) 1,3-
7-4-1 (3kl, trr -> CHI <
. -Cl Kano) Elemental analysis value C engineering, Ii, l03B Calculated value: c 63.52; H7,21; M 4.
36 Actual value: c 63.49B M? , 25; M
4.45 isomer l (minor product): Melting point 188-189℃ ■l Carp 3: 3430, 17201aX I ml (100MHz, CDC13)':
a 65-1-42-1.58, 1.68 (3H each
m s ×4 y -CH3 × 4) * 1.75 (
IM, Peng, >c<; ), 2.92 (IH, Otori, >C
(Dan). 14-18<3i, m, >cll-summer<, -CH
20-) Elemental analysis value C engineering, H23No3B Calculated value: C63,52! H7,216M 4.36 fruit
Measurement, value: C63,3511I 7.13; m 4.
46(2) 8-oxo-2,2-cymethyA/-3-oxo
Thor 1 - Azabi V Kuro [Rumor, 2.0] Made from octane
Method diiso FG vinyl amine 1.74s/(12mmol)
Anhydrous tetrahydrofurin 211sfM solution was subjected to an electric atmosphere test.
Bottom, 15% n-1 chilllithium/hexane &
Add 4sg (13mmol). This solution contains 8-
Oxo-2,2-dimethyA/-3-oxer-1-azabi
V-chromo(4,2,0)octane (193fc6 mol
) of anhydrous tetrahydrofuran for 10 minutes.
Add while stirring, and continue stirring for 5 minutes. Add to this mixture diphenyldisμF1.31f (6
mmol) of anhydrous tetrahydrofufun 6s [*internal temperature -
Keep the temperature below 73°C and drip for 15 minutes, then leave for 5 minutes.
Mix the mixture and add 2IIt of anhydrous acetone for 5 minutes.
Stir for a while. Saturate this reaction mixture with ammonium agglomerate
Water (50 WIt) and acetic acid f! In a mixed solution of <30w1>
While cooling (-10°C), add to the mackerel while stirring with your fists.
Separate the organic layer and extract the aqueous layer with t# acid ethyl chloride. organic layer
After combining and sequentially washing with Q, 5 M NaOH, and water,
Dry (N5LZSO4) and evaporate the solvent. Residue
Treatment of the distillate with hexane yields the title compound (isomer mixture)
, IM]il spectrum shows that the mixture is about 20:1) and is colorless.
Obtained as crystals (1.36f). Concentrate crystallization mother liquor
Kafuri Ichimatogufu using AM T silica gel
-(hexane-Hp1mx+py-4, 1,1:l)
When attached to Tofunsu T-phenylthio-8-oxo-2
, 2-dimethyμm3-oxy+-1-azabicycloC4.
2. QE octane a O 4 1, am compound 111
f) 1LWk body B0.03F, kjUlkWk body AL1
31 (combined 1.52f, 79.0 whisper) each
Obtained as colorless crystals. Reference example 3 T-methylthio 8-oxo 2,2-dime 1,000 μm3-
O I+-1-7 Zabi5yPac4.2.0]Octanes)4 So7"a Hifiyl t N o.z 5sJ
(1.4 mmol) of anhydrous tetrahydrofubu
5 5rjl [Kil Soho Surroundings, 15≦ at -78℃
n-butyllithium/hexane 1. 0ml (1.
8 mmol) Add 1k while stirring. Ko(
f) MftLVC-7 9-, t*so2 at 8℃,
2-dimethyA/-3-oxer 1-azabicyclo [4. 2,0] Oct/7 1 5 5v(l mmol
) for 10 minutes by adding 1d solution of anhydrous tetrahydrofuran.
Stir for a while. Translated by Jimechiμ JisuμFα1-1
After stirring for 15 minutes, the reaction mixture was completely saturated with ammonium chloride.
Add ice-cold water to Monium water and extract with ethyl butyrate. Lottery
After washing the effluent with water, dry (Na, 80, )L, #ll medium.
to remove. Scrape the residue using A/￥
p matogufui (hexane-#acid ethyl μm 3:
l) K-attached 41M compound (Xi!), l+mixture
) as a colorless oil (1401ijF, 70%)
can get. NMR (5QMHz, CDC1,)': 1
, 23.1.75 (6 3H. 8X2, -C■s ”2)t 1.3 (2H, fat,
-CH2-). 2, 1 11 (3H-s, -CM5
) - 3.4-4.3 (4H, m. -B-C1ll<, >CM-N<, -CH20
-) Reference example 4 T-(1-hyphrokiv-1-methypethyne-7-methy
ruthio-8-oxo-2,2-zomethyum3-oxer
1-Azabicyclo r4.2.0) Octane N4 Solobi A/7 Mi7Q. 25m (1.4
mmol) of anhydrous tetrahydrofufun 5Iat bath solution K
Il raw atmosphere, 15% n-gurichikufu at -18℃
/Hexane1. 0 yd (1.6 mmol
) t*kimase & kara addition, do. Reference example 3 for Jin's M liquid
The obtained I-methylthio-8-oxo-2, 2-1'
Chill-3-oxa-1-1f hissy? RoC 4, 2
, 0) Ok IIin I 4 011 (a 7 x
awrol> 1 m solution of anhydrous tetrahydrofuran
Add at 8°C and stir for 10 minutes. Then anhydrous acetone
After adding α5+wJt and stirring for 15 minutes, the reaction solution was saturated.
Add 1 scoop of water-cooled ammonium chloride to water and add with ethyl acetate.
Extract. The extract was washed with water and dried (ma, 80
,) L, dissolve at distillation. Remove the residue using silica gel
Column chromatography (ethyl chloride)
3=1) gives two isomers of the title compound (4,B)
You get it. 2 (isomer) Colorless crystal Yield: 95 drops (52.81
)Melting point 95-97℃ IRshi':,':'ai''': 3410.172
0 old gB (60MHz, CDC13) I: 1.27
．． 1.43゜1.4L 1,72 (3H each, ax4
, -CH3×4) ht, 8 (2H= in
, -CH2-) #2-35 (3H, s. -8CH3),! ? −4,0(3H,m, >CH−
14<. -CH0-) Elemental analysis value Cl2H2,N03S Calculated value: c 55.57; H8,16; M 5.
40 fresh measurement value: c 55.23; H8,00; H
5,49 isomer 1: colorless oil yield 101v (5
, 6%) IRJ/N'3&tai1: 3450. 1
740Wk&X Old IRC60MHz-CDC13) J: 1.37
, 1.47. 1.63, 1.80 (31' each) B ×4 a
-CM3X4) +1.9 (2H, m, -CH
@-)-2,23(3H18--8CH3)-17-
4,1 (3H, vn, > CM-N < . -CH20-') Reference example 5 T-(2-bisaitvthio)-8-oxo-2゜2-di
Methyl-3-oxa-1-azabicyclo(4,2,0)
Octane diiso 10 bi-amine a, 56s/ (4, Ommol
) of anhydrous tetrahydrofuran 10 - Nitrogen atmosphere for melting
Bottom, 15% n-lithium/hexane 2 at -78°C
．． 7IIl (4,3!1111101) t Stir
Add while doing so. Add 8-oxo-2,2-dimethylene to this solution.
Ru-3-oxa-1-azabicycloC4,2,0]oc
! 310 Da (2, Ommol) of anhydrous tetrahydro
Add Fufun 2d solution. Then di(2-viridifi/
) No disulfide 440# (2, Ommol)
Add Water Tetofhi F Lofuran 2d bath solution and stir for 15 minutes.
Mix. Pour the reaction solution into saturated anhydrous sodium chloride water under ice-cooling.
and extract with ethyl acetate. The extract was washed with 1iaOH for 1 summer.
After sequentially washing with water, dry (N to So,) and distill off the solvent.
. Dab the residue using silica gel
When attached to E (#acid ethyl--hegisan-1:2), it becomes a title.
The compound (trans isomer) is an oily substance (396 Da, 74.9%)
obtained as. In, Naat,,,i l, 1rs
. 11aX NMR (60MHz, CDC13) a: i, 41
．． 180 (each a ur s X2 v -C
M, ×2)s 2.0 < 2 ■t m+-〇 M
t-) , & 6 (I H# Ill -> CHN
< ) -185 (2H9 Otori, -CH,O-), 4.
66 (IH, d, J-2Hz, >CI-Go-), 6
．． 9-7.8 (41d, m, aroma, H) Reference Example 6 7-(1-HydroxyV-1-methyethyl)-7-(2
-Biridylthio)-8-oxo-2,2-dimethyA/-
3-oxer 1-azabicyclo[4゜2.0]octane diisopropyl amine α63Mt (4.5 mmol)
Anhydrous tetofhydrofufun 17w1 bath solution under nitrogen atmosphere,
15sn-butyllithium/hexane 3wt at -18℃
(4.8 mmol) was added while stirring. This solution
7-(2-pyridylthio)-8-oxo-2,2-di
Methyl m3-oxa-1-azabi V-chloro(4,2,0)
Octane 793 da (3,0 mol) anhydrous tetrahydride
Lofuran 4IIt# solution was added at -78°C, then anhydrous aqueous solution was added.
Add 1.0 s/t of setone and stir for 30 minutes. Reaction solution t# Aqueous phase liquid (30Id) containing acid (0,8IIl)
) Under water cooling inside, or I! Add while stirring. acid back into the mixture
Add aqueous sodium to adjust the pH to 7 and extract with ethyl acetate.
do. After washing the extract with saturated saline, drying (NagSO
4) Distill the L solvent. Using residue t silica gel
Column chromatography (ethyl acetate-hexane-1
:2゜2:1), the title compound (isomer mixture) is
Obtained as pale yellow crystals (773'lF, 80.0°C)
Ru. One point 124-125℃ (decomposition) IRJ/KBrz1:1735 ax 111<90MHz, CDC13) I: 1.3
0, 1.4G, 1.64°1, 70 (α9H,
sx4. -cH3x4), i, 39°1.41.1.4
9.1.71 (each 2゜I H, 8X4, -CH2N2
). 1.0-L @ (I H, *->C<a)
, L 8-2.3 (IH, m, >C< ), 3.
72 (2H, 臘, -CM, O-). 4.15 (IH, da, J-10, 5Hz, >CH-N
< ). 7.0-7.8 (3H2m, arom, ■), &3(i
H, a+. aromami, il) Elemental analysis value C16H2gC16H2 Calculated value: C59,60t H6,87; M 11.
68 dormitory measurements: c 59.49; H7,17; N
s. 61 Reference Example 1 7-(1-(2-methoxyethoxymethoxy)-1-methoxy)
Chi-N]-7-phenylthio-8-oxo-2,2
-8'MethiA/-3-oxa-1-azabicyclo [Dou,
2.0) Octane 7-[1-hydroxy-1-methylethyl]-8-oxy
So-2,2-dimethy14/-3-oxer1-azabi V
Talo(4,2,0)octane (II in (1) of Reference Example 2)
369 MIg (1,15 mmol)
Diisopropylethylamine in methylene chloride 6dlIII solution
A60a? (145 mmol) and 2-methoxyV
Etok V methy μ chloride a39yd (142 bile mol
) and stir for 5 hours at a rich temperature under an electric atmosphere. Sara
KsIF iso10 biμethylamine 0.20d (1,
15gaol) and 2-meFki V etkinmechiku
In addition to lorido a13Id (1.13 mmol), 1
After standing at home temperature for 4 hours, the reaction solution was mixed with water, 2% acetic acid and water.
Wash and dry in sequence with (NJ12804) L. Solvent is distilled off.
Wow. Cafum black using residue t5/Rikagu 1L/
Matogufui (Ethi μ ether-hexane-1:1,
3:1), raw material (recovery) 132q and title
Compound 264 Da (87.4% based on unrecovered raw materials, colorless oil)
) is obtained. Neat -1゜IR-01, 1750 MMR (60MHz, CDCl5) I: 1
．． 40 (61, s. -CH5x2), 1.51, 1.62 (3H, 1I, respectively)
X2゜-Cl, X2), about L 8 (2H2m --C
Hg-) e 141 (3H, s, -0CH3), 1
47-4.3 (711, m. > CH-N < , -oca2- X 3 )
-4-83 (2H, a5-OCR20-) *7.
1-7.9 (51, m, aroma, H) Reference example 8 7-(1-hydroxy-1-methyμethyl A/)-8-mono
xo2.2-8'methiμm3-oxa-1-azabisi
Black (4,2,0) octane (1)? -(1- Hiroki
V-1-methyμethyμ)-1-phenylthio-8-oxy
So-2,2-dimethyfi/-3-oxer-1-azabisi
ChloroC4,2,0) octane (JK type) and water bulking
Isomer 4160'l (0.5 mmo
l). Azobisiso 1 t, 4/16N (α1 mmol
) and tri-n-butyltin hydride α435d (1,
6 layers! 101) in acetone 5all solution under nitrogen atmosphere.
, and heated to reflux for 16 hours. Melting #1. and remove the residue by distillation.
Power chromatography using V lyca gel (hexa
- Ethyl acetate 1v-1:1) When attached with K, the ala compound f
) S/) Body 771'lF (72,2%)
24”f (215%) of each substance was obtained as colorless crystals.
Ru. Cis form: melting point 125127°C Iujol. I IIi&m&3cd, 3450. 172
ONMR (60MHz, CDCl3)':
1.30-t, 43.1.50-180 (3 each
H* a x 4 , -cm3X 4 ) r t,
9 (2H+ll5-0%-), 3.27 (IH, d,
J=5Hz. >CI-Co-), 3.1-4. IC3H,vn,>C
H-N<. -CHlO-) Mass spectrometry Grave/e: 213 (M”) Elemental analysis value C
Engineering town, NO3 Calculated value: C61,94 answer n 8.98; x 6.5
7* Measured value: c 61.68; H8,85; II
6.73 trans isomer: melting point 102-104°C III J/Nuj016': 3450. 17
20nax IMB (60MHz, CDCl) J: 1.30
, 1.37.1.431.77 (each 4311.sx4
．． -013 ×4), 1.9 (2Hs rich, -C1,-
) s 2.91 (1n, d, J-2Hz
. >CM-GO-), 3.5-4.1 (3H, m
, >CH-M< . -CH, O-) Elemental analysis value C□□H19Jio3 Total I value: C61,94; H8,98 gates M 6.57
*S value: c 62.07; n 8.90; x 6
．． 52(2)7-(1-hydroquine-1-methylethylμ
)-1-phenylthio-8-oxo-2,2-dimethy,
4/-3-oxer 1-azabicycloC4,2゜o〕
Octane A substance FA) and hydrogenated tri-n-buty! tin
In the manufacturing method reference example 2 from
+ol). Azobisiso 1 Tyroni)! JA'8W (ao 5mm
ol) and hydrogenation)! 1-n-buty tin 0.22s
? ((18d cabinet.l) acetone 3-solution in an electric atmosphere
Heat to reflux for 5 hours. The solvent was distilled off and the residue was
Kahumutaromatogufui using Kage μ (hexane)
When subjected to ethyl acetate/%/-1:1), the cis
body 371v (7aO%) and trans body 121f (2
2.6%) are obtained as colorless crystals. (3) 7-(1-hydroxyV-1-methylethyl)-7
-pheniμthio 8-oxo-2,2-dimethyl-3-
Oxa-1-azabi V black (4,2゜0) Ok!n (different
compound) and tri-n-butyltin hydride?
In the production method reference example 2 of et al.
4:1)2aOf (62mmol), azo
Bisisobutyronitri A'101 (12m5nol
) and tri-n-methyltin hydride56.4-(21
0 mmol) of 77 tons 500 Wt melt f & til
The tube was heated to reflux for 16 hours. Distill the solvent and leave the residue
Add 100 ml of chloride to the distillate and remove insoluble matter.
Filter using a filter. Concentrate the filtrate and isolate the residue.
When propylene ether μ is added to % coral, 27 Il-compounds 8
．． 13 F is obtained as colorless crystals. Concentrate the crystallization mother liquor.
Condensed and the residue tV Lioghe/I/l-Used Kahum Chroma
Attached to tographie (hexane-acetic acid?A/-1:1)
Then, an additional cis isomer 1.7 (1 (total yield! 1.83F
(74,1%)) and trans-isomer 2.61F (19,
7%) are obtained as colorless crystals. (4)? -(1-Hydroquine-1-methylethyl A')-
7-phenylthio-8-oxo-2,2-dimethyl-3
-oxa-1-7zabiycro(4,2゜0)octane(
Isomer A! mixture) and hydrogenated triphenyls
A mixture of isomers A and A obtained in Production Process Reference Example 2 (proportionally 20
: 1) 1501F (α4 (i mmol)
, Azobi x y7f-a=,) 9A/15IIi/(
α09 mmol) and triphenyltin hydride a
Add 32f (0.92 mmaol) of A7ton 4sn solution.
Heat under reflux for 22 hours in a phonetic atmosphere. 1III medium is distilled
Add a small amount of Yudaroform to the residue,
Filtration using t-filter. Concentrate the filtrate and reduce the residue tV
Likage/L'l used Kafumu chromatoku' Fufui (he)
When attached to xane-ethyl acetate (j'l/-1:1), the standardization
27 compounds 81WII (79,7≦) and trans
171v (16.3%) of each body was obtained as colorless crystals.
Ru. (6)? -(1-hydroxyV 1-methylethyl)-1
-methylthio-8-oxo-2,2-dimethyl-3-o
xa-1-azabicycloC4,2,0)octane (isomer
95 da (α37 mmol) of the ^-isomer obtained in Reference Example 4 of the production process from tri-n-glytin hydride and n-glytin hydride. Azobisisobutyronitri A'l 1ml (107mm
01) and hydrogenation)! j-n-buti~tin α32sJ
(1,2 mol) of acetone 3D solution in a phonetic atmosphere.
Heat under reflux for 17 hours. The solvent was distilled off and the residue
Power chromatography using Kageμ (hexane-
Ethyl acetate/l'-1:1) When attached with K, the starting material (recovery, 6
5III), cis form of the title compound IT Shizuku (6 & 8%, unsaturated)
(based on recovered raw materials) and trans isomer 4# (1621,
(based on unrecovered raw materials) are obtained as colorless crystals. (6) 7-(1-hydroxyS/-1-methylethyl)
-7-(2-pyridylthio)-8-oxo-2゜2-cy
Methi~-3-oxer 1-azabi V KuroC4,2,0)
Obtained in Production Method Reference Example 6 from octane and tri-n-butyltin hydride? -(+-hydroxy-1-methy~ethyl
/&/)-7-<2-pyridylthio)-8-oxo-2
,2-dimethyA/-3-oxt-1-azabi V taro [4
,2,0) octane (mixture of isomers) 500IjI(1
, 55 fin O1), azobisisobutyronitrile 50~(
Q, 3 mmol) and hydrogenated tri-n-butylvnus
゛1.45s/(5.3mmol) of acetone 13
mg solution in an atmosphere of FFI and heated for 16 hours. The solvent was distilled off and the residue was used to make Kahumukuro.
matoguffy (ben(-acetone)-10:1,5:
l), the raw material (one isomer G one point 162i64℃
(Disassembly). 1301F), and the cis form of the title compound 143417
1 whisper, based on unrecovered raw materials), 41 Mg of tofunsu (1
512%, based on unrecovered raw materials) respectively as colorless crystals.
obtain). Physical property values of the compounds obtained in (2) to (4) above (one point
. IP and IME spectrum Iv) are those obtained in (1) above.
It matched that of the. Reference example 9 V suit-(i-(2-methoxyV ethoxymethoxyV)-
1-Methi! Ethyl]-8-oxo-2゜2-dimethyw-
3-Oxer 1-Azabi V Kuro C4,2,0) Octane (1) V Suit-(1-HiFrokiV-i-Methi~Ethi*
)-8-oxo-2,2-dimethyl-3-oxa-1-
Process for preparation from azabicycloC4,2,0)octane cis-7-(1-hydroquine-1-methyμethy)-g
-oxo-2e2-dimethyw-3-oxer1-azabi
V black (4,2,0) octane 7.00f (33mmo
Add 1 lipie of diiso to 130gt methylene chloride bath solution of l).
Thiamine 18.92IIIt (1011 mmol)
and 2-methoxyV ethoxyV methylta 1:19F12.40
mg (109 mmol) was added, and the mixture was heated to room temperature under an electric atmosphere.
Let stand for 21 hours. The reaction solution was mixed with water, 2% acetic acid water, and Kazugan clams.
After sequentially washing with oxyhydrogen solution and water, dry.
Na280. ) L, when the solvent was distilled off, the title compound was obtained.
Quantitatively determined as a pale yellow oil. Neat -1. IN ~8□ 3.175O NMR bar 60MH2, CDCl3)a: 1.27
．． 1.35.1.45°1.65 (3H, eX4.
-CH5X4), ca, 1.9 (2H, m, -C
H2-), 3.10 (IH, d, Jw-5H2゜-C
HCo-) -3,30(31,s, -0CH3)
-3-3-19 (6i[,in, -〇HzO-×3
) p 4,78 (2He ” e-OCH,O-
) Wei)? -CI-(2-methoxyethoxyVmethoxy)
-1-MethiμEthi#)-7-PhenyμThio 8-Oxo
-2,2-dimethyA/-3-oxer1-azabi V-chloride
C4,2,0) Preparation from octane 7-(1-(2-methane)
Toki V Etoki V MeFki V)-1-Methi~Echi*)-7-
Phenylthio-8=oxo-2,2-cymethyA/-3-
Oxer 1-azabicyclo(4,2,0)octane 26
0q (Q, li4 mmol), azobisisobutylene
Lonitri μ21q (αl 3 mmol), hydrogenated
Tree n-Buchi μ tin A5 Hatake-(2,13mm01)
and acetone 5wl solution tl [bulk # under atmosphere, heated for 17 hours]
Heat reflux. Distill the solution #& and put the residue into a cuff using V Rikage fi/.
Mukp Matogufui (hexane-ethyl acetate-2:1
, 1:2) K indicates that the title compound is its tofus isomer.
(IM
Determined from T3 spectrum μ); colorless oil s164Mg)
obtained as. Reference Example 10 C, c-4-(2-: Floki V ethiμ)-3-CI-
(2-methoxyethoxyVmethoxyV)-1-methyNethylμ
]A(thidine-2-one V-7-(1-(2-methoxyV ethoxymethoxyV)-
1-MethiμEthiμ]-8-oxo-2゜2-t)MethiI
4/-3-oxa-1-azabinclo(4,2,0)o
Cutane 603”f (2mmol) fc narcotic acid (14m)
and water (12 m) and stir at room temperature at 8 o'clock.
Zeru. Add chloroform to the reaction solution and remove the solvent under reduced pressure.
leave When the residue is treated with ethymu-ether, it becomes sulfuric.
The compound was obtained as colorless crystals (345q, 66.0 hiss).
Ru. From melting point 75-76℃, νNL'j010g": 32g0.3200.
1720ax IMm (90MHz, CDC13)': i, 36
= 1.50 (3H each, @x2.-CH5x2)
, 2.0-2.3 (2Lmm-C-CHgOH), 1
6 (IH, b, -0H), 128 (IH. d, 7m5Hz, >CHCO-), 3.31C3He8
#-ocn3), 3.4-4.0 (7ii, m, -cm
2c tan 20h. 〉CdanIH-, -ocn2cnlo-), 4.83
(2H, s. -0CR20-), 6.6 (IH, b, -NH-) elements
Elementary analysis value Cl2 MB2 N05 Calculation: c 55.15s H8,87; I 5.
31i screen measurement value: C54°75SH9,097N 5.5
4 Reference Example 11 V-3 (1-(2-methoxye)If3'methoxyV)
-1-methyμethyl)-4-(2-oxoethyl)a(
Tidine-2-one Anhydrous pyridine α32- in 1 layer of methylene chloride (6ml)
Add 2001v of lime acid and stir at room temperature for 15 minutes.
. Add to this mixture Vcou 4-(2-hydroxyethyl/u)
-3-(1-(2-methoxyV ethoxymethoxyV)-1-
methyl ethyl μ] azetidin-2-one 110”f (a4
Add 2 mmol) of methylene chloride 1s [* and bring to room temperature.
Stir for 15 minutes. The reaction solution was filtered using cerai) and washed with methylene chloride.
do. Concentrate the filtrate and dissolve the residue in ethyl acetate.
The dissolved portion is filtered again using Cephite, and the filtrate is concentrated. The residue was chromatographed using silicage μ.
(butyric acid ethyl fi-/), the target compound turns out to be a colorless oil.
(70 Da, 64%). II #””ar”: 329Q, 1750.1720
aX JIME (60Mll5, CDCl5)':
1.33-1.51 (3M each, eX2.-C11
, ¥2), 13B (3Ht13$-0CH3), 12
-4.3 (8H,yx, >CHCO-. >C3i-1j<, -CH!, Co-, -CH20
-¥2), 4.85 (2H, s, -0CH20-)
-6,4(IH-b, -HH-). 9.96 (IH, s, -CHO) Reference Example 12 2.2-V cloheki V-8-oxo-3-oxt-1
-AzabicycloC4,2,0)octane 4-(2-HiF
Loki V ethyl)-2-azetidinone LOf (17,3
mmol) and cyclohexanone 15 f (25
,5m]lol) of anhydrous methylene chloride #*K IF3
・Et20 (47%) 0.2 d (1,98n
ool) and stir at 25°C for 90 minutes. f # medium
was distilled off, and the residue [V Likagel] was
When attached to Guofi (hexane-ethyl acetate-1:2)
The title compound appears as colorless crystals ('1.8F, 53.3 whispers).
can be obtained. Melting point 71-72℃x R#KB r N
1, tra. Ma! 11MB (60MHz s CDCl5)':
L 38-2.40 (12H-Otori s-CH2￥6
' * L63 (I H+ d d # J, = l
4 # 2 HN t(6)H) 劃01(IH, dd,
J=I4,5HiyC(7)H). 320-3.72 (I H, m, C (6 voices), 3
．． 74-3.7! I (211゜grave, -C(4)H)
) Elemental analysis value CnH1'F”2 Calculated value: C67,66s H8,781M 7.17
Dormitory measurements: C67,57i H8,85t M 7.0
6 Reference Example 13 T-phenylthio-2,2-spiro V cloheki VA/-
@-Oxo 1-Azabi V Chlo(4,2゜0)Oc I V Isopropylamine 1.89s/(13,5 mmol
) was added to a solution of 40 mg of anhydrous tetofhydro7 with nitrogen surroundings.
15% n-buty~lithium/hequina at -78°C
While stirring 79d (l 4.4 mmol)
Kael. Add 2,2-spirocyclohexyl V-8 to this solution.
-oxo-3-oxa-21-azabicyclo(4,2,
'O) Octane 1.76'f (9wool) nothing
Drop the solution for 10 seconds/10 minutes
Stir. Then, to this mixture is added
F 1.96 f (9, mmol) of anhydrous tet
FuhiFshifufun8'Id Keep the bath liquid at an internal temperature of -70℃ or higher.
Add it dropwise and stir for 10 minutes. This mixture is saturated with chloride
Add Ancenicum to water under ice cooling, Te) 71:F Rofun
The layers are separated and the aqueous layer is extracted with ethyl acetate. Combine the organic layers
Washed with a5M NaOH and water sequentially, and dried.
After xa 2s o a ), the solvent is distilled off. residue [
When exposed with isopropylede μ, the title compound, trans
One piece is obtained as colorless crystals (1,42f). crystallization
Concentrate the mother liquor and transfer the residue to Kahumukuro using v9 Kagel.
Subjected to Matogufui (hexane-ethyl acetate-41)
and further trans isomer α55f (total yield j11.97f
. 72.2%), and 27 bodies of the title compound 0.08 F
(2.9%) is obtained as colorless crystals. Trans form: melting point 133-134°C IBIIhj01aIr1: 1730, 1nlLX MQ, B, < 90 MHz, CDC13)
': 0.8-2.4 (j 2 H. Otori--Shima-¥6>, a, 4 (1 town?ra,>CH-N<
). 3, I, 7. (211,m, -CHllO-), 3.
88 (IH, d, J-7Hz, 8>CB-, -Go
-), t 7.2'-7,6 (5H mountain rom, H) Original rate analysis value C engineering, H2□MO1!3 Calculated value: c 67.30; 118. Q+ x 4.
62nd dormitory measurement: C67,24; H6,771M 4.
From 37V body two points 134-135℃, Tl: 1725 Otori & X 111B (110MHz, CDC13) J: 1.
$-2,4<12a. Ugly 5-CH2-×6) a 18-4-0 (3Hz
m#>Cl-1<, -CH,20-), 4.
60 (IH, d, J-5Hz. -8>CB-CO-), 7.2-7.5 (511
,m,arom,H) Elemental analysis value C1'/"g□m
o, s Calculated value: C67,30s H6,98; M
4.62 unexpected value: C66,94; H6,98i
M 4.69 Reference #114 7-(Hot-Hiroki#/-1-MechiyEchiμ)-7-7
x2μ, t-2,2-subirocyclohexypy-a-
Oquin-1-azabicycloC4,2,0)octanediyne 10 biμamine α83g/(5,9a+mol
) to 20 dllj of anhydrous tetrahydrofuran solution,
Atmosphere [lower, 15% n-gff1yUftum/
Heki9n4d (6.4 mmol)! While stirring
Add. Trans-1-phenylthio-2,
2-spiro V clohexa$/A/-9-oxo-1-aza
BiV Kuro (4,2,0) Octane 121f (4,0mm
ol) Add anhydrous Detofuhhi F Rofufun 9I# solution to 78
Add at °C and stir for 15 minutes. Then anhydrous acetone 1
．． After adding 51 dt and stirring for 30 minutes, the mixture was saturated.
Add tetofhydrofufu to ammonium chloride water under ice cooling.
After extracting the aqueous layer with ethyl tII acid,
Combine the machine layers, wash with water, dry (Iaz804)
Distill the medium. Column using Silicage A/IP for the residue
Chromatography (hexane-ethyl acetate"4:II:
l), l[I4 (recovery, Q, 13f) and mark
Title compound (isomer mixture) 1.03fl1%, unresolved 1
[1 [based on the material] is obtained as colorless crystals. Melting point 9B-100°C MMII (90MHz-CDCls)':
1.3-2-3 (eye I. layer, -cH3x2, -cH2-I6), 3.4
-4.1 (3H, breath. >cm-summer<,-cm2o->,?-2-7.7(
5H, Peng. aro heavy, H) Elemental analysis value C2oH,, No, 8 Calculated value: C66,45; H7,53! H3,8? dormitory
Measured value: C66,53; H7,56t N 4.09
Reference example 15 7-(1-hyphrokiV-1-methipethiμ)-2,2-
spiroV clohexaVμm8-oxo-1-azabicyclo
(4,2,0)Octane Reference Example 14-t"N7't7-
(1-4)'R*! /-1-Methi~Ethi*)-7-Fue
2 μ thio 2,2-subirocyclohexyl $/A/-8-o
Xo-1-azabicyclo(4,2,0)octane 870
"IF (2,4 mol). Azobisisobutyronitri* 87111 (0,53 mol)
■o, l) and hydrogenated n-)! j-butyltin 110
d (7.9 mmol) in 25 m/solution of acetone.
Heat to reflux at 14:00 under bare atmosphere. Distill ## &;
Column chromatography using residue t1/9kageμ
-(hexane-ethyl acetate*-1:1) gives the title compound
77 bodies of 450# (73.8%), and trans body
120q (19,7 hiss) each obtained as colorless crystals
. V-substance: melting point 153-154℃, hI: &Y1or-': 3500.17
20IMB (90MHs * CDCl3)'
: t, 27 m L 47 (3 it each, sx2
．． -c ■, I2 > , 1.3-3.0 < 121
1slls-CL, γ8), 118 (111, d, J-
5Hz, >ClIC0-). 18-3-9 (3H--->CH-N<, -C
H20-) Elemental analysis value C1-IrO3 Calculated value: C66,37; H9,15; M 5.5
3 surprises: C65,95; H9,08; M 5.
5G trans isomer: melting point 83-84°C Nujolml: 3500. J'm& from 171G
X IMR(10MHz-CDCl5)': 1-
27-L33 (3H each. s I2 e -CH3'2) * 1.3-14
(12He m , -Ci[1rX6) t2, TI
(1M, d, J"2Mg, > CHCO-) J5 (II. Otori = > Cto1 < ) a 11-8 (2H2m
--CHg0-)yI:, IK analysis value C14H23
IO3 calculation value: C66,37s Hil, 15; M
5.53*Fuchi value: C66,37g H9,02i
15.65 Reference Example 16 V suit-(1-(2-methoxyethoxyVmethoxyV)-
1-methy~ethy~)-2,2-subirocyclohexyl V~-
8-oxo3-oxa-1-azabicyclo(4,2,
0) Octane V Soo 1-(1-hydroxy!/-1-MethiIethiμ)-
2,2-Spiro V Kurohekki! /A/-8-oxo-3-
Oki t-t-y Zabi Vri ac4.2. L)) Octane 3
8011F (1.5 mmol) dissolved in methylene chloride 8d
Diiso 10 bits in the liquid! Amine 0.86s/(5,0
mmmol) and 2-methionyl
Add FQ, 56sF (5,0j) and heat at wi temperature 15
Let stand for a while. Furthermore, diiso-10-biethylamine 0.
086gd (0.5mmol) and 2-methoxyVe
Toki V Mechiμ Chron) 0.056s/(0.5mmo
After adding 1) and leaving it at room temperature for 1 hour, the reaction solution was washed with water and washed twice.
Wash sequentially with acid water and water, dry (Ha!, 80.)
When the solvent is distilled off, the 1lII%m compound becomes a pale yellow oil.
can be obtained quantitatively. ■・at l. Engineering R” lax car, 174G ■ Rei R (60M
Hz, CDCl5)': 1.27-L
47 (each 3H, ・X2.-CH, X2), 1.2-
2.7 (tau, Im. -CH2-x8), 3.13 (III, d, J-
5Hz. -a'H-CO-), 31.32 (3H,s,
-QC->, 3.4-3.9 (7H1m --CH
20-X 3- > CH-1i < ) a 4.8
G (2il mm, -0CR,0-) Reference example IT Vcou 4-carboxymethy A'-3-CI-(2-meth
xyethoxymethoxy)-1-methylethyl
Re-2-one (1) Vku-4-hydroxyethyl-3-[1-(
2-methoxyVethynemethoxy)-1-methylethyl~]
Production method from azetidin-2-one
EtkiVmeIF)-1-MethyμEthiμ]Azetidine-2
-on 26G”f (1 mmol) of acecin 10 jil
l solution with water-cooled F, Jones #ic drug (anhydrous pm acid 2
In addition to 71 tl1M 23- and water 40ato rope liquid,
Add water and make wI4 to make total volume tloO-.
In (2) to (4) below, good reagents prepared in this way are used for one month.
Add 1.5sZ and stir for 3 hours. -Reaction solution
After processing isopropanol and stirring for 5 minutes, chloride
Dilute with methylene and filter through Cephite. Filtrate [
After concentrating and dissolving the residue in Coulophore, add a small amount of saturated food.
Wash with lime water. Wjl, mackerel (M~so,)L, the solvent is distilled off. residue
tiso10bi! When treated with ether, the compound becomes free.
Obtained as colored crystals (21089, 7&, 4%). one
Point 87-89℃ III ν 3 :35GG-2800,176
5゜aX 730 11MI (90 violet Hz, CDCl5) a: 1
．． 33, 1.51 (each 311°aX2.-CHx2
), 2.7-14(3H, Peng, -CH, -Co-. >CTi1-CO-) -137(3H, s, Oc
H3) -3,4-3Ll(+l,m,-0CI,CM
lb->, 4.0(lHs"e>CH-summer H->,
4.83 (2H, -0CH20-), 7.2 (111,
b, -IH-), &6 (IH, b, -COOH) elemental content
Analytical value ClgHgINO6 Calculated value: C52,35g H7,69i ear 5.09-
Dormitory price: C52,50; lit, 41i
15.21(2) V no 3-(1-(2-methoxyeth)
ximethoxy V)-1-methyμethy~)-4-(2-oxy
Soechi μ) Manufacturing method from azethi V-2-one cis-3-
(1-(2-methoxyethoxymethoxyV)-1-methyl
ethyl)-4-(2-oxoethyl)a(thidine-2-
40”F (0.15 mmol) of acetone 1-dissolved
Add Nu-ns test@tLOamt to the liquid under ice cooling for 10 minutes.
Stir. Add isopropano ~0.1s/ to the reaction solution.
After stirring for 5 minutes, add methylene chloride and
Filter using a filter. Concentrate the filtrate and remove the residue with chloride solution.
Dissolve in tyrene, wash with a small amount of saturated saline water, and dry (Ia
z 804). The solvent was distilled off and the residue was
When treated with lopyl ether, the title compound forms colorless crystals (
33q, 80%). (3) V suit - (1-(2-Methoki V Etoki V MeFki
V)-1-methylethyl-8-oxo-2゜2-y
Chil-3-oxa-1-azabicycloC4,2,0)o
Production method from cutane 7-CI-(2-methoxymethoxy)-
1-methylethyl-8-oxo-2゜2-dimethyl-
3-oxa-1-azabi V-chloro(4,2,0)octane
10. Of(33mmol)β7-k)ton 330s/bath
Add Jones Wipe 1133s/l to the liquid under ice cooling at 4 o'clock.
At a moment's notice. Furthermore, add Jones reagent 16sr.
After stirring for 1.5 hours, add In 10 Panol 16 to the reaction solution.
Gradually add m and stir for 15 minutes. The reaction solution was diluted with chloride.
After diluting with tyrene (15Qsd), insoluble s'
Filter using a filter and concentrate the filtrate. Chloro in the residue*
Add 200s/t and wash with saturated saline (8/).
After cleaning, dry (lIa, 804) l,, leave the bath mtm
And, the l1iIlia compound is a colorless crystal (''1.241
, 80.1%). (4) Cis-? -(1-(2-methoxyethoxymethane)
Toxy-1-methylethyl)-2,2-spirositalohe
KiVI&-9-oxo-3-oxa-1-azabicyclo
M' cis-T-CI- from (4,2,0]octane
(2-Methoquinethoxymethoxy-1-methylethyl)
-2,2-subigV chlorohexy, py-@-oxo3
-oxer1-azabicyclo(4,2,0)okune5
10JV (1.5mmol) of acetone 15d# solution
Add 2.3sf' of Jones reagent to the solution under ice-cooling for 3 hours.
Or 1! Mix. Add 1.5 dt of iso-10 panol to the reaction solution.
After stirring for 5 minutes, dilute with diluted methylene,
Filter to remove Sat using a filter. Concentrate the filtrate and leave a residue
Dissolve it in Chlorop*lum and wash with a small amount of saturated saline. Dry (lm280.). Distill the water and remove the residue.
When treated with Soso 10 Viruete μ, the marked compound becomes colorless.
Obtained as crystal (270~, 65.6%). Il+ and N of the compounds obtained in (z) to (4) above
The MB spectrum μ is the same as that of the compound obtained in Section 1 (1).
It matched. Reference example 18 V-3-(1-(2-methoxyVethoxyVmethoxyV)-
1-methy)vethy/M)-4-(3-(4-nitrobene)
μoxycarboni1v)-2-oxoglobin〃〃a(
Tidine-2-one, V)-4-JF/l/boxime
Chi/'-3-(1-(2-Metoki V 工 [Ki V Me F Ki $/
)-1-methy~ethyμ]azetidin-2-one 7.78
F (28 mmol) of anhydrous tetrahydrofuran 230
1.1'-carbonyldiimidazo-f to m#F# at room temperature
Add i/6.37f (39 mmol) and stir for 6 hours.
Mix. This solution of mono-4-nitrobene acid
Genis Tl1lf)-1 Gune Vt Mujli 14.0
1 (28 mmol) ' and at room temperature for 17 hours.
Come on. Add ethyl acetate A/Vt to the reaction solution, dilute hydrochloric acid, and water.
After washing sequentially with water and water
, dry (Nano) 4 and distill off the II medium. Use the residue in V Rikage I4/Kura
When attached to Karafukuroi Todatsufi (ethyl acetate),
The compound is obtained as a pale yellow oil (10.50 f. 82.1%). XBI/”'at-1:3300.1760-172
0tax MIIB (60MIIz-CDCla)
a: t, 30, t, 48 (311°e each
X2 e -CH3×2 ) s & 33 (3H
m e s -OCH3) s 3.63 (2H-e
a-0001gCO-)-3-2-4-word (3H,
m. >CHCO-, >CHC! 4ACo-), 4.2
(I H,!I!.〉CI-Summer H-), 4.80 (211,s, -0CR
20-), 5.27(21,a, -OCRgAr)
, 6.52 (IH, bs , >Ml). 7.53 (2M, d, J=1111z, arom, H)
, 8.20 (2H, d, JmllHz, arom, I
I) Reference Example 9 V-4-[3-diazo-3-(4-nitrobenzyl)
KiνcarbonyA/)-2-oxopropyl]-3-(1
-(2-methoxyV ethoxymethoxyV)-1-methylethyl
] Aitidin-2-one V-3-CI-(2-meth)
EtkinmeFxy)-1-methylethyl)-4-[
3-(4-2)pbenzyloxyVcarbo=fi/)-2
-Oxo 10bi v] 1ze f9n-2-171G, 5f
(23,2 mol) of anhydrous acetonitrile/&/300
dlljflKO℃p-)Luens phoniμAjiF5
．． 48f (2″1.8 mmol) (i’) Anhydrous 7
-k)=)9. A/30mg% solution was added, and then Torie
Add 11.6wt (814mmol) of thylamine
. After stirring for 30 minutes under ilm except for cooling, the reaction solution
Add ethyl butyrate A/ to the solution, wash with saturated saline, and dry (I
ag8o,). The solvent is distilled off and the residue is removed using ttz liquid.
When attached to p-matoguffy (#acid ethyl, 4'), the title compound is obtained.
The product was obtained as colorless crystals (9,801, 8 x 3 t).
Ru. Melting point 97-91'C II'"Nu"13': aaso, 3210.
214G. 1111LX 1730, 1705. 1640 IMB (90MHz, CDC13)':'1
．． 37 jl, 53 (3H each. EIX2.-CB5X2), 137 (3H, 8, -0
CH3), 3.3-4.0 (VH, m, -CHC
o-, -Cl, Co-, -0CH2CH20-). 4.2 (11, m, >Cdan-NH-), 4.85 (2H
,s. -0CH20-), 5.40 (2H, a, -
OCHgAr), 6.33 (IH, bs, -11H-
), 7.57 (21, d, J = 11 Hz. arom, H), B27 (2H, d, J = 11 Hz,
aroma, H) Elemental analysis value CglHP! 6N409 Calculated value: C52,71i H5,48i N 11.
71 east value: c 52.291 H5,36; N
11.64 Reference Example 20 Vno 4-[3-diazo-3-(4-nitrobene S/A
/OkiV force~Boniy)-2-Oxo1pBiμ]-3-(
1-kF LokiV-1-Methi〃Ethiμ)Azetidine-2-
oncis-4-[3-diazo-3-(4-nitrobene v〃o
Kisy*A/bonip)-2-oxo10biru]-3-(
1-(2-methoxyVethoxyVmethoxyV)-1-methyleth
Chilcore (Tijin-2-one 1.0Of(2,1111
mol) of dry methylene chloride 42d solution under nitrogen atmosphere.
, 1.45 mg (112 mmol) of titanium tetrachloride at 0°C
)l and stir for 1 hour. The reaction solution was diluted with saturated potassium carbonate.
In a mixture of water (50 mg) and methylene chloride (50 af)
Add to the mixture while stirring at an internal temperature of 0°C. This mixture
Filter using a filter to separate the methylene chloride layer. water layer
After extracting with methylene, combine the organic layers and add water. Washed sequentially with dilute hydrochloric acid, 11 water, and water, and dried (Ha280.
) and distill off the solvent 5#! J4 Rumono T Ben (escapes with N)
Then, the title compound appears as pale yellow crystals of benzene solvate (0,
8Of, 81.7 whispers). Melting point: 90°C (solidifies once dissolved>, 154-155°C (
3400. 3310.2
130゜ax 1740.1880 1℃Mi (9G MHz, CDCl5)'
: 1.3 G −1,51 (3H each. sX2 m −0M3x2 ), 3.2-17 <
3H, IS, >CHCO-. -C1, -Co-), 4.1 (111, Peng, NCHMM
-), 5.36 (2H, s s -O0% Ar )
-& 2 (I H-b -> N H) -155(
21, d, J-9Hz, aroma, H), 8.27 (2
HtdtJ-9Hz, arom, H) Elemental analysis value C1'F B18 H4o, ・C6H6 needle
Calculated value: C58,97; H5,16; N 11.9
6I*Ghost value: C58,64t B5.23; N 1
1.82 Reference Example 21 5,6-$'su--(1-hydroxyV+'l-methy
ethyl)-1-azabicyclo(3,,2,0)
4-nitrobene-3,1-dione-2-bento acid
Dyl ester cis”-4-[3-diazo-3-(4-nitropendyl
OxycarponiN)-2-o, chirapropyl]-3-(
1-kF Loki S/-1-methy~ethy A/)a(thidine-
2-one (pen(en) solvate) 1.17f (2,5
Otori mol) and rhodium (II) acetate) 60J
V of anhydrous benzoate (125-125-suspension) for 10 minutes through an electrolyte.
and deoxidize it. Next, mix 1 & i1 search atmosphere 11 [lower, or
While stirring, heat at 78℃ for 45 minutes. Cool the reaction solution
After that, it is filtered using Cef4) and the solvent is distilled off under reduced pressure.
The compound is a colorless foam (0,!11f, 100%
B: Obtained as follows. IHwKBrta+': 3500. 1780-1
720 de &X IMR (90MHz, CDC13) J:1.28-1
．． 53 (3H#8×2 #-CH3×2 each)
+ 1.9 < I Hlb T-on) #
2.63 (IH, ddjJ-19, 7Hz, ->C<H
), 167 (iH, d, J-6Hz, >CHCO-),
196 (IH, dd. J=19.10Hz, >C<, ), 4.25 (IH
, m. O- 〉Cdan-nito→,4.70(IH,s,n11CIII
<). 0-5=30 (2H, ABq, J=16-1
3 Hz, -OCHgAr) -7,55(2
H, d, J = 9Hz, aroma, H), B27 (2H. d, J = 9Hz, aroma, H) This compound was
When treated with benzene, colorless crystals (1/3 mole of benzene
(including). Its physical properties were as follows. One point 55
-60°C (softening). IB wKBrcl': 3550,178G-1
720naX Original 31 min 4f [C,, H engineering, II, 07-1/3 C
6H6 calculated value: Csa, z6i H5, 19i H7
,21!11! Measured value: C58,7 odor H5,17iM
7.0 For the second step reaction, the solvent obtained by distilling off the solvent
The crude compound tvl was used. Reference Example 22 5 # 6- 'Su6-(1-(2-methoxyethoxyethoxy)
VmethoxyV)-1-methy~ethyl A/-1-azabicyclo
(3,2,0)hebutane-3,7-sion-2-
4-Nitrobene S/v SDE μ5 t 6 ”-
'su-4-(3-$/azo-3-(4-2)pbenzyl
oxoderobi-3(1-1
-methoxyV etho, etc.VmethoxyV) -1-methy~ethyβ]A
(Tidine-2-one 320”l (0,67mmol
) and Logi9A (1) Acetate 16q anhydrous benzene
Deoxygenate the suspension with nitrogen for 10 minutes. Then mix
Combined solution tWl element IF[C'F, -b-@18℃ while stirring
Heat for 50 minutes. After cooling the reaction solution, use Celite to
After filtering and distilling the solvent under reduced pressure, the title α product turns into a pale purple color.
Obtained as a colored oil (0.30f, 100%). IR&””=1:1780-1740 ax imn(60iniz,cnct3)a:1.30.1
．． 51 (31.1lX2.-Cl5X2 each), 2
．． 60 (IH, aa, J-18°7Hz, >C< )
, 130(3H,e''';-〇〇H3>s 3.4
-17 (5H,11,>Cl-Co, -0011,
CI, 0->. ■ 3.8-4.4 (2H mountain>C<dan,>CH-M< ),
4.65 (1n a e > to c II < ::
2), 4.71 (2H, a. -0CH20-), 5.20 (2H,s, -0CH2-
Ar), 7.42 (21, d, Js-9H1, aroof
fi, H), &1G (211, d. J-9Hz, aroma, H) This product was used for the reaction in the first step. Reference N25 T-(1-hydroxy-1-methy~ethyμ)-8-ox
So-2,2-dimethy, A/-3-oxt-1-azabi V
7-(1-) obtained in Reference Example 2
hydroxy(V-1-methyμethyl)-7-phenylthio-
8-oxo-2,2-t)me+5y-3-t*+-1-
yza'vlpw(4,2,0)octane (isomer A)
3.14 f (176m weight 01) and hydrogenated triphe;
~Tin 7,02 fC20,0 mmol) of acetate 1
00sJjll solution in a high pressure mercury lamp tube under nitrogen atmosphere
The sample is irradiated with light for 6 hours (inner temperature: 38°C-42°C). precipitation
After the sedimentation was filtered, the filtrate was concentrated and
Column chroma meter Gutufi (hexane-acetic acid) using /
ethyl, A'-1:2), 41[-17 compounds
1.567# (75,3 whisper) and trans body 0.36
3f (17,5 hiss) are each obtained as colorless crystals. number
The physical property values (melting point, XB and IME spectrum μ) are for reference.
It was placed on top of the one obtained in Example 8 (1). Reference Example 24 7-(1,1-dimethyμaminothiocarbony-thio)-
1-oxo-2,2-dimethyfi/-3-oxer 1-
Azabi V black (4,2,0) octane diiso 10 pinN amino 70.59 m (4,2 mmol
) in an anhydrous Tetotsu tFa Futsun 9d solution under an electric atmosphere,
15% n-butyrrhizicum/hexane 31d at -18°C
Add while stirring. Add 8-O to this solution at -78°C.
Xo-2,2-dimethyA/-3-oxa-1-azabine
Black (4,2,0) octane 31G11 (2mm'ol
) Anhydrous Tet? tl'$27F73af#[t'additional
Stir for 5 minutes.
Oka~Boniμ)] Jijisura Fit 240JIy2mmo
l) Anhydrous tetrahydrofufuran 3d solution required 110 minutes.
and add. After stirring the reaction solution for 10 minutes, saturated chloride
Add to ammonium water under water cooling and extract with ethyl acetate.
. After washing the extract with water, dry @ (1 la 280.) L, dissolve
Distill the medium. When the residue escapes with hexane, the title compound is obtained.
The substance is obtained as pale yellow crystals (3601F, 66%).
. Melting point: 128-129°C B (80MHz, CDCl5) J:
1.4G -1,75 (3n each. a x 2s -Cl5 x 2) m 2.1 (2H
s m a -C”g -) #3-37150 (each
3 H, e X 2 , -CIaX 2 ) s 1
3-3.5 (ILm, >CH-N< ), 3.8
(2H, m, -CH20-), 4.68 (III, d,
J-1,5Hz, >CH-Co-) elemental analysis value C
Engineering, 500”g o, 8 Calculated value: c 4g, 15;
H8,61; N 10.21 dormitory value: C48,3
1i H6,75; M 1G, 23 Reference Example 25 T-(1-hydroxy-1-methy~ethyl A/)-7-(
1,lI-dimethylaminothiocarbonylthio)-8-
Oxo-2,2-dimethyA/-3-oxa-1-azabi
DichloroC4,2,0)octane) 7-(Summer 2M-Simethymethyminothiocarboni~thio)-
8-oxo-2,2-cymethiμm3-oxo-t-1-aza
Preparation from bicyclo(4,2,0)octane V-inpropylamine 0.17 m/(1,2 mmol
) of anhydrous Teshitsuhi F Loalan 4d solution.
Bottom, 15≦n-butyμ lithium/hexane (
Add 19sft. Add 7ml to this solution at -18°C.
I-$/Memethiaminothiocaμbonythio)-8-oky
So-2,2-dimethy#-3-oxa-1-azabidiclo
(4,2,0)octane 214'IF (1mmol
) of anhydrous TetrahyF Lofuran 2 was added to a single layer solution at -78°C.
Stir for 10 minutes. Then 0.3 ag of anhydrous acetone
After stirring for 30 minutes, the reaction f& was mixed with ammonium chloride.
Add to Monium water bath solution under cooling and extract with ethyl acetate.
. After washing the extract with water and drying (LL, 80.), I#
The medium is distilled off and the cuff is removed using a
Muchromatoguffii 6 (hexane-ethyl acetate μm4
:1,2:1), the starting material (recovered, 20q) and
4iIl orchid compound (199"11.60%) is obtained
. The Shindaku compound is obtained as a mixture of two isomers, and
From ■, the ratio is 3:1. Both are isoglovir
D] -Tefi/ was isolated by a crystallization method. True substance (minor substance): Melting point 166-167°C IIMR (60MHz, CDC13) J: 1.
37.1.42. i, 52°1.72 (3 H each,
s x 4 , -CH5X 4 ) e 2-2 (2
M #III #-CM2-), 3.50 (6n,
e, -1cn3x2), 3.8Bn. m, -0CH2-), 4.2 (11, m, >C11-1
< ). 5.75 (IH, s, -0H) Elemental analysis value 014I[j! 4'ffi, 0382 calculation
Value: C5G, 59! H7,28s N 8.43 Sea sushi
Value: C50,66+ 117.39i N 8.31
Melting point 124-126°C IuJol-1. IR “wax”, 1000 Summer MR (IOMHm*CDC13) 11.45 (6Hs
8゜-CH2N2), 1.60, 1.72 (43 each
H, s x 25-CB, X2), 2.2(2
H, 臘, -CH2-), 3.47 (gill
. a + -ICl3 ×2 ) a 3.9 (2H#
m, -0CRJ! -) s 4゜3 (In, Maro,
>CH-M< ), 4.5 (IH, a, -011) elements
Elementary analysis value C14Hj! 4”20381!!Calculated value:
c 50.59; II 7.28 ink M 8.43 tribute
Value: C5G, 661H7, 40t I 8.55B
) 8-oxo-2,2-cymethyA/-3-oxa1-a
Preparation from Zabi V Chlo(4,2,0)octane Diiso-1a piμamine 2.9 ng (21 mmol)
In a nitrogen atmosphere, add 50 sJ of anhydrous detoxifier solution.
, tssn-butyllithium/hexano solution at -78 °C.
Add 15 mt while stirring. Add this solution to -78°C.
8-oxo-2,2-dimethyμm3-oxer1-aza
BiV Kuro (4,2,0) Octane 1.55f (10mm
ol) Anhydrous? ) ffk: Add Fp Rafufun 15s solution.
Stir for 5 minutes. Add to this mixture dimethymu-amino (thiocarbo = ~)
] JIS N F 1.20f (10qmol)
Anhydrous tetofhydrofufurin 30m solution t - required 15 minutes
After stirring for 5 minutes, add 2dt of anhydrous acetone.
Add to. The reaction mixture was stirred for 40 minutes at -78°C.
After that, the ammonia agglomerates are cooled in water using nitrogen pressure.
Add to the mixture while stirring and extract with ethyl acetate. extract liquid
After washing with water and drying (Ia, 80.), #l solvent is distilled off f,
6. Mint$'9* Kahum chromatograph used by game μ party
to fluoride (hexane-ethyl acetate/""4:1, 2:1)
When attached, 7-(1, M-Nmethy~aminothiocarbony~chi
e) -8-oxo-2,2-dimethyfi/-3-oxa
-1-AzabicycloC4,2,0) octane (pale yellow color)
crystal, Q, 14f) and matrix compound [isomer mixture (I
Mml to 3:1), colorless crystals (isopropyl ether
-hexane Mjl), melting point 116-117″c, 1.1
7F (35%)) is obtained. Reference example 26 7-(1-hydroxy-1-methyμethyl A/)-8-o
Xo-2,2-dimethyl-3-oxa-1-azabicita
B(4,2,0)octane 7-(obtained in Reference Example 25)
1-Hydroxy-1-methy-ethy-)-7-(lI,N
-dimethylaminothiocarbonylthio)-8-oxo-
2,2-dimethyμm3-oxer-1-azabinclo[4
゜2.0] Octane (3:1 isomer mixture) 1601f
(148 mmol), Azobisiso 1 Tyronitri A/1
6III (Q, l mmol) and hydrogenated tri
-〇-Tin (133m? (1.2mmol))
Acetone 5-solution under an electric atmosphere for 5 hours side 5II1 flow
do. mII & was distilled off and the residue was purified using V Rikage 14/
column chromatography (hexane-ethyl acetate 1
v-i:1) gives the cis isomer 761f (7
4,2 regret, one point 125-127℃) and trans isomer 2
2 Da (21,6≦, one point 102-104℃) is colorless
Obtained as crystals. ! j! Weaving example 1 5.6-V-3-[2-(4-nitrobenzio, etc.)
carbonyl)aminoethylthio)-6-(1-hydroxy
C-1-methylethyl/L')-7-o-1-azabi
Citalo C3,2,0)hebuto-2-nin-2-carvone
#14-nitrobenzyl esterμ 5.6-cis-4-[3-diazo-3-(4-2'+ro
Penji ~ Oxo V Carboni A') -2-Oxo 10 Biμ)
-3-(1-hydroxy-1-methyμethyl&/)a
(Tidine-2-one (ben(one) solvate) 250”F
(0.52 mmol) according to the method of Reference Example 21
Prepared 5, 6-$'susu--(1-hyphrokiv-
1-methylethyl-)-1-azabicitalo C3,2,0)
He1tane-3,7-thion-2-force μboxylic acid 4-nito
25mt solution of Repency μ ester in anhydrous aceF nitrile
Under a diner atmosphere, at 0°C? N ii"/f'C'bivx+yy
Add mini y O, 12Mt (Q, 7 ■ meal 01), and then
De V Tsueni μ phosphoric acid loli F0.14sr (Q, 7
smmol) and stir for 90 minutes. This mixture
Add diiso 10 biμ ethylamine (120 mg (1,
1 mmol) and N-4-=trobenzi μoki Vka
μboni A/, S/steamine 250IIg (1,0μm
ol) and stirred at 0°C for 2 hours, then at -20°C.
Let stand for 16 hours. reaction M

[Dilute with ethyl acetate and add ice water.]
and separate the organic layer. Wash the organic layer with water and dry.
After drying (Ha2So,), #! Distill the solvent and filtrate the residue.
Karamuku using reseal (+00-200 Metsu V Yu)
chromatography (acetone-hexane-1:2)
411M compound (170q) as a pale yellow foam
can get. xB'yKBrci': 3400,1770
．． 171011&X UV A”0Hnm(E”):264(303),3
13wax 13 (165) MMB (100MHz, CDC13)':
1.28 jl, 52 (3H, sX2.-CH3 respectively
×2), 3.02 (3H+m. -80H, CM, H< , >C<'i), 3.46 (
2H, m. -8CI, Cdan aNH) s 3-60 (I H,
d, J-6Hz. 〉CdanCo-), 4.0-4.4 (211[, m, >C
Dan version<. >C<, ), 5.18 (21,s, -0C11j!
MUr), 5.36 (2H, MUBq, J”29,
f4iiz, -0CR, Mr), 7.48 (211
, d, J-9Hz, arom, H), ? , 65 (2Hs
d+J=lHr, arom, H), 8°20(4H, d
, J quake 9Hz. arom, H) Dormitory Example 2 5.6-cis-3-(2-aminoethylthio)-6-(
1-H)a-xy-2-methylethyl)-7-oxo-1
-Azabinkuro r-3, 2, 0) 1 to 2-engine-2
-carboxylic acid 5,6-8'su,3-[2-(4-nitropendiμ
okiVcapboniμ)aminoethylthio)-6-(1-hi
Doroki V-1-methy~ethiμ)-7-oxo-1-aza
Bisitalo (3,2,0)hept-2-en-2-carbo
4-nitrobenzyl ester A' 14 GIlf
(Q, 23 !111001) Tetofuhi F Rofuhun
211 sl, pH 7.0 phosphoric acid solution 14 ml and water 1
Add 10 whispers of Pd-C140aft to 45g of mixed liquid, and seal
Hydrogenate at room temperature for 2 hours under normal pressure. 10 P (1-C1
After adding 40 aft and hydrogenating for another 3.5 hours,
Filter and wash with a small amount of water. Combine the filtrate and washing liquid and distill the Tetofuhhi F Rofufun under reduced pressure.
The aqueous layer was washed with #ethyl acetate and concentrated under reduced pressure. dark
Café black using MAD-21-
Added to matoguffy (u2o, 5% ItOH), ay
Collect the spectrum with absorption at 295 am and freeze it.
When dried, the wn compound forms a colorless powder (30Iv).
can get. KBr-1 1RJ/m, 3: 1750 H01 UV Human 2nm (E,): 295 (219) In&
χ IMR (100MHz, D20) #: 1.32-1.
45 (3H, @X2, -CH3X2, respectively), 2.9-
3.3c 5H, rn r4.4 (IH, Maro, >CH-
PI<) *Example 3 5.6-$'s--(2-acetamidoethylthio)-
6-(1-hyfluoroV-1-methylethyμ)-1-oxy
So-1-azabicyclo[3,2,0) to 7')-2-
4-nitrocopenediester 5.6-Vcou 4-[3-diazo-3-(4-nitrebe)
(4/quinyl)-2-oxopropyl)
-3-(1-hydroxy-1-methylethyl)a(thiV
-2-one (benzene solvate) 25G'lf (0
, 52 mmol) according to the method of Reference Example 21.
5,6-cis-6-(1-hydroxy-1-methyl
ethyl)-1-azabicyclo[3,2,0) to 1-tane-
3,7-v-on-2-forceμbonic acid rumor-nitrobenzine μe
Stell's anhydrous acetonitrile 20sU [under nitrogen atmosphere]
, 0.12 m of diiso-10-pyruethylamine (Q,
7 irises 1 aol), then diphenyl phosphate
p9F0.14s/ (0.7mg+ol) f added
and leave it for 90 minutes. This mixture IICθ℃ diiso
10Biruethylamine 0.13yd (0.75mmo
l ) and summer - acetic pvst svy l 79 Q
Add ``l ((175 mmol,)'' and stir for 2 hours.
After that, add 3 m of V isoalobyl ethylamine O1
/(0,75m101) and summer-A7? μ cysteami
NSO Shizuku (0,75mm01) tJJi added, 4 hours?
IIltzell. Reaction [1--2 (after standing in 1 for 14 hours,
Dilute with ethyl acetate and wash with water. After drying (NA380a), the solvent is distilled off. A silent thing
When treated with a small amount of ethyl acetate, the marked compound turns into black crystals (
110q). Melting point: 185-187℃
70G. 650 (262) ffMR (90MHz, DM80-d6) J:1.19
j1.35 (each 3 H, a ×2 e -CH3x
2) * 1.82 (3H, a # CH:s C
0-) *z, sa, + (5H, ws, >c<
, -80H2Ck12M<). 3.59 (1B, d, J=8Hz, >CH
-CO-), 4.0-4-3 (2Hpm, >
CH-N<)>C< a ) j4-70 (
In-s. -ou), 5.37 (2a, mu"q * J-21, 1
4Hz. -OCRgAr) y T, TT (2H, d, -J-
8) [z, arom, H). &lO(Ill, b, -II-), 8.27(薯He
d# J-8Hz. arom, H) Elemental analysis value cllH25”3 o7 s-AH2゜total
Calculated values: c 53.38s n 5.55; w 8.
89 dormitory measurements: C53,58i II 5.43i N
8.89sJ! Weaving example 4 5.6-F-3-(2-acetamidoethylthio)-6
-(1-HydroxyJ/-l-MefμEthiμ)-7-1
*y-t-y-y bi$1lff (:3.2.0) hepto
-2-En-2-carboxylic acid sodium salt (1)
)-6-(+-Hydroxy-1-methylethylμ)-7-
Oxo-1-azabicyclo(3,2゜0) to 7”)-2
-ene-2-carboxylic acid 4-nitropene ester
by catalytic reduction using Pd-C of
-(1-hydroxy-1-methy~ethyμ)-T-1*y
-1-1-yt BiV Kuro C3, 2, 0) to 7") -2-
En-2-carboxylic acid 4-nitrobeneNfiyxT
A/73”f (0.15mmol) (Dj Totsuni
Dorofuran 14sZypH7-0 phosphate buffer 7d and
Add 10% pa-C100 da to the mixture of water and water T@t.
Hydrogenation is carried out at room temperature and under normal pressure for 1 hour. 10% pa-c
50 Qf: After addition and further hydrogenation for 2 hours,
Filter the catalyst and wash with a small amount of water. Combine the filtrate and washing liquid.
After death, in addition to 20 ml of sodium hydrogen hydroxide,
Lahydrofuran is distilled off under reduced pressure. Remove the aqueous layer with ethyl acetate
After washing with
Power chromatography (H,O) used for AD-2
Attach to. The component that has absorption at 298 nm in the UV spectrum
- is collected and freeze-dried as a gray powder (50 Da).
The title compound is obtained. Add this product to Diaion
HP-20 (Sankaseisha m1) T-Power Tsumuchroma
Add to togutufi (H, 0.5% KtO■) and finely roast.
Then, the JIajI#l compound becomes a colorless powder (301F).
can be obtained. Old IB (100MHz-DaO)' ”
L 33 m 1.44 (3H each. a'25-Cl3x2's 2-02 (3H
x s * −〇〇〇I! 3) s2.9-4.0(6
H, -80H, CH2N<, -C)I2-),
3.74 (II, d, J-6Hz, CH-GO-)
, 4.3 (IH, ml. >CHI< ) (2) 5,6-cis-3-(2-aminoethylthio)
-6-(1-hydroxy-1-methylethylμ)-7-o
xo-1-azabicycloC3,2,0)hep)-2-
-Production method by reaction of bonic acid and acetic anhydride 5#6-F-3-(2-aminoethylthio)-@-(
1-HyfurokiV-1-MethiKazethethyl/I/)-7-oxo
-1-Azabicyclo(3,2,0)hept-2-ene-
2-power N bolic acid 1 fern water 4wIt and tetrahydro
Sodium hydrogen legate &, 8q in 4ml of furan solution at 0℃
Add 2.55 gm of water, then 5.2 gm of acetic anhydride
Add 1d solution of TeFhydrofufurin and stir for 20 minutes.
Zeru. The reaction solution was concentrated under reduced pressure and diluted with Diaion HP-2.
Column chromatography using 0 (manufactured by San-ai Kasei Co., Ltd.)
(H, 0° 5% ItOH) with K. UV spec) μ in 2
The fraction with absorption at 98 nm is collected and freeze-dried to become colorless.
The title compound is obtained as a powder (+2v). Physical properties of this product (spec) A/, UV spec F/L/
) matches that of the nine obtained in (1). Example 5 5.6-VO3-C2-(4,6-dimethylpyrimidine)
NiA/)thio)-6-(1-hydroxy-1-methyp)
H1v)-7-oxo-1-azabicyclo[3,2,0
) hept-2-ene-2-power ρoxylic acid 4-nitrobene
Dyl ester 5.6-Vcou 4-[3-diazo-3-(4-nitrobe)
N5ypvOkiVforceμbonyA/)-2-Oxo10Bir
)-3-(1-HiFlokiV-1-MethiμEthiA')Aze
Tidin-2-one (benzene solvate) 94”f(Q
, 2 mn+ol) according to the method of Reference Example 21.
The prepared 5,6-V-6-(2-hydroxyV-2-pro
Pi#)-1-azabicyclo[3゜2,0) to 7”/
-3,7-tri-2-tri-IWtN acid 4-nit
Add nitrogen to an 8 m solution of lobenzyl ester in anhydrous acetonitrile.
Diiso 10 μm at 0℃ in an elementary atmosphere! amine a04
Add 4 mt (0.25 mmol) t° and then diphenyl
Phosphoric acid chloride 0.052IIt (0.25 mmol)
Add 4,6-di to the mixture and stir for 90 minutes.
Methi A/-2-maker lithium salt of tovirimidine 11
．． Add 6”% F (0.8 mmol) and incubate at 0°C.
After stirring for an hour, it was left to stand at -20°C for 14 hours. reaction
Dilute the solution with ethyl acetate and add it to ice water.
Aliquot 1. After washing the organic layer with water and drying (Naz804)
, the solvent was distilled off, and the sample was filtered into a column using silica μ.
to romatogutuffii (hexane-ethyl acetate μm1=1)
When attached, the title compound is obtained as colorless crystals (46JIF).
It will be done. One point 164-166℃ (decomposition) IR*IIuj01ci": 330G, 178
0.1700aX 1% UV λ nm (E, all): 263 (154)
, 32GaX (162) MMB (90MHz - CDC15)': L
27-1.51 (3njsx2.-an3x2 each)
, 1.83 (111,s, OH). 2.41C611,a, -C113X2), 3.4-
3.8 (11, m. dan〉C<1), 3.65 (1H9d, J-6H2,〉cH
-co-). 4.2-4.5 (211jm, >C<m
, ＞CH-N< ) , 5.40 (2H, MUBq#
' 25 + 14 Hz # -OCl zm
r), 6.80 (111, a, arom, H), 7.
69 (21, d, J-9■2゜arom, H), 8.2
5 (2H, d, J-9Hz, ar) m, H) Elemental analysis
Value CJ! 3H24N4 o6B calculated value: c 57.
02 series H4,99iM 11.561*Lower value: C57
, 14f H4,97i M 11.73 Dormitory Example 6 5.6-3' Sue 3-[2-(4,6-dimethylbilimi
(dinyl)thio)-6-(1-hydroxy-1-methie)
μ)-7-oxo-1-7zabicyclo(3,2,0)
He1-2-en-2-carboxylic acid sodium salt strength ~ 4-nitrobene ν ester of carboxylic acid 901I
g ((12 mmol) of Tetofuhhi F Rofufun 18d,
pH 7, mixture of Q phosphate buffer 9d and water 9s/K
Add 140 dabs of IO powder, press 60 min at room temperature.
Hydrogenate for a minute. 10 Added pa-c90 cape,
After further hydrogenation for 75 minutes, a small amount of
Wash with water. Combine the filtrate and washing liquid and
The aqueous layer was washed with ethyl acetate and then evaporated under reduced pressure.
Concentrate below. S condensate t amber phyto zAp-21-
Column chromatography used (H2O, 5% ItO
ii). UV spectrum: 300 nm Kv
The fractions with k yield were collected and lyophilized to give a gray powder (43
The five products that are considered crude title compounds as
Column chromatography using Inverphytoem D-2
When it is made by subjecting it to
The title compound is obtained as a colorless powder (38q). KBr-1 1II wmaXex: 1750UV AH
2'ntmCE'%): 300 (338) wax
1cII IMB (100MHz -D t O) a
: t, 25 e L 42 (31 each, @X2.
-CM,X2), 2.45(6H,s, -CM,X
2). (IH, dd, J-17, 9H2, >C<,), 176
(IH. d, J-6Hg, > CHCO-), 4.4 (IH, m,
>CHI<). 7.12 (IH, s, arom, II) Elemental analysis value
C16M18131a o, 8 ・2ag. Calculated value: C47,17!115.44+110Jl
tHa 5.64 ★Measurement value: C46,82; H5,39; N 1G,
09;Il & 5.60 Example 1 5t 6-'-3-(2-pyridylthio)-6-(
1-HiroFlokiV-1-methy~ethy~)-7-oxo-1
-Azabicyclo(3,2,0) to 1 to 2-en-2-
4-nitrobenzyl ester p 5.6-8'su4-[3-cyacy3-(4-nitro
BenjiμokiVforceμponip)-2-oxo10bi/')
-3-(1-hydroxy-1-methylethylμ)azetidi
-2-one (benzene # solvate) 234”f (0
, 5 mmol) according to the method of Reference Example 21.
95,6-3'-6-(1-hydroxyv-1-methip)
ethylp)-1-azabicyclo(3,2,0) to 1-
3,7-Sion-2-carboxylic acid 4-dibenzi μ
Anhydrous acetonitrile A/20-solution of ester in nitrogen atmosphere
0.11 ml of diiso-10bi-ethylamine at 0°C
(063 飄鳳O1), then add di7eN phosphoric acid
Loli FQ, 1:1II (0.63 mmol) iH added
and stir for 90 minutes. Add 2-mercaptopi to this mixture.
Lysine lithium jjil 17”F (1, Ommol
)l and stirred at 0°C for 2.5 hours, then added 2-merca.
Lithium salt of topyridine 59q (0.5 mmol)
Add and stir for another 2 hours. The reaction solution was diluted with ethyl acetate.
Dilute it with water, add it to saline solution under ice cooling, and separate the liquid layer.
. After washing the organic layer with saline and drying (summer & 28o),
The solvent was distilled off and the residue tV Rikage J & It-
Mucochromatography (hexane-ethyl acetate μm 1:1
), the target Tsumugi compound appears as colorless crystals (94JIF).
can get. Melting point 159-160°C
320 [1st ward 114LX $3 (332) 111B (90MHz, CDCl5) a: 1.2
5. 1.53 (31 each, sX2.-CI, X2),
3.09 (111, di, J-17°9Hg, >C<,
), 3.58 (IH, d, J-6Hz. > CI-Co-), 3.95 (IH, d4. J-I?,
8Hz. ■ >C<a), 4.31 (IH, m, >CH
-M< ) -5,37 (2H, MBq, J=24.1
5Hz, -0C112Ar), 7.14-5155(
8H, m, aroma, H) Elemental analysis value CI! 2H21
'3 o5 B calculated value: C58,01i H4,64
i H9,22*Measured value: C57,54! H4,58
; H9, 27 dormitory example 8 5.6-V no 3-(2-pyridylthio)-6-(1-
HyFlokiV-1-methylethyl)-1-oxo-1-a
To Zabirikuro (3,2,0) 1 to 2-kun-2-**
4-nitropene of ponic acid sodium salt
Tet of diester 9 elf (0.20 mmol)
Fuhydro 7F 718111, pH 7,0 phosphate buffer 9
- Add 10% Pd-090q1 to a mixture of 9 d of water and
Then hydrogenation is carried out at room temperature and under normal pressure. 10 Regret Pd-C
After adding 90 da and hydrogenating for another hour, the catalyst t
Filter and purify a small amount. Combine the filtrate and washing liquid and
After distilling off the Fuku Dorofufun under reduced pressure, the resulting aqueous solution was soaked in vinegar.
Wash with ethyl acid and concentrate under reduced pressure. The concentrated solution was purified using Amberphyto HAD-2.
Added to matogufui (it20, 5% ItOH), U
Collect the amount of absorption at 304na+ in the mass vector.
When freeze-dried, the title compound becomes a colorless powder (32q).
can get. )10 1% UV λrni! nm (El, ): 304 (353) N
MR (100MHz, D20)':
l-20-1,42 (3H each. 8X2.-CH5X2), 2.70 (III, aa
, J=17.10Hz e >C< a ) e 3
-58 (I Hs d d x J-17s 9 ■
z. ■ >c < n ) * 3.71 (IH, d,
J=6Hz, >CH-Co-). 4.30 (IH, a, >CH-N< ), 7.4-&5
(4H, m. arom, H) Example 9 5.6-cis-3-(2-pyrimidinylthio)-6-(
1-Hydroxy-1-methylethyl)-7-oxo-1
-Azabincro C3,2,0)hebdo-2-en-2-
5.6-$'susu--[3-diazo-3-(4-nitro
Bendi~Oki V carboni A/)-2-oxopropyμ)
-3-(1-hydroxy-1-methylethylv)a(thi)
Zin-2-one (ben(nI! solvate) 234#(0
, 5 mmol) according to the method of Reference Example 21.
5,6-3'-6-(1-hydroxy-1-methyl ether
ChiA/)-1-azabinclo(3,2,0)hebutane-
3,7-Sion-2-ponic acid 4-nitrobenzyl
Esthetic μ anhydrous ace) -4! j * 20ml 1ll liquid and dipping sauce
Under atmosphere, at 0℃
d (0.63 mmol), then V phenyl
Add phosphoric acid chloride 0.13j (OJ3mmol)
Stir for 90 minutes. This mixture 11klK2-me~force 1
Lithium loading of toviridine 14 G# (1,2 mmol
) and stir at 0℃ for 4 hours. Reaction solution t-acetic acid
Dilute with water, add to ice water, and separate the organic layer. organic
After washing the layer with water and drying (Iag804), the solvent was distilled off,
Chromatograph the residue using Silikageμ
(hexane-ethyl acetate A/-1:2, 1:3)
The title compound is deposited as colorless crystals (125q). Melting point 160-162°C (decomposition) UV λ”Hnm (E”): 262 (164),
315W1gz 13 (11i5) 1]131 (90MHz, CTJC13)'
: i, 24, L 50 (each 3nt s×2s-
CH3×2), 1.80 (IH, a, -0
H) t3.5-18 (In, m, >C<dan), 3.6
3(111,d,,T=6Hz,>CH-G
O-) * 4.0-4.5 (2H, fl'. ■ >c<dan, >CH-N< ), 5.39 (2H, mBq
, J=25.14H2,-0CH2Ar), 7.07(
11,t, J-5Hz. aro, H), 7.65 (211, d, J=9Hz,
arom, H). 11.22 (21, d, J=9Hz, arom, H),
153 (2H. d, J-5Hz, arom, H) Elemental analysis value C2□H,)I406S Calculated value: C55,26IH4,42; M 12.2
7* Volatility value: C55,49i H4,49+ 112.
18 Dormitory Example 10 5 * 6- 'No 3- (2-birimishiiμthio)-
6-(1-℃ doroki ¥-1-methipethi A/)-7-o
1 to 2- to xo-1-azabinculo [, 3, 2, 0)
Sodium-filled p-bonic acid
4-Nitropenzylester μm 22q ([27mmo
l) Tetofhydrofufun 25sf, pH 7.0 phosphorus
Acid buffer 12II! and water 12s/(Dfi combined IEK
Add 10% Pd-C122M1t and heat at room temperature under normal pressure.
, hydrogenate for 1.5 hours. Filter the catalyst and add a small amount of water.
After washing, combine the filtrate and washing solution and add tetofhydrofuran.
Distill under reduced pressure. Wash the resulting aqueous solution with ethyl acetate
and concentrate under reduced pressure. Kabumuku using concentrated liquid AmberphytoX D-21-
Added to Romatoguffy (K20, 5% EtOH),
Collect the components with 295nm K absorption in the U mass vector.
When freeze-dried, the title compound becomes a colorless powder (62III).
It can be obtained by XHap""ci': 175G bile JLK! l MB (100MHz s D a O)
': L 26-1.42 (3M each. 8X2, -CH3x2) -3,19 (IH, dd
, J=17-10■>C<a), 3.78 (I H-d, J
-6Hz -> CM-Co, -) a4.40 (1
111, m, >CM-H< ), 7.34 (IH, t
, J=51z,arom,H), 8.66(2H,d,
J-5Hz. arozen, H) Example 11 5.6-$'susu--(3-(6-methy〃viridas/2
*) Thio)-6-(1-hi)'a*5z-1-methie
H)-7-oxo-1-azabicitaro (3,2,0)
He-1-2-ene-2-carboxylic acid 4-nitrobendi
ester 5.6-Vsu-4-C3-$/7zo3-(4-dito
Lopenzyloxycarbonyl)-2-oxopropyl)
-3-(1-hydroxy!/-1-methylethyl)a(
Tidin-2-one (ben(one solvate)) 234 da(0,
5 mmol) according to the method of Reference Example 21.
5,6-v-6-(1-hydroxyly-1-methy-ethyl
μ)-1-Azabicyclo[! 1.2.0) to 1 tan-
3,7-Sion-2-Polyponic acid 4-; Trobenziμ
A highly toxic atmosphere was added to 20 ml of anhydrous acetonitrile solution of the ester.
*T, ◎Diiso10V at ℃
．． 11 d (0.63 mmol) and then diluted with
Phenylphosphoric acid loli F0.131d (8,63mmo
Add l) and stir for 90 minutes. Add 3-methane to this mixture.
Lithium loading of capto-6-methylpyridan 131 da
(1, Ommol) was added and stirred at 0°C for 2 hours.
Then, lithium of 3-mercapto-6-methylpyridazine
Add salt 66119 (0.5 mmol) and
K11 Stir for 1 hour. The reaction solution was diluted with methylene chloride acetate.
, and add it to saline solution under water cooling to separate the organic layer. organic layer
After washing with saline and drying (lla80), the solvent was distilled off.
4. When the sample is removed and heated in an ethyl process, the title compound is obtained.
is despised as a pale yellow crystal (831F). Melting point 1g? -188℃ KBr -1 1B &,,,a: 175Q (294) Elemental analysis value Cg! H! ! ! 2'4068 Calculated value: C
56, l&s H4, 71B N 11.91 dormitory measurement:
C55,71; H4,9 (b M 11.39 Dormitory
Example 12 5.6-V-3-(3-(6-methylpyridazine fi
/)? -e)-6-(1-hydroxy-1-methy~ethyl
*) to -7-oxo-1-azabicyclo(3,2,0)
But-2-nidi-2-carboxylic acid sodium salt 4-nitrobene') 14/1) = fμ
8 G'f (0.17 mmol) of detofhydride a7y
16-m, methanol-μ4m! , pli7.0 phosphate buffer
l Q % P to a mixture of liquid tosg and 105 g of water.
Add d-C (80q and hydrogenate at room temperature and under normal pressure for 70 minutes.
Add. After filtering the catalyst and washing with a small amount of water, the filtrate and washing liquid are
are combined and the organic solvent is distilled off under reduced pressure. Obtained 9 pieces
Wash with liquid ethyl acetate and concentrate under reduced pressure. -The liquid
Amperfi) Katsumu chromatograph using XAD-2
Attached to phi (K20, 5% EtOH), UV spectrum
Collect WjAt with absorption at 2960 kai and freeze-dry it.
The title compound is then obtained as a colorless powder (34#).
. IRv”rail: 1750 11LX UV ABtonm(E”):296(28&)@@
z lc* N M R (100M Ht jD20 )' =
1-20- L 41 (each 3 H, s X 2.-
CH5X 2) e 2.6? (3Hws,
CM, ) C2,72 (IH, dd, J=17.10
Hz, >C<). 161 (I H-cl d -J-17-9Hz -
>C<a), 3-74(I H-d-J
11-6 Hz m > CII-CO-), 4-3
5 (I H-m, >CH-fuki< ), 7.60 (
IH, d, J-8Hz, arom, H-in L/HIH
, d, J-8Hz, arom, H) Example 13 5.6-$'susu--(2-acetamiFethymuthio)-
6-CI-(2-MeFkiVethoxymethoxyV)-1-Me
-1-oxo-1-azabi V black (3,2
, 0) hepto-2-en-2-forceμbonken 4-=)ro
5,6-Sinu prepared in Bendi ρ Ester Reference Example 22
6-[1-(2-methoxyVethoxyVmethoxy)-1-methoxy
Chip Echi~]-1-Azabi V Kuro [3,2゜OC to pig
ion-3,7-sion-2-carboxylic acid 4-= ) a
Hen NpvxxvwO, 301 (Q, i 7 mzen o1
) of anhydrous acetonitrile) in a nitrogen atmosphere.
Diiso-10-billethylamine 0.145a at 0°C under air
f (0.88 mmol) t-added, then diphenyl
Add 0.172 m (0.83 mmol) of chloro9F
Stir for 15 minutes. Add diisopropylene to this mixture.
Thiamine 0.17m (1.0mmol) and 1-a
Ceti A/p stearamine 120 da (1.0 mmol)
In addition, stir at 0°C for 2 hours under nitrogen atmosphere, and then dilute
Iso-10biruethylamine 0.17s/(1,0mmo
Add l) and mix at 0°C for 17 hours. Reaction solution t#
Dilute with ethyl acetate, pour into ice water, and separate the organic layer. After washing the organic layer with water and drying (Siri 804), the solvent was distilled off,
Kafumu Chromatoduffu using Rikage~
E-(ethyl acetateμ. Ethyl acetate-methanol-A/-95:5)
The compound is obtained as colorless path A (27011v). Melting point 128-130℃ IRy”jolarl: 3310,1?75,170G
. ax 11!50 ゛1tOH1% UV λ nm (V 1c, ): 265 (20
9) -31511LX f239) 13JR (60MIiz, CDCl3)a: 1.
35.1.52 (3M each. a x 2s-CH3 x 2) e L 9 b (3H
r s + -Cocii, ) C18-17 (10H
, m, -8CH2CM2N<, >an-co-. > CH-N < ) -4,77 (2Hja, -0
CH207) * 5.35 (2H, MUBq#' =
20-14 Hz *-0CIIIJ! Mr), 6.
2 (IH, b, -NHCO-) j7.61 (2M, a
, J-9Hz. arom, H), 8.20 (2H, d, J”jHz,
arom, H) Elemental analysis value C25H33'309 B
Calculated value: c 54.44; n 6.03; M 7
．． 61 dormitory measurement: C54.4G! II 5.78;
N 7.61 dormitory example 14 5, $-8'-3-(2-acetamidoethylthio)-
6-(1-(2-methoxyethoxymethoxyV)-1-methoxy
-7-oxo 1-azabi Vri OC3,2
,0) to 1-2-en-2-iIβbonic acid sodium
Mu salt snn ~ 4-nitropendiester of bonic acid ~ 130q
(0,24 mmol) and sodium hydrogen envyate 40
q of tetofhydrofufun 13sJ and water 13s/mixture
Add 10≦pd-C130 inches to the solution and heat at room temperature and under normal pressure for 2 hours.
Hydrogenate for an hour. After filtering the catalyst and washing with a small amount of water,
Combine the filtrate and washing liquid and distill Tetofhi F Lofuran under reduced pressure.
leave The resulting aqueous solution was washed with ethyl acid and concentrated.
, a car using Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation).
Humu chromatography (H, 0.5% EtOH, 10
%]1itOH). 298Gm with UV Spect
When the amount of K＠yield is collected and lyophilized, the target compound is obtained.
It is despised as a colorless powder (90Jv). KBr-1 rto#Tn&xaIl: 1750.164ONMR(
IQOMHz, D20) J: 1.36, 1.46 (respectively
3La' 2 + -CHa ×2) s 2. Q
1 (3H-s p -COCH3) -2,8-3
,9(IIH, , -F3CH9CH2M< , -
CHg-. >cnco-, -ocH2c11. o-), &33(3
La. -0CHs), 4.30 (l H-m, >
CH-N< ), 4.83 (2H911,-0CH2
0-) Example 15 5.6-V-3-ethquincarbony-methylthio-6
-(1-hydroxy-1-methylethyl)-7-oxo
-! -Azabi V black (1, 2, 0') to 7") -2-
N-2-carboxylic acid 4-nitrobenzyl ester 5,6-! /susu--[3-diazo-3-(4-2F
lobenzyloxycarbony)-2-oxopropyl)
-3-(1-hydroxy-1-methylethyl A')a(thi)
Zin-2-one (benzene solvate) 117”f(0
, 25 mmol) according to the method of Reference Example 21.
5,6-cis-6-(1-hydroxyV-1-methy-ethyl
Chi μ)-1-1 Zabishiku C3,2,0) Hebutane-3
, 1-dione-2-carboxylic acid 4-nitropencyle
Stell's anhydrous ace
Ambient air [, V isopropyμethyl amine 0.055 at 0°C
m(0,31m■01), then add diphenylene
Acid chloride a065sg (0.31, mmol, )
Add -O and open-at. Add diiso 10 to this mixture.
Biμethylamine 0.064sJ (0.36mmol
), and the next one is Ethyl Me μ force 1 door 7 Tate 0
Add 041d (0,36111101), tte0
℃? 31? Interval: 641 zeru. Reaction solution t# Dilute with ethyl
Then add it to ice water and collect the organic mt. Wash the organic layer with water,
After drying (Naz804), the solvent was left in place and
Lolige, 4/< 100-200 mesh)
Column chromatography (#acid ethylhexane 2
:3), it gives IA Sabahika Gold Compound Colored Crystals (26wit).
> Closed and despised. Melting point 120-121℃ (275) NMR (90M HZ, CDCa)'
: 1.28 (3H, t, J-L5) 1 small, -C
H2CH3>, 1.29, 1.53 <31 each
1. sX2゜-cu, x2) -t, ss (IH,
a, -OH) -3,09 (1M.q, J-17,9Hz, >C<dan), 3.51-3.
63 (3M. m, > C, H-Co +, -5-c once, -co-)
, 4.06-4.0C4M, *, >CM-H<, >c<
: , -0H2CII3). 5.37(21,mu”q #J=24 #1
5 Hz + -OCH, mr)j″7.18(21,
d, J-8Hz, arom, If), 12g (2M
. d, J+m@Hz, aroma-H) Elemental analysis value C2!1H24N2 o88 calculated value: C
54,30t H5,21; M 6.03 Eastern survey value:
C54,05; H5,05; M 5.94 dormitory example 1
6 5 m G ”-’su-3-ethoxytifi/bonyl
Methylthio-6-(1-hydroxyy-1-methy~ethyl A
/) to -7-oxo-1-azabicycloC3,2,0)
1-to-2-ene-2-force μbonic acid sodium salt 5.6-V-3-ethoxy\hl&/boni〃methyμthio
-6-(1-hyphrokiV-1-methyethi)-7-o
xo-1-azabicycloC3,2,0') to 1-2-
2-carboxylic acid 4-nitrobenzyl ester J'
60'f (0.13 mmnol), Me oxyhydrogen sodium
Liumium 16”f (0.19 mmol), tetrahydride
10 attacks Pd-c in a mixture of Ro7 Hun 6d and Water 6to
Add water and add water under normal pressure at room temperature for 2 hours. Filter by touch, wash with a small amount of water, and combine the filtrate and washing liquid.
Wash with ethyl acetate and concentrate the aqueous layer under reduced pressure to obtain a concentrated solution.
Power chromatograph using Amberlite XAD-2
Fufui (H, 0,5%T:tOH)K attached. 17Vs
Collect the fraction with 296 nmK absorption using Pectμ and freeze it.
Upon drying, Shiteran compound is obtained as a colorless powder (28q).
It will be done. xw w""ci': 17'50ix Uma λ"0Mm (Tobi): 296 (256), 1az
1cm III II (90MHz - DJ! 0)
': L 42 (3II, t-J-7, 5H
z , -CHIC[) -1,43-1,53 (respectively
311. sX2゜-CH5x2 )-3,20 (11th year
．． q, J-IL911! ＃〉C＜′￥i）, 3-8
4 (2H-s -8CX zc O-) -&'1
16 (1M, d, J=6Hz, >CM-Co-), 19
8-4.57 (2H2ho, >cH-m< , >C<H
), 4.38 (2fl, q. -CH,Cl5) Example 17 5.6-cis-3-benzithio-8-(1 and yvaki
S/-1-methylethyl)-1-oxo-1-azabisi
Chlo(3,2,0) to 1-2-ene-2-force ~ Bonic acid
4-Nitrobenzyl Esde I 5.6-$'Sus--[3-Diazo-3-(4-nitro
Bendi~oxycar~boni#)-2-oxo10biμ)-
3-(1-hydroxy-1-methy~ethyμ)azetidine
-2-one (benzene 5sua) 234”f (Q,
5 mmol) according to the method of Reference Example 21.
5,6-V-6-(1-hydroxyV-1-methy)
Ethi)-1-azabiliclo(3,2,0)hebutane-
3,7-Sion-2-Power~4-Nitrobenzyl Bonic Acid
Esthetic hot water acetonitrile μ20m? Dioxide atmosphere in solution
Diisopropyl pethylamine 0.11 s at 0°C under
# (0.63 mmol 1.) and then add diphenyl chloride.
0.13 m ((Li2 mmol)
Add and stir for 90 minutes. Add diiso 10 bicarbonate to this mixture.
~Ethylamine 0.17s/(Q, 97 smmol
) and then add benzene μcaptan 0. I Is
/(0.97 mmol) and stirred at 0℃ for 24 hours.
Mix 9. Dilute the reaction mixture with ethyl alcoholic acid and add to ice water.
Separate the organic layer. 1111klljt water IF, ,
4ell) (!Ia, 804) v, ll#ll
1k was distilled off, and the residue
cuff chromatography to be used (#acid
When applied to ethyl hexane (1=2), the title compound was colorless.
Obtained as crystals (96MI). Melting point 180-181°C IRvKBrts”: 1760 UV, Inm (K 1.): 26
5 (255)-3201 Whisper (312) IMB (60MHz, CDC13) J: 1
．． 20-1.49 (311 each, sx2.-an3x
2), t, 670H, s, -on). 2.16 (lH, q, J=17.9Hz, >C<
), 3.5・(Ht, d, J=6Hz, >CH-Co
-), 4.13 (2H, s. -sc town mr), 3.94.3 (2H, m, >C<
. dan>CH-M< ), 5.36 (2H, MUBq, J
-Ha, 15Hz. -oc, m2mr), 7.28(5H,s, ar
om, H), 7.57 (2H, d, J-9Hz,
aroa+, H), &1a(2Hed+J=llH
Z, arom,! ,) 7C element 1frlli
C2, H2, II, o6s calculation value: C61,53;
H5,16! I 5.98 true open value: c 61.8
2s H5,09;
FlokiV-1-methy-ethyμ)-7-oxo-1-aza
Viriclo C3,2,0)hebuto-2-nin-2-carbohydrate
4-Nitrobenzyl ester of phosphoric acid 4-nitrobenzyl ester of phosphoric acid jolt
(119 mmol), hydrogen carbonate F Licum 24q (12
51usual), tetofhydrofufun9- and
1Q%Pd-C90IIVt' was added to 15t of water FB1 mixture.
Then, 1 g of water was added at room temperature and under normal pressure for 2 hours. Filter the catalyst
After washing with a small amount of water, combine with the filtrate and add ethyl acetate.
Wash with water. Aqueous layer [Concentrate under reduced pressure, and remove the concentrated liquid from the amber layer.
- Ophthalmic chromatography using PhytoXAD-2
(no, 10 whispers of EtOH). UV Spect 3
4 minutes absorbed in 0 On 臘 - Collect and lyophilize.
The compound is obtained as a colorless powder (30MI). I B 5rIBras': 174GaX UV A ” nm (E”): 300 (275) w
ax 1m 1M! ? (90il Hm-D JI O)
': L 39-1.51 (3H each. 8X2.-CH5X2), 3.17 (IH, dd, J=
17゜>CH-CO-), 310-4.43 (2
H,a,>C<H. >CH-M< )-4-28(2H, a, C
Hg-mr), 7.60 (5H,s,arom,H) Example 19 5.6-V-3-(3-pyridacydiμthio)-8-(
1-hydroxy-1-methylethyl)-1-oxo-1
-AzabicycloC3,2,0) to 7”)-2-ene-2
-Carboxylic acid 4-nitrobenzyl ester 5.6-Vsu-4-[3-diazo-3-(4-nitrobenzyl ester)
carbonyl)-2-okinderovir)-3
-(1-HydroxyV-1-methy~ethyμ)a(thidine-
2-one (benzene # solvate) 234”v (0.5m
mol) according to the method of Reference Example 21, and then 5.
8-v Sue 6-(1-HiFi"*$' -1-)fpy
, x Chi A/)-1-7 Zabi V Kuro (3,2,0)
-3,7-1'one-2-carboxylic acid 4-nitrobene
Anhydrous acetonitrile fi/20m #! to
diimpropylethylamine at 0° C. under an electric atmosphere.
Add 11s/(0.63mmol) and then add V-phenylene
μ phosphoric acid p-lide 0.1Sm (163mmol) t-added
Stir for 90 minutes. Add 3-mercapto to this mixture.
Lithium salt of pyridazine 115ay (1,0 mmol
) k plus 2 hours at 0℃ 1! After mixing, 3-merka
Lithium salt of topyridazine 59q (α5 mmol
) for another 18 hours or 11 hours. Reaction solution t#
Dilute with acid ethyl alcohol, add to saline solution under ice cooling, and separate the organic layer.
take. Wash the first layer with saline and dry (M&2S04
) After that, the Sat was distilled off and the sample was treated with ethyl ether.
The title compound was obtained as Ik orange crystals (109IF).
It will be done. Melting point 159-160°C (222) *m Example 20 5.6-cis-3-(3-pyridazinylthio), -6-
(1-hydroxy-1-methy-ethy-)-I-oxo-
1-Azabicyclo[3,2,0)hep)-2-en-2
-force~boxylic acid Sodium base M carboxylic acid 4-dimethyl
Robenzi μSDE 9.51F ((120mmol
) TeTfu7fu720d, methanol~5s/
, pH 7.0 phosphate buffer 121d and water 12s/
Add 10% Pd-C95 to the mixed solution and let it cool under normal pressure! i! warm
Hydrogenate for 90 minutes. After filtering the catalyst and washing with a small amount of water, combine the filtrate and washing liquid,
The remaining 41m solvent is distilled off under reduced pressure. Add the resulting aqueous solution to vinegar
Wash with acid ethyl chloride and concentrate under reduced pressure. Karafukuro using the concentrated solution as Amberphyto XAD-21
Attached to Matogutufi (H2O, 5 whispers EtO!i), U
Collect the part with absorption t at 296 nm using the mass vector.
When freeze-dried, the marked compound becomes a colorless powder (31 drops).
can get. IR&KBrcM″”: 1750 ax IME (90MHz, D20)’:
1.32, t, 53 (3H each. s x 2.-CH5 x 2) # L9 G (I
H, d d p J ~l 7-10Hz, >C<dan)
, 3.71 (IH, dd, J-17, 9Hz. ■ 4.47 (11, m, >CH-11< ), 7.76-
9.26 (3H. m, aroma, H) Example 21 5.6-V no 3-phenylthio-6-(1 hydroxyv
-1-methylethyl 14/)-7-oxo-1-azubi V
Kuro C3,2,0) to 1 to 2-en-2-#I14/
Bonic acid 4-nitrobenzyl ester 5,6-$'su--[3-diazo-3-(4-nitrobenzyl ester
Robendi-2-oxopropyl)
-3-(1-hydroxy-1-methylethyl~)azetidi
Pen-2-one (Pen-2-one hydrate) l 881F (
11 according to the method of Reference Example 21 from 0.4 mmol)
1m! L*5.6-cis-6-(1-hyfuroky-1-
Methi〃Echiμ)-1-Azabishiku1'1.2.0)to1
Tan-3,7-thion-2-ponic acid 4-nitrobe
Anhydrous acetonitrile 16d solution of ester
Diimpropylethylamine 0.08 at 0°C under atmosphere
Add s/(0,45 mol)l, then add
Sour Loli No. 093sJ (0,45iamol)
Add to boil for 90 minutes. Add 10 bits of diyne to this mixture.
Ruethylamine 0.14m (-0.8mmaol)
and thiopheno aao a 2s/ (0,8+nmo
l) Add f and stir at 0℃ for 3 hours, then at 16:00.
Let stand for a while. Dilute the reaction solution with Ichishun ethi μ and wash with cold water.
After drying (summer a2804), the solvent is distilled off. Sannemono [
Kahum chromatography using silica gel (hexa
When it is applied to Ken-Ethi fi/-2:l), there is no Shintsumugi compound.
It is despised as a colored crystal (10G#). Melting point 165-167℃ (decomposition) IRj/7 No. 01Gj": 3460.1770.17
50゜690 tOH Uv'wax nm ([ni): 265 (2112),
315(333) IMR(60MHz-CDCls)'
: L 12-1-48' 3H each. sX2. -cm3x2), 2.39 (Ht, aa, J
-16m8Hz, >C< ), 3.53 (IH, d,
J-6Hz. >CHCO-), 14-4.4 (21, m, >CHli
<. >C<H)-5,41(2H, A Bq e J-2
2-14Hzl-OCHJ! Mr)C7,4(5H,
o, aroma, H), ? , 67 (2Ha d # J
Ken911 z a arora, H), C22 (
2Hp dnJ-9Hz, aroma, H) Elemental analysis value cg3Ha! 12N! ! C6B needle calculation value:
C60,78i H4,88; H6,16 dormitory value:
C61,24i H4,87; M 6.00 dormitory example
22 5.6-$/su3-phenylthio-6-(1-hyFro
KiV-1-methyμethyl)-7-oxo-1-azabi$
'? 1)-2-z so 2-carvone to 0(3,2,0)
Acid: 4-nitrobenzyl ester of sodium chloride acid 100"
F (0.22 mmol), IJe1111 hydrogen
vinegar)! 7um28q<α33ryu01), tetrahydrof
10ag of feces and 10srf of water) i1 go UK l O
Add % pd-c100q4 and soak in water at room temperature for 1 hour under normal pressure.
Added soot, 10Lpa-c 10G1ft
After further hydrogenation for 1.5 hours, the catalyst was filtered off and a small amount of
Wash with water. Combine the filtrate and washing liquid and stir
After 1 hour under reduced pressure, the superior water solution was treated with acetic acid.
Wash with ~ and ays under reduced pressure. concentrate t amberf
cuff chromatography ff fee (
H, 0, 5% EtOH) with K, UV 7°bec)
A/Collect 11 more @ for 3QOZ111 and freeze it.
When dried, the title compound was obtained as a colorless powder (35q).
It will be done. "'rnaxam: 1750 U Y A"20nm (E'%): 300 (329)
In, LX 1aII N M II (90MHz -DzO)'
: L25-L50 (3H each. s x 2, -CH5x2) -2,53(lH
, ad , J −17m 10Hm −>C<
M ) -160(I Hld d -'-17e
9 ll2Ip>C< x ) −3,75(I
H-d z J ~6 Hz ->C, M-CO-)
C4,25(III, ma, >CH-1<), 7.6(
5H, m. arom, H) Example 23 5.6-cis-3-C2-CM, M-dimethy-aminoe
Chi ~) Chio) -1! -(1- and yaxy-1-methyl ether
Ch~>-r-oxo-1-azabi V taro (3,2,0)
Hebut-2-ethyl-2-benzoic acid 4-nitrobenzene
Lueste ~ 5.6-V no 4-[3-diazo-3-(4-nitrobe
Nji~OkiVka~Boniμ)-2-Oxo10Biμ)-3
-(1-hydroxy-1-methylethyl A')a(thidine
-2-one (benzene solvate) 234"11F (C
5tsaol) $Reference Example 21f) Prepared according to method
5,6-cis-6-(1-hiFlokiV-1-methy~
Ethyl A/)-1-azabicyclo[3,2,0)hebutane
-3,7-Sion-2-carboxylic acid 4-nitrobendi
Anhydrous acetate ester A/201It# liquid Kl
[Diisopropyl pethyl amine 0.
11 m ((0,63 ma + ol) l (add, then dilute
Phenylphosphoric acid chloride 013m (0.63mmol
) Add and stir for 90 minutes. Add to this mixture
Soglobylethylamine 0.35d (2.0mmol
) and N,N-dimethysteamine hydrochloride 14
Add 2'l (1.0 mmol) and incubate at 0℃ for 4 hours.
Stir. The reaction f& was diluted with ethyl acetate μ and placed in brine.
Add a water cooler to the solution and separate the organic layer. Wash the organic layer with water and dry*
(Na2S2.) After that, the solvent was distilled off and
When treated with a small amount of ethyl acetate, the title compound forms colorless crystals (
841F). Melting point 148-150℃ (decomposition) I RJ/, 1LXax: 1770U V A
nm (EL): 266 (265). t0111 ELX 317.5 (291) MMB (6!MHz, CDC13) ': 1
．． 27, i, 52 (3H each. sX2.-〇H3×2), 2.26(6)I+8
, -ca3×2) C2,2-3,3(5)(,m,>
C<-,-5-cn2cH2-a<>. 157 (la, a, J=6Hz, >CH-Co-), 4
．． 0-4.4 (211, m −> CH-N < , 2
C<)e 5.33C2H. danABq, J=23.14Hz, -0CIi2Ar)
, 7.60 (2M. d, J-811z, aroa+, H), 8.17 (2
11, d, J-8Hz. arom, H) Elemental analysis value 02□1127M306S calculated value: C5
6,11 series H6,05; M 9.35 series measurement value: c
55.62; H5,91; N 9.52 Example 24 5.6-cis-3-[3-(6-methoxyviridazine f
i/)thio)-6-(1-hyphrokiV-1-methy~ethyl
p) to -7-oxo-1-azabicycloC3,2,0)
1-2-en-2-carboxylic acid 4-nitrobenzyl
Ester 5, is'su4-[3-siacy3-(4-dito
RobenshiμokiF*A/Boni~)-2-oxoglopiμ
)-3-(1-HiFrokiV-1-Methi〃Echiμ)Aichi
Zin-2-one (benzene solvate) 234q (0,
5 mmol) according to the method of Reference Example 21! death
Ta 5, 6-! 'Susu--(1-hydroxyV-1-methane)
Chiμech〃)-1-azabicyclo(3,2,0) to pig
4-nitrobene
Dyl ester in anhydrous acetonitriμ20IIt solution
Diyne 10 biethyl amine 0.1 at 0℃ under a poisonous atmosphere
1m? (0,631111101) and then dilute
Phenylphosphoric acid chloride 0.13m (a63 mmol
) and stir for 90 minutes. Add 6-metal to this mixture.
Lithium salt of doxy-3-mercaptopyridazine 164
sy (1,1 mol)! Add and stir at 0℃ for 2 hours.
After mixing, add 6-medki F-3-merca 1 toviridazine.
Lithium salt II 21Iw (0.55mmol) t
Stir for 18 hours. Add the reaction solution to vinegar
Dilute with ethyl chloride, add ice-cold F to saline solution, and separate the organic layer.
take. The organic layer was washed with brine and dried (Na, 80
．． ) After sit distiller distillation residue t7a Lizzie #(10
Cuff chromatography using 0-200 Mets V Yu)
"-(#Acid Ethyl μm Hexane-3:2)
The compound is obtained as yellow crystals (4611). Melting point 1 @ 9-171℃ A1111LX 3: 1770UV A”
0Hnm (If: 264 (31G), 308TIJ &
X (21113) Example 25 5s@-vsu-3-<4-pi91)14yfyt)
-1-(1-hydroxy-1-methylethylμ)-7-o
xo-1-azabicycloC3,2,9)
-2-carboxylic acid 4-nitrobene V〃For esthetics + 5. @-ysu 4-[3-diazo-3-(4-
Nitrobenzyloxycarbonyl-2-2-oxinprobi
, 4')-3-(1-hydroxyV-1-methyμethy)
a(thidin-2-one (benzene solvate) 47q(
a 1 mmol) according to the method of Reference Example 21
5, 6-V No 6-(1-Hiroki S/-1
-Methiμethip)-1-azabicycloC3,2,0)
Butane-3,7-thion-2-force μboxylic acid 4-nitro
Electron to a 4d solution of benzyl ester in anhydrous acetonitrile
Diyne 10 biμ ethylamine 0.02 at 0°C under atmosphere
Add 911/((LITmlII+01), then dilute
Phenyl phosphate phosphoric acid replacement FO,036IIt(0,17
! 1111101) and stir for 90 minutes. child
To a mixture of 4-mμ 1 lithium salt of tobilysin 231
Add 1I (Q, 2 mmol) t″ and keep at 0°C for 1 hour
Or 1! After death, 4-mercaptobilicin was further added.
Add um salt 23'f (0.2 mmol) for 5 hours.
Stir. The reaction solution was diluted with t-ethyl acetate and placed in ice water.
In addition, separate the organic layer. The organic layer was washed with water and dried (Nag
8o4) After distilling off the solvent, the remaining tV Rikage ~ was used for cultivation.
Preparative thin layer chromatography (ethyl acetate-hexane)
7:3) K-t and the title compound as colorless crystals (9q)
can get. Melting point 175-178°C (decomposition) (172) Run #126 5.6-V no 3-(2-(N,N-dimethylaminoester)
thio)-6-(1-hydroxy-1-methy~ethyl)
#) to -7-oxo-1-azabicyclo[1,2,0]
4-nitrobenzyl ester of carboxylic acid 9 G”
F(Q, 20 mmol) Tet”Fk:Fl+27
Hun 18Mt, water 9- and pH 7,0 phosphate buffer 9-
- 1G%p to the liquid! d-c 1oovt added, always
Hydrogenate with pressure F'il for 2 hours. Touch# [filter and separate,
After washing with a small amount of water, combine the filtrate and washing liquid to reduce the organic solvent.
Distill under pressure. Wash the resulting water with ethyl 5at-s acid.
and concentrate under reduced pressure. Amperlite XmuD concentrate
-21 used for Cuffum black T-hornfish (H2O, 5%
1tOH) K attached, 294nmK @ collection with UVX vector
When four portions of w4t- were collected and lyophilized, the title compound was eliminated.
Obtained as a colored powder (1Tq). KBr-1 Engineering RJ/wax”: 175G UVλ nu (Ee): 294 (177) IMR (90
MHz, DgO)': 1.42, 1.55 (3H, respectively. aX2. -CM, X2), 2 near 5 (6H, 8, -C
H5X2). 17-4.2(IH,m,>C<”), 4.45(l
Jm. dan]CH-M< ) Example 21 5.6-￥su 3-[3-(6-medoxypyridazinyl
)thio)-6-(1-hydroxy-1-methylethyl~>
-r-oxo-1-azabicyclo(3,2,0)hept
-2-ene-2-carboxylic acid sodium salt - 4-nitrobenzyl ester of carboxylic acid T I'
ll (0,146 mmol) of tetofhydro7 I
Sd,) evening/-Iv4 ml, pH 7, O phosphoric acid
Add 10% pa-c to a mixed solution of 9 dk- and 9 Ist water.
Add 71M' and add bulk water at normal pressure and room temperature for 2 hours.
. Add 10LPd-071q to the reaction solution and add 1
After hydrogenation for an hour, the catalyst is filtered off and washed with a small amount of water. The filtrate and washing liquid are combined, and the organic solvent is distilled off under reduced pressure. After washing the obtained water + 1# with ethyl acetate, concentrate under reduced pressure.
Then, the concentrated liquid was added to the cuff using Ampartite XAD-21.
Subjected to Kumatogofu (H, 0.5% EtOH). Collect 4 294nmK Vt with UV Spectrum
When freeze-dried, the 411 compound becomes a colorless powder (2.Da).
obtained as. From “max”: 175G UV ^” nm (L L): 294 (
282) max IMR (90MHz, D20)': 1
-30-1-54 (each 311゜a-pt2.-cH
3x2), 2.77 (in, aa, J-iLIQHz,
>C<i), 168 (1M, dd, J-17°9
Mg, >Chi), 3.72 (IH, d, J=6H
z. > CH-CO-) * 4.21 (3H, a --
0CH3) -4,38(lfI, m, >CH-N<
), 7.39 (11, d, l-8Hz. arom, H), 7.93 (IH, d, J-8Hz, a
rosm, H) slI! Example 28 5.6-cis-3-ethylthio-6-(1-hydroxy V
-1-methylethyl A/>-7-oxo-1-azabicic
C3,2,0)hep)-2-en-2-carboxylic acid
4-Nitrobenzyl ester 5.6-cis-4-[3-
Diazo-3-(4-nitrobendiμokiVkaμboni~)
-2-oxopropy~)-3-(1-hydroxy-1-
Methylethyl μ)a(thidin-2-one (benvin solvated)
from 234 Da (0.5 mmol) to Reference Example 21
5,6-cis-6-(1-hydroxy
V-1-methyp-ethyl)-1-azabicycloC3,2,
0) Hebutane-3,7-! /on-2-force〃ponic acid 4
- anhydrous acetonitrile of nitrobenzyl ester 25d
Add diimpropyl ethylamine to the solution at 0°C under a highly toxic atmosphere.
Add 0.11 s/(163 mmol) of
Diphenyl phosphate chloride 0.13Wt (0.63mm
ol) Add and simmer for 90 minutes. to this mixture
Diyne 10bi-ethylamine 0.22dC1.3mmo
l), then add
Add s/(1.3 mmol) and stir at 0℃ for 11 hours.
Mix. 1 ljat was distilled off under reduced pressure, and the residue was diluted with ethyl acetate.
Dissolve in ~, wash with water, dry side IL2804) and then distill off the solvent.
do. Cuff chromatograph using Sanonmono T Flori v-~
When applied to roughy (hexane. hexane-ethyl acetate, ”-1:1), the title
Things are looked down upon as colorless crystals (100 Da). Melting point? ? -80℃ (softening), 133-135℃ (remelting)
) X B h"rrx-': l 7.70, 174
0.1690m&X UV λ';, pnm (g"): 262 (247), 3
115aIl (244) Summer MR (@OMHz, CDCl 3) ”L
27-1.47 (3H each. @X 2 # -CH3x2) e l-30 (
3Hr t + '-7H" m-CH2c6),
2-87 (2He q −J −TRg −−CI!
J! CH3). 2.1l-12 (IH, Rei, >C<Ji), 3.57
(III, a. ■ J-8Hfi, >C11l-CO-), 3.9'-4
,4(,2HIll#>C< , >CM-N< )
, 5.30 (2H, ABq, J-22°14Hz,
-〇CH! mr), 7.57 (2H, d, J-8Rg. arom, II), &10 (2H, d, J-8Hz, a
rδm, summer) Elemental analysis value C19HHH2,068-1
20 calculated value 2 C53,76 + H5,69! H6,59
Agree value: c 54.12; H5,36Hw 6.2
7 Example 29 5.6-V-3-ethylthio-6-(1-hydroxy\
-1-methy~ethyl A/)-7-oxo-1-azabi V
ro(3,2,0)hept-2-ene-2-carboxylic acid
4-Nitrobenzyl ester of the sodium salt title acid, TO''f
(Q, 17 mmol), sodium hydrogen llate
14111, Tetofuhi F Rofuran 7j, pii7.0li
Add 10% Pd-C70# to the acid buffer Tmofi mixture.
In addition, hydrogenation is carried out at room temperature under normal pressure for 1.5 hours. 10 whispers
After adding pac-c 7G# and adding water S for another 3 hours
, the catalyst is filtered off and washed with a small amount of water. Combine the filtrate and washing liquid.
Tetofhydrofuran [After distilling off under reduced pressure, the obtained
This solution is washed with ethyl #acid and concentrated under reduced pressure. concentrated
cuff chromatography using AD-2
Attached to Gufui (H2O), υV spectrum ~ is 297
When the fraction with absorption t at nm is collected and lyophilized, the title compound is obtained.
The product is obtained as a colorless powder (21q). Engineering/Image: 175G m&X UV λH20nm (WE): 297 (268) Weight &
X IMB (90MHz, D20) #: 1.33 (3H, t
, J-7Hz. -CI! , CI, ) , 1.43 , 1.53 (each
3H, sX2゜-CH2N2), 2.98(2H,
q, J-7HI, -CH2CH3). 3-23' I H= d d , J-17p l
OHz, > C < a f ). 1113 (IH, d, J-6Hz, >CH-Co-),
3.98 (IH=dd-J-17#9Hz
, > C < x ) s 4.3 4.6 (IM,
Maro, >CH-M< ) Example 30 5.6-V-3-(2-hydro-diethylthio)-6
-(1-hydroxy-1-methylethyl)-7-oxo
-1-azabicyclo[3,2,0) to 7')-2-ene
-2-carboxylic acid 4-nitrobenzyl ester 5,&-3'-4-[3-diazo-3-(4-nitro
Bendi-oxycarbonyl)-2-okinprobiμ)-
3-(1-hydroxyV 1-methylethyl)a(thidine
-2-one (benzene solvate) 3511F (0,7
5 mmol) according to the method of Reference Example 21.
5,6-cis-6-(+-hydroxy-1-methylethyl
)-1-azabicyclo(3,2,0)hebutane-3,
7-Sion-2-★μ bonic acid 4-nitrobenzyl es
Teru's anhydrous acetonitrile fi130d solution with a base atmosphere
V isoprobideethylamine 0.16M (Q
, 93 mmol), then di7=)v phosphoric acid
Lorido Q, 19511t (α93mmol) i plus 9
Stir for 0 minutes. Add diisoglobilethyl μ to this mixture.
Amine 0.255s/(i, 44 mmol)k
Add, then 2-meter force y” to xl no N0.105w
Add t(1.44m Oboro 01) and stir for 16 hours. The reaction solution was diluted with tS acid ethyl chloride and added to the saline water.
Separate the organic layer. The organic layer was washed with water and dried (Iag804
), the solvent was distilled off and 1. Residue at 70 lj-fi/l
- Kahum chromatograph used (hexane-acetic acid ester)
When exposed to water, the compound turns into a colorless insect (14
21F). Melting point 129-133°C (decomposition) KBr -1 1Rνmax 3: 177G (2H) IMN (60MHz, CDC13) J: 1.27
．． 1.49 (each 3H. sX7, -CH2N2), 1. Si2 (2
H, b, s -, -OH x 2 people dan 2.9-1f (3H, m, -8C dan, CH2-, >
C<11). 155 (IH, d, J=6Hz, >CH-Co-),
3.6-4.3(4H,!l, -8CH2C!2-
OH, >CH-M<, >C<dan). 5.32 (211, M B (l a J=24, 15H
z, -0CH2Ar). 7.10 (21, d, J-5lHz, arom, H),
11.21 (2H*d, J=8Hz, arom
, 11) Elemental analysis value 019H22”2 o, S needle
Calculated value: C54,02s II 5.25; M 6.
63 dormitory measurements: C53,77i H5,16i N 6
．． 2G Casting Example 31 5# 6-Psu 3-(2-HydroxyVethyμthio)-
6-(1-hydroxy-1-methylethyl)-7-ox
So-1-Azabi ν entrance (3,2,0) Hebuto 2-Kon
-2-carboxylic acid sodium salt - 4-nitrobenzyl ester of carboxylic acid μ91 (
(L211mamol), leg acid hydrogen +)! J”7A3T
Da (a◆4 鳳Bol ) a Tetrahydrofuran 9-O
Add 9 d of water and 9 d of water,
Hydrogenate at normal pressure and #1 temperature for 2 hours. Separate the catalyst by filtration,
After washing with a small amount of water, combine the filtrate and washing liquid and
Fufun is distilled off under reduced pressure. The resulting aqueous solution was diluted with ethyl acetate.
Wash with μ and concentrate in vacuo F. Concentrated liquid t amber fi
Cafum chromatography (H,
O) and has absorption at 298n in the UV spectrum.
The title compound was collected and lyophilized as a colorless powder (3
3#) is obtained. X R, ] [Br il, t 750Wa &
)11LX MMR (9G11Hz-D20)': 1
．． 45-L60 (each 3i[.ax2.-CH5X2), 3.11 (2 tuna 9.
t, -scCH20H). 120 (11, ad, J=17y 1GHz, >C<dan
). 3.88 (11, d, J=6Hz, >CH-C
o-), 3.8-4.1 (3H1 tumor, >C<H, -
BCM, CH20K), 4.45 (IH, m, >C
H-M<) Example 32
#l&/bonyl)aminopropyNthio]-6-(1-H
Floki$/-1-MethiμEthi14/)-7-oxo-1
-Azabicyclo[3,2,0)hebdo2-en-2-
force μ bonic acid 4-2F Lopendi ~ Esthe μ 5.6-
Ny/I/OkiS/ForceμBoni, &)-2-Oxo10Bi
)-3-(1-hydroxy-1-methyμethyl)a(
Thidine-2-one (pen(n) hydrate) 2!?O”l(
Prepared according to the method of Reference Example 21 from 0.53 mmol)
5s &-'No 6- (1- to droxy-1-meth〃
Ethi μ)-1-azabicyclo i, 2.0) hebutane-3
, 7-Sion-2-Bonic Acid 4-Nitrobenzene
Stell's anhydrous acetoni) UA/25s [nitrogen atmosphere in the liquid]
Below, diyne 10 biethyl amine 0.11 m ((
L, 88 mmol), then shift ``1''
*! Chronic acid 9pH3wJ (Q, 63 mmol)
Add and stir for 80 minutes. Diinzolo in this mixture
, pyx-amine Q, 14m (0,8mn+
ol) t” and then 3-(4-nitrobendiy
Oxycarbohydrate ~) Aminopropanethio A' 179
Add 'f (0.64 mmol) and keep it at 0℃ for 3 hours.
After death, Diine 1g PiH Echimuami 70.07s/
(0.4 mmol) 1F3- (4-nitropene
Diμoki V KaμPoni Jv) Aminopropanethio-pv
89q (0.32ml 1ol) [Additionally 16 hours
Stir the two reaction solutions and dilute them with Ajisen Echip and add to the saline solution.
Add an ice cube and separate the organic layer. Organic mt water washing, drying (
After (M% 804), the solvent was distilled off and the residue was
Cafe Chroma F Goufui using μ (#acid ethiμm
When applied to xane-2:1), the title compound was converted into a pale yellow foam (
1311#). υma λ n m (EL): 264 (2
8G), 318ax (164) lflLR (90MHz, CDC13) J: 1.29
．． 1.51 (3M each. aX2.-CH3x2) + 1. a-2,0(2Hs”
*-5cm2c5 C112-)-2,01(I Hl
l1l --On) #2.7-14 (5H-v
a --8CHZ CH2Cdan, N<, >C<")
. 159 (la, a, Ja-5Hz, >CH-CO-),
4.0-4.5 (2H, m, >C<dan, >Ca1
l-1 < ), 5.111 (2H, s. -0C4m r ), 5.31 (2H, m B q * J
-24g 15 H2s-OCH2Ar), T,
2-g, 3(8H, m, aroma, H) Example 33 5.6-cis-3-(3-aminopropyNthio)-6-
(1-hydroxy-1-methyμethyl A/)-7-oxo
-1-azabicycloC3,,2,0)hept-2-ene
-2 4-nitropendyl ester of 134”
f (0,22 mmol) of tetofhydrofuran 25
m, a mixture of 12 m of pH 7.0 phosphate buffer and 12 d of water.
Add 10% Pd-C134# to the combined solution and 1111 under normal pressure.
-1-9 (llllf hydrogen Jl addition!.tospa-
After adding c5ooqt and hydrogenating for another 2 hours,
Filter the catalyst and wash with a small amount of water. Filtrate and washing fI/L
are combined and tetrahydrofuran is distilled off under reduced pressure. profit
The aqueous solution was washed with ethyl acetate, concentrated, and amber
Column chromatography using PhytoHAD-21 (
Subjected to H2O, 5% EtOI (). U mass solid) Collect one absorption amount to 298 nu with μ
When freeze-dried, the title compound becomes a colorless powder (28q).
can be obtained. III v cm: 1000m&X UV λ2am (I'%): 298 (246)! II
JLX 13 IMB (90M Hs e D t O)'
: L 44.51.57 (each 311゜a x 2.-
CH5X2) $ 1.9-2.3 (2H*”
s-5-8CH! , CHR->, 19-3゜4<
5 Ht m +-sc Danme: H2CM) Summer < ,
>C<-), 3.86 (IH, d. J-111m, >CH-CO-), 3.8-4.2
(III, 臘. > C < x) e 4-8-4.6 (I H*
m e > CH-N < ) Practical inversion 5.6-V Sue 3-(2-7~Holinoech~Thioto-1
i-(1-I:Fp-1-methylethyl A/)-7-
Oxo-1-azabicycloC3,2,0)hebdo-2-
4-nitrobene y ~ ester 5, @-t/su 4-[3-diazo-3-(4-nitro
BenzyloxoV Calponiμ)-2-Oxo-1a Biμ)-
3-(1-hydroxyVi-methylethyl)itidine
-2-one (benzene solvate) 2341F (0,
5mm+ol) according to the method of Reference Example 21.
5, 6-V-6-(1-hydroxy V l-methie
H)-1-azabicycloC3,2,0)hebutane-3
,7-thion-2-force~bonic acid 4-nitrobenzyl ether
Super poisonous atmosphere in the anhydrous acetonitrile 1v20st solution f&
Diisopropylethylamine 0.11 at 0°C under ambient atmosphere
sg (0,833 mmol) t-added, then diluted with
Phenylphosphoric acid chloride 0.13wl1 (Q, 63
mmol ) for 90 minutes or l! Mix. This mixture
diisopropylethylamine 0.14s/(0,
8iamol) f, then 2-μholinoethμ
Me μ force 1 tongue 94q (0.64 mjl mol)
Add and stir for 6.5 hours. In addition, diiso 10 biμe
Thi-Amine Q, OTml (0.4 mmol) and 2-
Mopholinoethyl memu captan 47 da (0,32++n
aol) and stirred for 15 hours, then diluted the reaction solution with vinegar.
Dilute with ethyl acid and add to saline solution under ice cooling to separate the organic layer.
take. After washing the organic layer with water and drying (Nag804), the solvent
was distilled off, and column chromatography using the residual tfluori v-μ
When subjected to tography (#ethyl acid), the title compound is colorless.
Obtained as crystals (100IF). Melting point 172-173℃ I Rw"raIr": 175Q 15LX UV λ nm (1'%): 265 (228), 3
20 Tobiyo Old 11ax1aII (260) IMR (6OMHm, CDCl5)': 1.
26.1.51 (each 3Hs ex2 y -CH
5X 2 ), L'T 8 (l H* s *-0
H), 2.32-3.08 (IIH, m, -8CH,,
CH2-. -8CII2C! ,,I< , >C<, , >C1
-N<, ;cm-co-). 5.32 (2H, MUBqa'-24p 15 Hz
-OCR2mr). 7.59 (2H, d, J-13Hz, aroma, H)
, 8.19 (2H#d, J-8Hz, arom, H) Elemental analysis value 023H29"30'i'8・'/H
,0 calculated value: C55,18+ H6,04; I B
, 39th dormitory measurement: C54,73it 6.03i M
8.17q Example 35 5.6-3'-3-(2-morpholinoethylthio)-
6-(1-hydroxy-1-methyμethy~)-7-oxy
So-1-azabicyclo(3,2,0)hebut-2-nin
-2-carboxylic acid 4-ditropendiester of the title carboxylic acid 105
(α2 mmol), tetrahydrofuran 20sf
, mixed with 10 sr of pH 7.0 phosphate buffer and 10 jp of water.
Add 10 whispers of pd-c105 cape to the mixture and bring to wi temperature under normal pressure.
Hydrogenate for 2 hours. Filter the catalyst and wash it with a small amount of water.
After that, combine the filtrate and washing liquid, and add tetrahydrofuran under reduced pressure to F.
Kla! l leave. Wash with the resulting water bath solution 10 ethyl ester.
and concentrate under reduced pressure. Zip the concentrate into Amberphyto
Column chromatography using 2 (H, 0, 10 ports)
toil) and absorbed it to 294n with σ mass spec μ.
When WIt is collected and lyophilized, the title compound is eliminated.
Obtained as a colored powder (12'f). I RνKB' s-1: 1760 1aX UV ^HROnu (1"): 294 (165)
Grave &
1.44, 1.57 (each 431yo[. so2. -CH5X 2 ) -2,91-162(
11H-4,24(5H,m, -80H2C'HJ, -
N<, >C<a. >CM-Co-), 4.51 (IH, m, >
CH-M< ) Guest Example 36 5.6-$'Susu--(4-pyridylmethylthio)-6
-(1-hydroxy-1-methylethyl)-T-oxo
-1-azabi V black (3,2,0) to 7')-2-en
-2-force ~ Bonic acid 4-nitrobenzyl ester μ 5 ,6-8'-4-[3-diazo-3-(4-nitro
Lopen vA/oxyca~boniμ)-2-oxy10bi*
)-3-(1-hydroxyV-1-methylethyl A/)a(
Tidin-2-one (penzene solvate) 234”f(0
, 5 m length o1) according to the method of Reference Example 21.
5, @-$'-6-(1-hydrikily-1-methyl
Ethi-)-1-azabicycloC3,2,0)hebutane-
3,7-Sion-2-carboxylic acid 4-nitrobenzyl
Esthetic μ's anhydrous acetoni) 'J/' 20M 1l solution
Under elementary atmosphere, 0°C
N0. i Add 111t (0.63mmol)f, then
De'diphenylphosphoric chloride 0.13 d (0,
65 mmol) f and stir for yo minutes. this
Add diisopropyl ethyl amine a, o to the mixture 7s/
(0.4 mmol) and then 4-mefi/S block.
Tomethi~pyridine 11 O”f (0.64 mmol)
Add and stir for 90 minutes. In addition, V isop
~Amine 0. OTd (0,4 mmol) and 4-
Memucaptomethi〃Pyridine 401iF (0,32mmo
l) was added and stirred for 18 hours, then the reaction solution t#
Dilute with ethyl chloride, add to saline solution under water cooling, and separate the organic layer.
take. After washing the organic layer with water and drying (Ia so ) for 2H, the solvent was distilled off, and the residue was purified using a filter using Florigi-A'.
Hum chromatography (#acid ethyl p-hexane-2:
1), the title compound was converted into colorless crystals (104+Il).
can be obtained. Melting point 181-182℃ I RyKBror': 177G ax UV A yam (Ei3): 262 (291), 3
15 (293) IMR (90MHz, DMSO-d6) #: 1.
13.1.20 (each frozen 3n, sX2, -CH5
X2 ) e 3.0-:(,29(tns m #
4, 17 (2H-a = -5ea2-)-ri, (
aNH, so-○ old-5, 31 (2H, ABq, J-2
1-15Hz*OCH>Ay'), 7.30 -1
169 (8H, m, aroma, H) elemental analysis value C23
H23N3 o58 calculated value: c 58.83; H4
,93; N 8.95 dormitory measurement: C5B, 76s H
4,981M 8.94 Example 3T5, @-v-3-(4-pyridylmethylthio)-
6-(1-hydroxy-1-methyμethyl)-7-oxy
So-1-Azabicitaro (3,2,0)Hept-2-En
-2-forceμbonic acid sodium salt standard-force~bonic acid 4-
Nitrobenzyl ester 200at (Q, 42 mm
ol), Tetofhi F Lofuran 40 d tpHl, 0
10 to a mixture of 205 g of phosphoric acid IIW solution and 20 d of water.
Add Pd-C200Qt and hydrogenate for 3 hours under normal pressure.
Add. Filter the catalyst, wash with a small amount of water, and wash with the filtrate *
1*- and distill off Tetotsu and Dorofuran under reduced pressure. The resulting aqueous solution is washed with ethyl acetate and concentrated under reduced pressure.
. Kahumuku using concentrate t Amberlite XAD-2
After separation using H2O, lyophilize
When dried, the marked compound is obtained as Shimairo powder* (58q).
Ru. Engineering Rν 3: 1750 1n&X UV λH2°nm (E”): 262 (144), 2
9B@H1a11 (252) IMil (90 Hz, D O)': 1.35s
1.49 (each 31°so2.-C1L, X2>
, 107 (IH, aa, J-17, i. Hz, >C< ), 3.75 (IH, ad, J=17
．． 9Hz. ■ >C<H), 176 (IH, d, J-6Hz, >C1l
[-co-). 4=25 (2H-s --5ca2-) s 4.
3 Q (l H, rm a>0H-N< ), 7.
62 (IH, d, J-GHz, aroma, li). 8.61 (IHyd, J-6Hz, arom, H) element
Analysis value C16H17N20a SNa' 3H20
Calculated value: 璽a 5.60 Refreshing value: Summer 5.40 Example 38 5.6-Vsu 3-(2-bili$/A/methiμthio)-
6-(1-and droxy-1-methylethyl)-7-ox
So-1-Azabi V Kuro C3, 2, 0) 1 to 2-kun
-2-carboxylic acid 4-nitrobendi~Sd y 5 s 8 ''-'su 4-(3-diazo-3-(4-
Nitroben 1u oxycarbonyk)-2-oxo 1a bi
)-3-(1-hydroxyV-1-methylethyl)aze
Tidin-2-one (benzene # solvate) 234 Da (N5
mmol) according to the method of Reference Example 21.
5, 6-5'-6-(1-hydroxydi-1-methy)
μeth/l/)-1-azabishik a(3,2,0)heb
Tan-3,7-sion-2-power/niboxylic acid 4-nitro
Anhydrous acetonitrile 2051g solution of Benji Esthep
diimpropyl-ethylamine Q at 0°C in an electric atmosphere.
, 115j (0.63 mmol) was added, and then
Diphenyl phosphoric acid loli) Q, 13sd (0.65 servings m
Add ol)k and stir for 90 minutes. I'm crazy about this corpse metal thing.
Amine Q, 14TIIl (0,8 sets n
ol) 1, then 2-mecaptomethylbily
Add Shin BO Misaki (0.64 mmol) and stir for 90 minutes.
Mix. In addition, diimpropylene amine 0.07s
/ (0,4 mmol) and 2-meμcaptomethyl
Add 740 ``11 (0.32 mmol)
After stirring for 4 hours, dilute the reaction solution with ethyl acetate.
Then, add it to saline solution under ice cooling and separate the organic layer. organic layer
After washing with water and drying (M smell 804), the solvent was distilled off and S! trade
Column chromatography using Florigi 14/
-(Ethyl acetate-hexane-1:1) When K is attached, it is a compound
The product is obtained as colorless crystals (102q). Melting point 87-118℃ Ward Br -1 Engineering HJ/, aX3: 1000 wtom 1 attack U v A! ll1 (N1.):
263 (307) 1318 (279) Otori ax IMB (60M IIs, CDCIs)
' : 1-25- L 52 (3H each. sx2.-C13x2), 1.93 (IH, a, -
0H), 3.24 (IH, dd, J=17.9Hz,
> C < 1), 3.59 (I H, d, I = 611 m
, >CH-CO-), 3.86-4.40■ (411,m, >C<dan, >CH-M<, -8C
H2-). 5.37 (211, MU B q s J -24-15H
z, -0CHz). 7.18-a, 39 (8H, m, aro+n, H) element
Analysis value C,”!!3”306 B・”72H20 total
Calculated value: C57,73 m 5.051 N 8.78
Screening value: C57.81; n 5.05; x 8.
8091! Example 39 5, li-$/su3-(2-viridiρmethiμ
)-6-(1-droxy-1-methylethyl)-T
-Okin-Sumi-Azabi V Kuro C3, 2, 0) Hebudo 2
-Kon-2-forceμbonic acid sodium wood 41M**bon
Acid 4-nitrobene! /A/Esthetic μ90 da (0,19
mmol), tetofhydropun 11IId, pH
7,0 phosphate buffer 9d and water fJd mixture WI 1
Add G'$Pd-C9G drops and leave at room temperature under normal pressure for 4 hours.
Hydrogenate. After filtering the catalyst and washing with a small amount of water, the filtrate
and the washing fIIL, and the Tetotsuhi F Loafun was placed under reduced pressure.
To leave. The resulting aqueous solution was washed with ethyl acetate μ and then dried under reduced pressure.
to make rope. Concentrate T Diaion IP-20 (Mitsubishi Chemical
Column chromatography <II, using Seisha Co., Ltd.)
0, lO%mton)KN, and dived with 10 attacks mtoH.
When the sample is freeze-dried, the title compound becomes a colorless powder (2
3#) is obtained. IR&=III! LXcs: 1750U λH
2°nm (1”): 264 (172), 2!ll11
1aX 1c11 (258) I M E' 9 Q' Hz -D 20)
''' 1.33-1-42 (3H each. BX2, -0M3X2 > , 3.13 (In, a
a, J-17゜10"is e>C<H)
e N74 (I H# d d#' ”” 17
-91z a > c < n > * 3-75 <
I H-a, x 1Hz #>CM-CO-),
4.30 (211,a, -BCM-), 4.
31 (11,a, >CM-N< ), 7.40-8.
67 (4H, m. arom, H) Example 40 5.6-5/su 3-[3-(6-dimethymu amino birylate)
Dajini~)thio)-6-(1-hyphrokiV-1-methyl
-7%-oxo-1-azabintaro [3,2,
0) Hebdo-2-ene-2-carphonic acid 4-nitrobe
ester 5,6-3'-4-[3-diazo-
3-(4-NitrobeneyluokiVpowerupo2μ)-2-O
xopropyl-3-(1-hydroxy-1-methy-ethyl
4/) A(thidin-2-one (ben(n) solvate)
234q ((15mm+ol) to reference example 21
1111 according to the law 5, 6-1' Sue 6-(1-Hi)
Doroki ￥-1-MethiμEchiμ)-1-AzabicycloC3
,2,0) Hebutane-3,7-cyone-2-hydrocarbonic acid
Anhydrous acetonitrile A' of 4-nitrobenzyl ester
20sf solution K11m atmosphere F, diiso 10bis at 0℃
Add μethyl μamine 0.11m/(0,63-O1)
E, then 0.13sg of s/phenyl phosphate chloride
(0.63 mmol) and stir for 90 minutes. child
6-dimethylamino/-3-merca-1 tovirida in a mixture of
Jin's lithium salt 1611If (1,04■m01)
In addition, 2 hours at 0℃! 1. Mix 5. Add #acid and ethyl alcohol to the reaction solution.
Dilute with ~, add to saline solution under water cooling, and separate the organic layer.
. After washing the organic layer with water and drying (lra, So, ), remove the solvent.
The residue was purified by column chromatography using Floatsie A/L.
Matogutufi (#ethyl acid) The title compound appears pale when attached with K.
Obtained as yellow crystals (Somisaki). Melting point 178-179℃ (decomposition) (356) Elemental analysis value C23Hgs l5068 calculated value: C5
5,30 animals 115.04; I 14.02g4 value:
C55,14i III 4.96i I 13.6
5 Guest Example 41 5 x 6- V no 3-(3-(6-dimethylamino)
Viradajiniμ)thio)-6=(1-hydroxy-1-methane)
μethyl/l/)-7-oxo-1-azabicyclo(1
,2,0)Hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester of µm 05
"f (0,21 mmol) of Tetofuhhi F Lofuran 20
m, main ~ 5 m, pH 7,0 phosphate buffer 12 m and
Add 10 whispers of Pd-C105#f to the mixture of 12-
I usually add water check sts at 2 o'clock in EET*al. Catalyst T filtration
After washing with a small amount of water, it is fine! Transfer the Il medium to Kfl under reduced pressure.
do. The resulting aqueous solution was washed with ethyl acetate and placed under reduced pressure.
Concentrate. Concentrate t Amberlite XAD-'lt-
Column chromatography (IIito, 5% 1t)
OH) and UN)L vector at 292 nm K1
When 1 μ of the sample was collected and lyophilized, the title compound was freed.
Obtained as a colored powder (41ml). I II m""ar': 175G Oboro & x6 UV AMgOnm (1"): 292 (382) 1a
x13WMB (90MHz-D20)':
1.30-1.50 (3H each. 5X7s-CHsX2'), 2.58 (in, dd, J
-IF. dan 101m, >c< ), 12@(iii, e, -
1(cH3)2). &@1 (I H, dd, J-17s 9Hz
, >c < H) −171(IH, d, J=6Hz,
>CI-Co-), 4.3 (11°ya, >C11-
K< ), 7.22 (IH, d, J 7gH
z, aroma, H). T, TO (IH, d, J=@Hz, arom, H)
Example 42 5, 6-8' Sue 3- (E-2-A7! Midovini pchi
e)-6-(1-hydroxy-1-methyethyl)-7
-Okino 1-Azabi V Kuro C3, 2゜0〕Hebudo 2
-Econ-2-carphonic acid 4-nitrobendi-este~ 5.6-Vsu-4-[3-diazo-3-(4-nitrobenedi
Oxygenyloxy cliff Boni A')-2-oxopropy~)-
3-(1-hydroxyV-1-methylethyl)a(thidine
-2-one (ben(n) solvate) 234q (Q, 5
++u+aol) according to the method of Reference Example 21
5,6-cis-6-(1-human V-1-methyl
Ethyl)-1-azabi Vri] 1 ton to the mouth (12,0)
-3,7-Sion-2-*W Bonic Acid 4-=)Lobendi
Anhydrous acetate of μ Esthe μ)=)9A/25s [Liquid in nitrogen atmosphere
Under ambient air, O"CeN4yyabiIWZfμmmiy0.
12d (0.69 mmol) and then Sipheni
μ Phosphate Loli & Do 1st 4s/ (Q, @ 8 mm
ol) Add? Mix jiO minutes or t1. this mixture
to 1IaI 750”liF (5msaol) and 1-
2-acetamidoethylene? Thiol @filling 167'llC
o, 75 mmol) and stirred for 2 hours.
Separate at filtration. After distilling off the solvent, add ethyl acetate and food to the residue.
Add salt water and remove insoluble S. Separate the ethyl acetate μ layer, wash with water, and dry (Na2804)
Afterwards, the solvent is distilled off. Residue [Florigi pt use body]
Tsum chromatography (ethyl acetate-hexane-2:
1. #Acid Ethyl μ), the title compound turns into pale yellow crystals (1
5551). Melting point 1:2-1113°C (decomposition) IRy"rs-": 175Q, 1700. 162
011&! 262 (38T), 3215 (371) MMB (@
QMIs, DM80-(16)': 1.15
-1.33 (3ii each, sx2.-cm3x2)
a 1.93 (3i, ts, -cocH3>. 2.9-13 (III, Otori #>C<i), 155 (l
it, d. J-@Hm, >Cl-Co-), lit-4,3(
2H, 11°>c<”, >CH7M<), 4.
7 (11, b, -01), 5.37 Hayabusa (2M, MU Bq # J = 21 # 14 Hz,
-0CHBAr), 5.87(In, d, J-1
411z, -8-Cl-CH-H<), 7.
07(III, dd, J=14.13Hz, -8-Cl
-Cl-Natsuto). 7.75 (211, d, Jm8Hz, arom, 1ll
), 8.20 (2! I, d, J-8Hz, arom, H
), 10.28 (IH+cLJ-131[x, -CH-
MH-) Elemental analysis value C2□H23m130.8 Calculated value: c
54.661115.02; II 9.11 actual value:
C54,58g M 5.26; I 8.92*
Example 43 5.6-cis-3-(E-2-ace!miFviniβthio)
-8-(1-hydriki V-1-methy~ethyl, 5k)-7
-oxo-1-1zabicyclo(3,2゜0]hept-2
-ene-2-carboxylic acid sodium salt title power ~ 4-nitrobenzyl ester of carboxylic acid 150'
f ((L33 mmol) of tetofhydride 97 hts
Add hydrogen chloride to a 15 mg solution of MI and water) 3Sall
O% Pd-C150aft addition, tte, s reduction 1ii
Hydrogenation was carried out for 4 hours at 1 o s pa during the reaction.
-c t1 hour tK150q, 50'lF addition after 3 hours
Add! ). After filtering and washing with a small amount of water, combine the filtrate and washing liquid.
The aqueous solution 1/l of organic Sat is distilled off under reduced pressure.
Wash with ethyl chloride and concentrate under reduced pressure. - Concentrate
Katsumu using Iaion HP-20 (manufactured by Mitsubishi Kasei Corporation)
Ta! Added to matogufui (H, 0, 5 ItOH),
UV smooth ~ 230 and 310 n+a Klt
If you collect 1m of at and dry it in a refrigerator, the title compound will be free.
Obtained as a colored powder (75q). Uma λ丑n璽 (I jcg): 23 G (
396) -310(444) M M B (100M Hjc-D t O)'
: L 30- L 44 (3H each. 172 (lH, d, J=@Hss, >CH-Co-),
3.75 (IH, ad, J=111.9Hz, >C<
), Ca, 4.3 (I H-ms>CHI<
)s i07 (I Had -J-13Hz--
8CI-CHI-Seal < ), 7.14 (IH, d, J"
13Hz. -F3CH-CH-M< ) *Example 44 5.8-$'susu--(Σ-2-acetamidobinis
FiniA')-6-(1- and FlokiV-1-methipethyl
/L')-7-oxo-1-azabi V KuroC3,2,0
) to 1-2-en-2-carboxylic acid sodium salt 5.6-cinu-3-(1-2-acetamidovinylthio)
-8-(1-HydroxyV-1-MethiμEthiA/)-7-
Oxo-1-Azabi V Kuro C3,2゜0] to 1 to 2-
Water of 83q of carbonic acid sodium salt 8af
Add chloroperbenzoic acid (80%
Purity) Add 45 sips and stir for 30 minutes. Reaction solution t#
After washing with acid ethyl alcohol, p17.9 phosphate buffer (0.5 g
/ ) and concentrate under reduced pressure. Dial the concentrate
Column chromatography using Ion IP-20 (manufactured by Mitsubishi Kasei)
It is separated by chromatography (H, O) and then labeled.
2IIIll isomer related to sph-VFK of the title compound
(mm~1)° are each obtained as a colorless powder. Isomers
It is distilled into the lungs of people. ) Yield 21L5q IRw7:as”:1rra, 1690.162
0UV 12GmcH'%): 252 (40(+),
287wax 13 (319) NMR (D,, O, iooMHz) #: 1.34, 1.
45 (each 31゜a X2 e -CH3x2) s
2-15 (3Hms, -C0CH3). 3.14 (Ht, dd,, r-1γa11az, >c
<->. 3.84 (1M, d, J-5Hz, >CM-co-),
184 (IH, ddjJ-17, 8Hz, >C<
)jC&, 4.6 days (l H-m s > CII-N < ) -L 3
Q (I H-d -J-14Hz 1-81-8C
H=C< )-7,55(IH,d, J-14hz
. -8CH Rape C Dan-1〈 ) True Form 1 Yield 34.2 drops IRy,,,as: 1rrG, 1706.1620
U11A”Zonm (EL)’ 244 (4
09) -290 speed &X (352) IMB (% O-100MHz) a:
L 34- L 45 (3M each. @x2 e -CH3x2) + L 15 (31
#8, - COCHs) C3,05suH,dd
, J=17,11Hz, >C<-). 3.81 (1M, d, J-6Hz, >CH-Co-),
19G (IH. dde'-1r + 9a z t > c < a
># CJL -4,5 (I Hem w>C
M-M<), 6.39 (fil, d, J=14Hz. -acdan-cm-x<), 7.55 (IJa, J-
14Hz. -80H-CM-N< ) Example 45 5, @-V-3-(3-ace!midoprop-thio)-
6-(1-hydroxy-1-methylethylμ)-7-oxy
So-1-Azabiliclo C3,2゜0) to 1)-2-engine
-2-carboxylic acid sodium salt 5.8-8'-3-(3-7minoprobi-thio)-1
i-(1-hydroxyV-1-methylethyl)-7, etc.
-1-Azabicyclo(3,2,0)hept-2-ene
-2- Cliff Rubon 911201111:) Water t5d and
Tetrahydrofuran 6.5s [* Hydrogen carbonate at 0℃]
Add 4.2 s UI of water to 15 q of U ram, and in the next step
acid a, 6 liters of tetrahydrofuran 5t, ssy solution
Add and stir for 20 minutes. Concentrate the reaction solution under reduced pressure.
After washing with ethyl acid,
Kabumu Chromatography (H,0
) Add K. 299nm Klt absorption in UV spectrum N
Collect the minutes11. Colorless powder (101Ig) when dried
The target compound is obtained as . KBr-1 1R&,. 3:1750. 1635trvaHg
°nu (1'%): 299 (248) 11JIX
la MMB (100MHz - D g O)'
: 1.33-L44 (3H each. 8X2.-CH,X2), 1.7-10 (21[, m.-8C1,CH40il,-), 102 (3H, 8
, -COCH,). 2J -4,0(@it, m, -80!!,C
1l, CM, M<, -CM, -). 3.74 (11, d, J-6Mm, >CM-Co-),
4゜2〇-4,43(1114,>CH-1< )V!
Example 4 @ e 1! -'Sue 3- (21 pieces Muimido Irua
minoethiμthio)-6-(1-hydroxy-1-methip)
Ethiμ)-7-oxo-1-azabicycloC3,2,0
) hept-2-ene-2-carvone-5.6-cis-3-(2-aminoethylthio)-1i-
(1- and F-roxy-1-methylethyl A/)-T-oxo
-1-7 ZabicycloC3,2,0) 1 to 2-engine-
2-Carvone #441FF) pH 17,0 Phosphoric acid 111
11[Add 2-Summer aoI f to the 11Mt solution under ice-cooling.
Prepare to pif&5. , pen y14/hoy in solution of jin
Fuimidate Hydrochloride 190IIIt - Small amounts for 5 minutes
Add as required. During the addition, the p of the reaction solution was adjusted with 2m-MaOll.
Maintain Ht 8.5 K, stir for 5 minutes, and after death, reduce the reaction solution to 1
Adjust the pH to 7.0 with Natsu HCI and wash with ethyl chloride. After concentrating the aqueous layer, Diaion MP-20C Mimo Kaseisha I
I) 1J@column chromatography (1120°
3S acetone) and eluted with 3A7F.
f: When collected and freeze-dried, the Hamagami compound becomes a colorless powder (32
11). XMB (8011Is, DzO)': 1
．． 43.1.56 (3 m each!. s X 2 , -cI3X 2 > m s, 0-3-
4 (8n e wm s -8c y CH2-. >Chi >, 3.6-4.2 (3H, m, -F3CH
, CM, II<. >C<H) -3-87(I H, d a J-6H
z->C1i-Co-). 4.4 (IH, ms>CH-M< )-1100(
I
-10bithio)-6-(+-hydroxy-1-methylμ
Ethiμ)-7-oxo-1-azabicyclo(3', 2.
0) to 1) -2-ene-2-force μbonic acid 5.6-cis-3-(3-amino-10-biruthio)-1(
1-tFa*y-1-methylethyl)-7-oxo-1
-Azabicyclo[3,2,0) to 1)-2-ene-2-
1py ponic acid 301fopH7,0 phosphoric acid iiw solution 7.
Add 1 ice-cold F2N-NaOH to the 5d solution and adjust the pH to 15.
Arrange. This 1lIIftKbensilhomuimidate
Add phosphoric acid jJ [134 da
Ru. During the addition, the pH of the reaction solution was adjusted with 2M-114LOH,
Keep it in the evening. After stirring for 6 minutes, the reaction solution was diluted with 3 l-HCI.
Adjust the pH to 17.0 and wash with ethyl acetate. water layer ts
After a, Diaion HP-20 (Mikaisei Kaseisha 111!>
Cafum chromatography (H,0,3≦A7) using
3 tons), collect the amount to be drawn out in 3-A7 tons, and
When dried, the title compound was obtained as a colorless powder (254).
It will be done. I” “alax C”: 1750.17
15UV λH laziness Onm (1'%) = 298 (2@1
) gallbladder X 13 NMTI (SO'MHz, D20)':
1.41.1.58 (3H each. aX2.-CH3×2), 1.9-2.3 (2nto+
-BCH2CH,CH2-), 2.9-3.4 (
5H, m. d, J=liHz,':<H-GO-), 15-
4.1 (IJm. >c<dan), 4.4 (IH,!II, >CH-N<
), 7.95 (1M. residence, >I-C 1-) Example 48 5 e 6-3' Sue 3-(2-Virrolidinoech~chi#
)-@-(1-Hydroxy-1-Methi voice Echi Sen-7-O
Kin-1-Azabi V Kuro [3,2,0) to 7”)-2-
En-2-carboxylic acid 4-nitrobenzyl ester ~ S, 6-\su 4-[3-diazo-3-(4-=trope
nvμoxycarboni*)-2-Okinderobi~)-3
-(1-hydroxy-1-methylethyl)a(thidine-
2-one (benzene solvate) 234 da (0,5 mmo
5,6-V prepared from l) according to the method of Reference Example 21
Ku6-(1-hydroxyv-1-methylethyl)-1-
AzabicycloC3,2,0)hebutane-3,7-cyone
-2-Carboxylic acid 4-nitrobene S/ru ester
Add water to etryl 20s/# solution under ambient air at 0°C.
diiso 1p biethylamine 0.11 m/(0,6
3 mol) tme, then diphenyl phosphoric acid loli F
Add O,14d (Q, 63 mmol) and make 9
Stir for 0 minutes. Add 10 bil of diyne to this mixture at 0°C.
Ethylamine 114m/ (0,8mmol) and
Pyrrolidineethanethio-4'84'F C0,64!1
1101) and stirred for 90 minutes, then
Diisopropylene ethyl pamine 0.07d (0.4mm
ol ) and pyrrolyleneethanethio-1"42"lF
(0.32 mmol) and stirred at 18:00 at 0℃.
3 reaction solution [Dilute with ethyl acetate ~, wash with water, dry (Ha
, So, ) After distilling off the solvent, remove the residue
- Kawomutaromatogufui using μ (ethyl acetate μm
When subjected to acetone-3:2), the title compound was converted into colorless crystals (8
01F). Melting point 172-174℃ 1 whisper UV λmax x n' (E 1.) ” 6
4 (243)-318(272) NMR (90MHz, CDCl3)': 1
．． 29, 1.52 (each 3111゜@X2.-CH
3×2), 1.70 3.20 (14H, m. -OH, -8CH2CH2-1<, -(CH2),
−, >C<H). 159 (1m, d, J-6Hr,,>CH-CO-),
4.05-4゜32 (2H1m, > CH-M <
,>C<H) -5-37C・2T1 a (1
# J-24, 15H2, -OCH, Mr), 7.69
(2H, de J-1811z s groyn -
H) z &, 22 (Z Hs de J garden @ Is, a
rom, H) Elemental analysis value CC23H29,06S Calculated value: C58,09SH6,14; M 8.83
Vl adjustment value: C58,04+ H6,11+ 18.4
0 Example 49 5.6-￥3-(2-pyrrolidinoethylthio)-6
-(2-hyfluoroV-1-methylethyl)-T-oxo
-1-azabicyclo(3,2,0) to 1 to 2-en-
2-force μ acid 11M carboxylic acid 4-nitropendi Esthe μ85 da
(0,111 mmol) of Tetofuhhi F Roa 5714d,
)ri/-v2d, pH 7,0 Il phosphate pre-solution 1d and
water? s#f) II mixture K 10% p (1-C85m
ft and hydrogenated at room temperature under normal pressure for 2 hours. Filter the catalyst
After washing with a small amount of water, combine the filtrate and washing liquid and add ethyl acetate.
Wash with The aqueous layer is produced under reduced pressure, and the concentrated liquid [Diai
Column chroma using ON HP-20 (manufactured by Kokoku Kasei Co., Ltd.)
1f20-15% EtOII),
Collect and freeze-dry the 15 mt fraction eluted with KtOH.
The title compound is boasted as a colorless powder (36all).
. UV λHR0nm (1”): 292 ('197
) maX 13 Summer MR (ilOMHs, D20)': 1.4J 1
．． 62 (each 3H. s × 2 m - cm3x2), l 13-2.34
(4Hs m #-C1og (Cs), CH2-
), 2.93-3.62 (9■, Satoshi. 34O (111, d, J=6Hz, >cH-Go-),
3.117-4.15 (111, m, >C<3I
), 4.51 (IH, m. >Cl-1< ) Dormitory Example 50 5#6-8'-3-(2-piperidinoethylthio)-
1i-(1- and F-roxy-1-methyμethyl A/)-7-
1)-2- to oxo-1-azabicyclo(3,2,0)
2-oponic acid 4-nitrobenzyl ester 5 #@-'Su4-[3-diazo-3-(4-2F
Lopen sIF μ Oxycarbon A')-2-Okingro
Biμ)-3-(1- and toxy-1-methylethyl)a
(Tidine-2-one (ben(one) solvate) 234 da(0
, 5 mmol) according to the method of Reference Yu 21.
5,6-8'su6-(1-hitofukis/-1-methy
! Echiμ)-1-AzabiVri0(7'j to 3,2,03
F-3s7-slt-2-1I~bonic acid 4-nit
Lopen s/fi/ester black water acetonitrile μ20I
Add diimprovir ethylene to the III solution in a highly toxic atmosphere f at 0°C.
Ruami 70.11sJ (0.63mmol)
Then, diphenyl phosphoric acid chloride 0.14af (a
63 mmol) and stir for 90 minutes. this
Diimpropylethylamine a21m (1,2
mmol) and 2-mecaptoethyl-bihe9 N71
Add 40”f (0.96mmol) f and 1 at 0℃
Stir for 8 hours. Dilute the reaction solution with t# acid ethyl μ and wash with water.
After drying (1 la 280.), the solvent tgl is removed. Residue
Tozumono T Florigi-/L/[Cuff used
(Acetone-ethybutyric acid μm 1:3)
The compound is obtained as colorless crystals (88q). Melting point 147-148℃ x RwKBrai': 177O m&X UV 4 nu (El2): 265 (20
2), 319tOH Tumor&X (229) IMI? (60MIz #CDC15)':
1.2 '3 (3H, a, -CI5) -1,
42-121 (1911, m, -cH,, -OH, -
80H20Mz Summer〈. >CM-Go-), 3.84-4.27 (2M, 臘, >
C<and . >CI-Summer<) = 5-211 (2Ha q -
' 甫24-15 Hz m-0011, mr>a 7
．． 57 (2H, d, J-8Hs, arom, 1 (). 20 (2H, d, J-8Hz, arom, H) element
Elementary analysis value 0544M311306 B・'Aa, . Calculated value: c 57.81 H6,46+ M 8.4
2IX! Adjustment value: c 57.98; H6,47s I
L35 Dormitory Example 51 5.6-cis-3-(2-piperidinoethylthio)-6
-(1-hydroxy-1-methyethyl A/)-7,-o
xo-1-azabicicgC3,2,0)hept-2-enzyme
N-2-carboxylic acid layer force N Bon Shun's 4-=) Lobenge Y Esthe~1251
1 (0,28iamol) of Tet9k) "G179n'"
lQd, pH″7.0 l phosphate buffer #10s/and
10 df of water) Add warm liquid KIO attack pac i25 da.
The mixture was then hydrogenated at room temperature under normal pressure for 3 hours. touch and separate
After washing with a small amount of water, combine the filtrate and washing liquid and add ethyl acetate μ
Wash with The aqueous layer was concentrated under reduced pressure, and the concentrated II solution was
PhytoXAD-2t
- (H, 0, 5% 1qtoa) K with L, 5sItOf
When the amount of li emitted in 1 is collected and lyophilized, the linear layer carboxylic acid is obtained.
phosphoric acid is obtained as a colorless powder (68#). x m az”rar”: 175GWi & X UV A g nma (1”): 295 (192)
O wax laI KM B (903g Hyt, D tt O)'
: 1-55 jL a 8 (3H each. aX2.-CI3X2) a 1.79-116 (6Hs
me-C1l, (C!,), Cl1ll-),
3.01-3.52 (911, m. HClig->C<-, -8CHBC112J<, -CHt-
M< ). 3.92 (IJd, J=6Hz, >CH-Co-)
, 182-4.18 (111 mountains>0<dan 2・4.58(
Mt.lii-C1l-1() Guest Example 52 5mG-s/Soot--(2-(4-Methylvipera N/)
zftatf#]-8-C1-*Fatry-1-Methi
Ruech*)-7-oxo-1-azabinclo (3,2,
0) hep)-2-en-2-car & 114I phosphoric acid 4-
Nidoben yfi/esthetic μ5, $-$/Sue 4-
CB-#Azo3-(4-Nitrobeney~OkiVCarbo
D#)-2-Okinpubi~)-3-(1-HydrokiV
-1-methylethyl)a(thidin-2-one(benyne)
Solvate) Reference example from 234”f (0.5 mmol)
5,6-cis-6-(1-
HydroxyV-1-methyp-ethyl)-1-azabicic&'
(3, 2, 0) to 7”jjy-3, 7-11-2-ka
Rubon # 4-Nitrobendi〃Esthetic Anhydrous Acetoni
) 9 and 20 wt solution at 0°C under nitrogen atmosphere.
10 Biruethylamine Lllmg (0,63 Fengfeng o1)
and then diphenylphosphate chloride l 13 d
(0.63 mmol) and the tio molecule itf
11. Diyne 10-biruethylamine in the Ni-Oa compound
0.21M1 (1,21 idiom.1) and 4-methylbi
9 N/ 1 ft-14y 154”F (0,
Add 9311 mol) and heat at 0°C for 20 hours. Reaction solution t
When applied to NO-*-3:1), the labeled compound -fi pale yellow crystals
(120q). Melting A1811-171℃ Inv”ras: 176G 11LX UV λ:axHnwa (EL): 265 (
224) -318 (2511) NMR (ilOMHz, CDC13) #: 1
．． 31-1.53 (each 3Hjs x 25-CHs
×2), 1.92 (IH, s, -OR)
a15Hz, -OCH, Ar), 7.65 (2M, d
, J-8Hs. aroma, li), 8.21 (2H, d, J-
8Hz jaroa+, H) Elemental analysis value 0g4H32
114o6s-lH2° Calculated value: c 5G, 12s
H6,4'rt M 10.91*Reduction value: c 55.
80; H6,16t H1G, 63t Example 58 5# @-$/Su3-(2-(4-methylvipera V)
) Ethylthio) -6-(1- and Floki\-1-methy~e
#)-7-oxo-1-azabinclo [3,2,0)
4-nitrobenzop-ester of he1to-2-ene-2-carboxylic acid compound lv100If
(12 mmol) of Tetrahydrolaf 720Id. pH? , 1lII phosphoric acid 10wt and water 105g
Mixture of NIK 10% Pa-c 10 osytm
Etetsune 11E'Fii! Hydrogenate in hot water for 2 hours. Touch#
& [Filter and wash with a small amount of water, then combine the filtrate and washing liquid,
Wash with ethyl acetate. The aqueous layer was concentrated under reduced pressure and dialyzed.
Cafum chromatography using Ion HP-20 (
H2O-20%Iton) KttL, 2011 It'
ll i”@The amount to be taken out- [Collect and freeze-dry to become labeled.
The compound is obtained as a colorless powder (43 Da). From J/aM:IT55 1!1aLx UV λlL! 0 nm (K”): 299 (222) m
&! 1 wound IMP (IOMHz = Dg O)': 1.
49.1.66 (8 31 (. 11X2.-CH5X2), 1119-3.511 (1
6Lm. 111g, >C11-Co-), 4.4! I(II,
m, >C<") Example 54 51 B-V-3-(2-ethoxyethyl-3-(2-ethoxyethyl)-6-
(1-hydroxyV-3-methylethyl)-7-oxo-
1-azabishitaro C3,2,0) to 7”)-2-engine-
2-Carboxylic acid 4-nitrobenzyl ester μ 5, @-”Su4-[3-diazo-3-(4-nitrobenzyl
diμoxycarbonyl)-2-oxopropylμ)-3
-(1-hydroxyy-1-methylethyμ)azetidine-
2-one (be7zene JII solvate) 2 g 4q (0
, 5m1m1ri1) from #4 according to the method of Example 21.
The prepared 5,6-cis-6-(1-hyfluorokiV-1-methy
μEthi#)-1-Azabicitalo(3,2,0)hebutane
-3,7-cyone-2-force μbon 4-nitrobendi
anhydrous acetonitrile μ20sfm liquid K111
- V isopropyl ethyl V amine at 0° C.9.
Add 11 mg (0.63 mmol), then diphenyl
Lurin acid loli, F al 4d (al 3 ga
ol) I watched YtlJD and stirred for 90 minutes, this proverb
V impp p pyruethyl μ amine 0.21 dC1,2 for hardware
mmol) & 2-ethoxyethylmerka 1 tough 10
Add 2"l' (0.98mmol) f for 20 hours at 0℃
Stir. Dilute the reaction solution with ethyl acetate, wash with water, and dry.
After (Nag804), the solvent is distilled off. 70% residue
Lizzie μ Society uses Kahumutaromatodahui (ethyl acetate)
-Hexane = 1:・1) When K is attached, the Sake compound becomes colorless.
Obtained as crystal (98■). Melting point 15G-151℃ ``'wax''1: 178Q xtoM1% Uma λ nm (''s) ' 263 (2
50'-315ax (279) 1][R(liOMHz, CDCl5)':
1.12 (3H, t, J-7Hz, -0CH
2C11l 3) -L 211 e L 52 (each
43 Hna ×2 +-CH5')' 2) -
1,68 (I H, s --OR) *182-3.6
1 (8H, Otori, -BCH2CH20CH2CH3,>C
<':,. > CIGO-), 3.80-4.23 (2H, a, >
c<".dan>CM-M<), 5.20 (211, (1, J-2
4.15Hz. -oci2mr L 7.4+ (211, d, Jx@H
z, aroma, H). &(12(2i1.d, J-8Hz, arom, H
) Likelihood analysis value Cal Hg611 j! 07B calculation
Value: C55,98! H5, 81 + H6, 22 * Loss value
: C58,35i H6,00i M 6.42 Toshi
Example 55 5.6-$'su--(2-ethoxyethylthio)-6
-(1-hyfluoroki\-1-methylethyl)-7-oxo
-1-azabicyclo[3,,,2,0) 1)-2-process
N-2-Force P Bon Shun Sodium WoodwI Title 1 Ifiy Bo
4-nitrobenzyl ester of phosphoric acid 90MII (0,1
9 mmol) of tetofhydride g7 fun 18s/, pl[
``1. Mixture of 9 d of O phosphoric acid solution and 9 d of water [K10
%pa-c 90Wt plus 'JliFii temperature at 2 o'clock
Hydrogenate for a while. Catalyst [filter, wash with a small amount of water, filter
Combine the solution and washing solution and wash with #acid ethymu. Water layer under reduced pressure
Cafum black using Diaion HP-20
Added to Matofufui (H2O-10 1 tOH), 1
Collect 1 ittt of the eluted portion with 0% EtOH and freeze-dry it.
Then, the marked hardware was obtained as Kumirokofunkyo (20JlF).
Ru. I RJ/KB"3': 1755ax cry λsnm (E1':, ): 297 (2 $9) 1
111X 1111B (10011Hz, D O) I: 1.30
(3H, t, J-7Hz, -0CII2CH3),
1.42, 1.56 (311.aX2゜5-CIN5'2, respectively) e! 17-3.46 (3H
-ms>C<ue-801gCH2), 3
．． 73-4.26 (5H, m, > CHCO+. -8CHgC3jgOCdan2CH3), 4.48-4.
72 (2H. ■ Proverb, >CM summer<, >c<dan) Dormitory example 56 5.6-cis-3-(2-((+-MethiμBiberaginiA
/)-1-po-ruoxy]ethiμthio)-7-oxy
So-1-Azabi V Kuro C3, 2, 0) 1 to 2-kun
-2-carboxylic acid 4-nitrobenzyl ester 5s8-''-4-(3-'7zo3-(4-nitroben
S/Luoki V Kay Boni A/)-2-Oxo10 Building)-
3-(1-hydroxy-1-methy-ethyl)azeticine
-2-on (Ben (N# Tsujiwamono) 234 da (0,5mi
5 prepared from mol ) according to the method of Reference Example 21,
6-cis-6-(1- and Fj*S/-1-, Ifl&/
ff1y) - 1-7 Zabi V9ro (3, 2,, Q)
Butane-3,7-thion-2-power Bonken Shizuku Nitro
Anhydrous acetonitrile of benzene to ester, A/20a/[
1 under an electric atmosphere at 0°C.
Add 0.11st (0.63w*mol)f, then dilute
Phenyl phosphate loli FO, 13sg (0,63mmo
l) Add and mix for 90 minutes. This mixture Ky
0.21 sJ (1.2 mm
ol) and 2-C(4-methy~bibefV2A/)-
1-Voice Report 2p Oxy] Echi~Merka 1 Tan Accumulation 96'I
Add C0.96 mmol) f and stir at 0℃ for 20 hours.
Mix. Dilute the reaction solution with N volumes of chloride, and add potassium legate.
The organic layer was separated by adding it to aqueous lII solution under water cooling. organic layer
After washing with water and drying (LIag804), the solvent was distilled off,
Residue 17p diy-A' (ethyl acetate-methanol
-5:1), the title compound appeared as pale yellow crystals (136 da
) is looked down upon as Melting point: 1.3-1-5°C KBr -1 1II v,,xs: 175G UV: "nm (11""): 264 (38
6), 318(181)1 M M RCS OM II z -CDCl5)'
” l-22, L 47 (respectively 3H, sX2.-c
a, x2), 2.0-2.48 (9stmt
CH- -OR, >C<, , -M<. Sea, > To CM3),
2.88-3.6(TH, m, >CH-CO-, -
8CH2CH20-. -0CR2Ar)7.51(21,d,J=8Hz,i
rom, H). 1611 (21!, d, J-gHz, arom, H) element
Elementary analysis value C, l1321.088-'AH20 calculated value
: c 53.84; H5,97; I 1G, 04
1j! Measured values: c 53.55; II 5.8i;
M 9.98 Dormitory Example 5T 5.6-Vsu 312-C (4-methylbivetudinyl)
-1-forceμbonylokile]ethiμthio)-7-1*y-
1 to 2 to 1 to y4 to vza [3, 2, 0]
- 4-nitropendyl S f ~ 120 If of carvone steep st compound (
Tetrahydrofuran 2o-1pH of 0.22mole
"?, D 10 ml of phosphate buffer and 10 ml of water (mixture)
Add drops of the compound KIO and Pd-Cl2G at normal pressure and temperature.
Hydrogenate for 4 hours. Filter the catalyst and wash it with a small amount of water [
, combine the filtrate and washing liquid and wash with ethyl acetate. water layer
Concentrate under reduced pressure and add amber phytoX D-2tJ@
Kahmu Chroma [Gutfy (Hj!0゜5%1tOH)
Marked with K, collected the eluted portion with 5% ton and freeze-dried.
Upon drying, the title compound was obtained as a colorless powder (33IIF).
It will be done. III shi::ai”: 1750.1700ty
v λushiam (bow): 298 (188) NMil (9
0MHz, D20)': 1.50-1.63 (3H each
. aX2. -CH,X2)l 2.58(3H,e,>
NCH3). >C< ), 4.06 4.65 (4H, m, >C
MN<. >C< , -80 tCH, -). And Dormitory Example 58
i~) aminoethylthio)-6-(”1- and Doroki V-
1-MethiμEchichi)-7-Okitsu 1-1 Dibicyclo(
3,2,0) to 1)-2-ene-2-carboxylic acid abbreviation -
diF lobenzyl ester 5,6-cis-4-[3-dia
Zo-3-(4-nitropene V-ruoxy, IF-rubonyl)
-2-Oxo 1g” Bill) -3-L l-Hiroki￥
-1 lythylethyl]a(thidine-2-one(ben(ben))
solvate) 234”f (0.5mm.1) Th et al. 1e1
5,'6-cis-6-(1
-HydroxyF-1-Methi~Ethi〃)-1-Azabinculo
(3,2,0) to 1tan-3ir-dione-2-pbo
Anhydrous attonite of 4-nitropenic acid ester
Li, 4/20jil [V in 1 under K nitrogen cloud sr, Oi
0biethiμamine G, ffs/(063 Shoho o1)j
Add ^, □ Then Shitse 2 μ phosphoric acid loli F l 13d
(0.63 mmol) Add k and stir for 90 minutes
Ru. Add 10 diynes to this mixture and 7 g of 1.2
1st (1,2mm.1) and summer-(2-mekura deto
Ethi A/) - Summer - Methyl urea 129 da (116 mmol
)k addition, tte0'cte181115!5-1. anti
Dilute with reaction solution t# ethyl acid, wash with water, and dry (Ia280.
), then evaporate. , treat the residue with ethyl acetate
Then, the Il- compound appears as pale yellow crystals (referred to as 9081).
It will be done. Kabumu chromatograph using mother liquor tflorigy
Additional crystals (1911I
I), melting point 195l95-1 160(2 51)I (901[Hm, DM80-d6)I
: 1.17-1.31 (3M each, @X3. -
CH2N2 ) s 2.51 (3a, a 1-IH
CIL3), 10-3.67 (61, tumor, -8CHf
fiCH211<. >Cl-Co-, >C< x), 3.92-4.32
(2H, Ill. >C< , >CM-11<), 4.68 (II
I, be, -0H) mutual 5-32 (2H# q s J -24-15HZ
#-OCH2mr). 5.611-IL30 (211, Zen, -M mutual COM and -
), 7.72 (2H. d, J-81s, arom, H), 8.2-'3 (21
, d, Jm8Hz. aro 臘, H) Elemental analysis value C21H26M, 07B・y, n. Calculated values: C51,74s H5,58s M 11.
49 score: c 51.45HH5,49; I 1
1.10 Example 59 5,6-V-3-42-(li-methyl force〃Bamoi
~)aminoethylthio)-6-(1- and do10V-1-
Mechi) vx Chi Jv) -7-4 Kin-1-7 Zabi V Kuro (
3,2,0)Hebdo-2-ene-2-carboxylic acid nato
Lium salt 11M1M carvone 4-nitrobenzyl ester~85#
(0,177m Otori 01) Tetofhydrofuran 18m,
Redemption of 9 d of pH 7.0 phosphate buffer and 9 d of water
Add 105pa-C8511 and heat w1 under normal pressure for 4 dark battles.
Filter the water to be hydrogenated, wash with a small amount of water, and filter.
Combine the solution and washing solution and wash with -acid ethyl chloride. Water Wt decompression
Concentrate below and cut using Amberlite XAll-2
Muchromatoguzzi (N□O) K indicates the target compound.
Obtained as a colorless powder (3811v). KBr -1 1I A' 1:11 :1750UN λ
"J!' nm (1'%): 29B (:H5) wax
1m! 1 Ill (90MHz-D20)':
L53- L66 (each'3H911X2.-C
H2N2), 2.91 (3H,s, -1110H3)
. 191 (IH, d, J-GHz, >C<H), 4.
06-4.67 (211, II, >C<, >Loto
Li
aminoethylthio)-5-(1-t:
KiF-1-methipethyA/)-7-oxo-1-azabi
V black C3,2,0) to 11-2-engine-2-*vbon
Acid 4-nitrobenzyl ester μU Example 58 ■-(2
-Meμ force 1 toechi ~) -y'-Methi〃Replacement of ureaj)K
l-(2-methymu)-1'-methymuthiourea
When reacted and treated in the same manner using
Obtained as crystal. Melting point 174-176℃ ■11 41m, Lxa: 1J5QUV core,
” nm (ml: 243 (382), 315 (224
) IMP (10MHz, DM80-da)'
: 1.19-1.32 (respectively 31, sX2,
-CM,X2), 2.77 (3H,d, -H
HC). 2.9l-169 (611, Otori, -8CH2CH24
M<, >CH-CO-. 'I)C<H>, 3.97-4.23(2J"m,>C<
i. >cm-x<>, 4.66 (11,s, -0H),
5.32 (2M. qIJ"24.15Hz, -OCH, mr), 7.10
-7.82 (21, w, , -111[c81rdan-
), 7.72<2H,d, J-811z. arom, H), 8.22 (2H, d, Jm8Ez, a
rom, H) Elemental analysis value C21H26”4 o5 s
2° IIaO calculated value: c 49.20; H5,51
; yi 1G, 93 dormitory survey: C48, 85; H5
, 36;
μ) aminoethylthio)-6-(1-hyvs*v-1
-Me+wx+14/> -7-O*y-1-Azabilik
C3,2,0) to 1 to 2-en-2-force μ-bonic acid
A total of 4-nitrobene 4-nitrobene vJv esthetics in the dormitory is provided.
When reacted and treated in the same manner as in Example 5s, the marked compound turns out to be a colorless powder.
obtained as a final product. U V mountain o nm (1! Ri: 233 (325),
297 (222) m&X IMB (! IOMHz, DgO)': 1.49-1-6
2 (3H each. s x 2 s -CH3 x 2) a 3-04-19
5 (5Hm m s4.08-4.67 (211,
臘、＞CH-1＜、＞C＜H) Dormitory Example I2 5.6-Voh3-[2-(4-nitrobenzyokV
i1μbony-amino)-4-thiazolylmethylthio)-
8-(1-hydroxyV-1-methy~X+μ>-1-ox
So-1-Azabinkuro [3゜2.0] 1 toe 2-kun
-2-carboxylic acid 4-nitrobene y~ester~ 5.6-cis-4-[3-cya/-3-(4-nitrobene
Nyruoki V Carboniμ)-2-Okitsubutabi~)-3
-(1-Hirokis/-1-Methi〃Ethi~)A(Tidine
-2-one (benzene layer solvation ml 234"F (a5
Dragon. 1) Prepared according to the method of Reference N21 5
, 6-V no 6-(1-hiFrokiV-1-MethiμEthi
7L/)-1-AzabicycloC3,2,0) Hede! Hmmm
3.7-Noone-2-*W 4-nitrobenzyl
King Stell's anhydrous 711219 ~ 2M solution under electric atmosphere
, V inpropylethylamine 0.11 m (0,
Add 63 Dipeng o1)l, then add diphenyl phosphoric acid loli
Add Fa13a/(063 mmol) and leave for 90 minutes.
Mix. Add 2-(4-nitrobenzyloxy V) to this mixture.
iIμboniμamino)-4-meth〃captomethy~thiazo-
Silver salt 30511 (0.71 wamol) and iodide
Add 750'l/(5mmol)l of sodium worm and at 0℃
Stir for 23 hours. Dilute the reaction solution with chloroform,
Add chilled chopsticks to the food water and filter through non-St Celite.
do. The organic layer of the filtrate was separated, washed with water, and dried (Ia, 80
4) After that, remove it from Liao Mei. Fluorize the residue with Florigi-A/
Kahum chromatograph used (atton-hexane)
-3:5), the target compound becomes colorless crystals (62jv)
obtained as. Melting point 124-126°C IN, Klril, s7r. A
(Cao99) NMR (90Mls, CDC1a)':
1.26-1.52 (3H each. sX2.-C1[3X2), 2.05(lH,s,-0
H), 3.02 (IH, q, J = 17.9JIIz, >
C<ii), 3.61 (IH. >CI-to○# 5.8 G (2H, s, -IHC
OOCdan2mr). 5.34 (2M, q, J=24.15Hz, -OCH,
Ar) J72 (lK, @, ts%, 7zodo IL/H)
, 7.56-8.19 (811, m. arozen, H) Elemental analysis value C119H27'50108! ”2゜total
Calculated value: c 50.64; H4,25; II 10
．． 1B! N! Price: c 50.58IH4,17;
N 10.00*Example 63 5.62$/,
Echichi) -7-oxo-1-azabi V KuroC3,2,0
) Hebdo-2-en-2-benzoic acid S) Si-loaded 5.1-cis-3-[2-1-nitrobendiμoxyv*
, 4/bonylamino)-4-thiacylyme
4 methylthio)-6-(1-hyfurokiV-1-methylethyl
)-7-oxo-1-azabi V taro [3°2.0] hep
T-2-en-2-carboxylic acid 4-nitrobendi)v
Esthetics A' 115. 'W (1171 mmol)
Tofuhi F Rofufun 20 d, pH'r, 0 phosphoric acid l!
11210- and water 10af's liquid KIQ Pd
Add -C20G drops and hydrogenate at room temperature and atmospheric pressure for 4 hours. Filter by touch, wash with a small amount of water, and combine the filtrate and washing liquid.
, wash with ethyl acetate. Sat the aqueous layer under reduced pressure.
Cafe Climatogra used for Amberphyto LAD-2
When subjected to fluoride (H2O), the target compound becomes a colorless powder (25
11). III j/3: 1000m & XUVA (EL): 26
G (204), 300 (249) W II B (90 MHz - D20)':
1. + 6-1-59 (each 4311゜sX3.-C
H5X'2), 3.27 (1n, q, I-IT,
10 (2Hms #-BC%Cgu), 4.47 (IH
, m, >CH-N<). 6.78 (lH, B, Konryo So, Knee JL/H) Example
64 5, s-cis-3-(2-acetylaminothiacylylmethane)
Chilthio)-6-(1-hydroxy-1-methy~ethyl A
/) to -7-oxo-1-azabicycloC3,2,0)
Budo-2-ene-2-carboxylic acid 4-nitropene v~
Ester projection 94@2 2-(4-nitrobendi〃okin*wbo)
niμ amino)-4-me~force 1 tome/L/thiazo-μ
#7411Ik] 2-acetylamino-4-methμ
Reaction and treatment were carried out in the same manner using a silver salt of 1F methylthiazo.
When analyzed, the rod compound is treated as pale yellow crystals. Melting point 131-133°C <195) 111B (90MHz - CDCl3)' =
1-30-1.51 (31yo[.sX2, -cH3x2), 2.21 (3H,
s, -NHCOCH3). 2.111 (III, be, -0111), 11
G (IH, q, J-17゜5.32 (2H-q -J
-24-15Hz, -00H8Ar) -K
71 (IH,s,'t-77-IL/H),
7.60 (2H, d*J-8112, arom, H),
8.19 (211, (1, J-flTlz. arom, H), 9.89 (IH, be, -NHC
OCH3). Elemental analysis value 023H24'4''/s2' 2H
2゜Calculated value: c 48.58; H4,96; x
915 dormitory scale value: c 48. j8+ H4,74; i
r 9.79 1llrh5 5e6-v 3-(2-acetylaminothiazolyl)
(tilthio)-6-(1-hydroxys/-1-methyμethyl
A/)-7-oxo-1-azabicyclo(3,2,0)
4-Nitrobene y/&/ester of sodium salt gravel layer carboxylic acid
When the reaction was carried out in the same manner as in Example 63, the target compound turned into a colorless powder.
obtained as a final product. K11r -1 X I J/, xcIIH175QH201% UV λm, Lx nm ("i,): 28
0 (210)NMB(90MH1,D!!O)':1
．． 42-1.58 (each 1t311゜eX2.-C113
X2), 2.49 (3i1.s, IHCOCjL3
). (III, d, J zero 6Hz, >CH-Co-), 3.8
8 (211°1+, -8CHBC,), 3.96-4.
60 (2n, m. >C<dan, >CM-H< ), 7.21 (1) 1.
a. Terako:)"-tvH) Example 66 5*6-sysus--(2-(4-nitropency)
μOki ViI~Poni*)-2-(4-nitropendi~O
KiVkuraμbonylamino)ethylthio)-6-(1-human
TakiV-1-methylethyl)-7-oxo-1-azabi
Siku0(3,2,0)hebdo-2-en-2-carvone
Acid 4-nitrobenzene-SED I 5.6-F-4-[3-diazo-3-(4-nitrobenzene)
NNA/OkiVkaNboniμ)-2-Okinprobiμ)-
3-(1-Hydroxy-1-methy-ethyl)azethene
-2-one (benzene l#jIIAs) 464 da(1
, 0 mmol) according to the method of Reference Example 21! iI
The prepared 5,6-nes-6-(1-hydroxyV-1-methyl
μeth~)-1-azabicyclo(3,2,0)hebutane
-3,7-v-on-2-carbon-,4-nitropene
/I/ Add ester to 40 dll of anhydrous acetonitrile solution.
Under bulk atmosphere, O'Cf$F4y1a bipvx f /M
7 Mi/Q, 22 d (1,26 mmol) f addition
Eh, then Zophenylphosphoric acid chloride 0.26 (1,
Add 26 mmol)' and stir for 90 minutes. This mixture
The compound contains L-2-(4-nitrobenzene)
)-2-(4-Nitrobene ν to OkiS/muboniμami
1113 drops (1.5 mmol) of silver salt of ethanethio
) and sodium iodide 1.5F (1G in+mol)
and stir at 0°C for 21 hours.
diluted with μ and added to saline under cooling to remove the insoluble part.
Let's separate. The organic layer of the filtrate was separated, washed with water, and dried (A280.
), then the solvent is distilled off. , using residual t Floriseal
voice Tsumuku p matogufui (ethyl acetate μm hekin fn)
1:1), the marked compound (J% columnar compound) turns pale yellow.
It is despised as a colored powder (210q). KBr-1 1RyI! l&xas: 1000 gton 1% av A,, xnmcz, ): 265 (382),
313 (155) IMR (901111z, CDCl3)J: 1
．． 2911.53 (3H each. 8x2p-CH3x2) *2.72-3.60
(3H#m#18C11,-,>Chi),
3.49 (111, djJ=6Hz. >CH-Co-), 4.0-4.8 (3H, m, >C
1-Hkl-. ■ >c<, , >C11-M< ), 5.08-5.
81 (611, m. -0CHRArX3), 7.25-&28 (
1211, rn, aroma, II) dormitory example 67 5.6-1'-3-(2-amino-2-carboxy
methylthio)-6-(1-hyfurokiV-1-methyμethyl
)-1-oxo-1-azabicyclo(3,2,0)hep
To-2-engine-2-force μbonic acid disodium salt Example 66
Nidota Ben y~OkiVjb~Boni A/)-2-(4-2
Tribens I μ ox V carbonylamino) ethylthio)
-fi-(1-kF ¥-1-Methi〃Ethi A/)-7
-oxo-1-azabicyclo(3,2,0)7')-
2-ene-2-carboxylic acid 4-nitrobenzyl ester
38-Oq (0.49 mmol) of tetrahydrof
Run 80s/, pH 7,0 phosphate buffer 40s/and
Add 570 qt of 10% PA-C to a mixed solution of 20 m of water.
Add hydrogen to the tank for 4 hours. Catalyst [filtered and washed with a small amount of water]
After that, the filtrate and washing liquid are combined and washed with ethyl acetate. Water J
1 under reduced pressure and using Amberphyto XAD-2.
Column chromatography (H2O) followed by dye
Column chromatography using Aion HP-20
The amount eluted with water is collected and freeze-dried to form a
The 21111 isomer of the compound is treated as a colorless powder. Isomer (I): 22~I FIJ/IBrti”: 1750I!1aX Uma λH2°I (Yumiji): 294 (214) 11a! Summer Lid R (100MH2, D20) J: 1.37, 1.4
7 (each l. 8 x 2--CH3 x 2) e 195- &66
(3H- Theory,〉C<dan. 180H2-) -177(I Hh d, J ”
6 Hz, >CH-CO-). 172-4-00 (2H-m j>C<n,>
C tan-min, ), 4.41 (III, a, >
CH-N< )isomer (II): 19 drops I B J/KB'6': 175 Gm&X MMB (l QOMHs, Dg O)':
1.37 jl, 46 (each 311°■ aX2.-CH2N2), 2.93-3.67 (31
,m,>C<'1-8CH2-) e 3.7@(I
H, d, J -6Hz #>CH-Co-), 3.
72-4.04 (21, m, >C<dan.>Cdan-HTlz), 4.40 (111, m
, >CH-H<
4-Nitrobendi-OkiV'iIA/Boni-Amino)E
tilthio)-6-(1-hydroxy-1-methylethyl
)-7-oxo-1-azabicyclo(3,2,O)hep
T-2-ene-2-carboxylic acid 4-nitrivendi
Ste μ 5 z 6- 'No 4-[3-diazo-3-(4-2
) Roben ysp Oki V Force μ Boni A/)-2-Okinpro
Biμ)-3-(1-hydroxy-1-methylethylμ)a
(Tidine-2-one (penlayer solvate) 234Q
(0.5 mmol) according to the method of Liao Example 21
95,6-cis-6-(1-hyphrokiV-1-methane)
Chi〃echμ)-1-azabicyclo(3,2,0) to pig
4-nitrobene
v〃S-D~'s Anhydrous AceF Nitri~20-Solution $liK
ml V isopropylethylamine G at 0°C under elementary atmosphere.
, 11 mg (0.63 ml o1), then dife
Niluric acid chloride 0.13d (0.63mmol
) Add f and stir for 90 minutes. Add diiso to this mixture.
Propylethylamine G, 14Wt (0.8mmol
) and L-2-methoxy***diA'-2-(4-dito
Ropensi N Okinka μ Pony Y Amino) Ethanethio-A/
Add 201# (0.64 mol) and keep at 0℃ for 2 hours.
Stir. Dilute the reaction ate with acid solution, wash with water, and dry.
After drying (I m B”!), the solvent [distilled away]
Column chromatography using Floriseal (#
When exposed to acid ethyl hexane (3:2), there was no Sake compound.
Excellent as a colored crystal (1@0 da). Melting point 17G-173℃ II J/KBrcm': 175011&X gtoa 1% UV An m (E 1.): 266 (
328) -31514LX (197) I MR (90M HE -CDCl3)':
1.27-1-51 (3H each. ex2.-cm3x2), 190-143 (3n, mm
Once 8C% -->C< a )-160 (I Ha
d -J-GHz ->CH-CO-) -181(3
H,,a, -0CH3) -4,10-4,77($
II-m->CH-MH-->C<x-
cii-g< 15.24 (2H, s, -OCH
, Mr), 5.30 (2Hsq*'-24= 151
j m --OC% Mr), 7.30-8.37 (8
11, m. arom, H) Elemental analysis value C29H3oN4o12s calculated value: C5
2,89; H4,59i N 8.5G! 1I11 Deep
Value: c 52.50: H4,53: H8,28 dormitory
Example 69 5e ft-5'-3-(2-amino-2-methoxy
V Riki Po Ni〃Echi μ Thio) -6-(1-HiFroki F-1
-MethiμEthiμ)-7-oxo-1-azabiV Kuro(3
,2,0)Hebdo-2-ene-2-carboxylic acid sodium
Example 6 5,6-cis-3-[2-meth etc. obtained in Luo V★
~Boni A'-2-(4-Nitrobenge~Oki V Power~Boni
ruamino)ethylthio)-6-(1-hFlokiV-1-
Methyl-ethyl A/)-7-oxo-1-azabicyclo(3
,2,0) to 1) -2-ene-2-carboxylic acid 4-
Nitrobenzyl Esthej"'155'l (0,235m
mol ) of Tet') and y Loftsun 25 m/, pH 7,
In a mixed solution of 13 s of 0 phosphoric acid lI buffer solution and 13 wt of water.
Add 101 pd-C275 da and heat at room temperature for 3.5 hours at normal pressure.
Hydrogenate for a while. #It - After filtering and washing with a small amount of water
, combine the filtrate and washing solution, and wash the aqueous layer with methylene chloride acetate.
Concentrate under reduced pressure and use Ampartite XAD-2i.
Put it on Humchromato Duffy and take a bath with water.
Freeze-drying gives the title compound as a colorless powder (18 Da).
can get. 111 B (90M II z -D z O) a
: 1.41-L54 (each 3H. sX2.-CII3X2), 105-3.80 (311
,m,-8CH,+. ■ >C< ), 3.82 (III, d, J-GHz, >
CH-Co-). ■ ■ 381-4゜10 (2H, m, >C<,
＞CH-HHJ! ). And 3.90(311,s+, -0CR5)-4,41(
IH, m. ＞CH-Summer〈 ) *Example T0 5 a 8-F Sue 3-(2-formimidoi~ami
Noech μthio)-6-(1-hiFrokiV-1-methy-e
H)-T-oxo-1-azabicyclo(3,2,0)
Helto-2-ene-2-carboxylic acid 5oovt-free
In addition to ALV (inner volume 17 mg), seal it. when using
Seal the sterile vial μ) and add the pyrogen into it.
The removed distilled water IIIt is added to prepare a solution for injection. Dormitory Example 71 5, 8-$'susu--(2-aminoethylthio)-6
-(1-hydroxy-2-methyI4/-1-methy)-
7-oxo-1-azabicycloC3,2゜O]heato-
2-carboxylic acid [250q (potency) black value
In addition to via I (inner volume 12d), seal it. when using
is the sealing cap T and 9 of the non-vipul, and the pyrogen is placed in it.
Add 1 jt of removed distilled water and dissolve to make N solution for injection.
. - Comparison 1A MIC for representative examples of target compounds that are neglected in refreshing examples.
(mcg) 10,000 liters! & Yoshibuchi and Table 1.
I stopped it. a) MICi of fi-method test compound! Rumor Amakizawa ff dilution (aglLr
dilution method)
. That is, the aqueous solution of the metal material to be tested is sequentially diluted.1. Osl
VCpetri dish), then
Tryptica
sa soyagar) 11. Pour Od and mix.
Zeru. #Ic experimental cocoon suspension fi on the mixed agar plate
(iello CFU/m). 1 at 37℃
After 8 hours of incubation and post-mortem, the test
The lowest concentration of test compound that completely inhibits growth
Tono 11c MIC: minimalinhibit
ory concentration). b) - Sumire Natsume 86838$εgεaSS 8 words 8

Claims (2)

[Claims] (1) Formula [In the formula, B1 is a linear hydrogen group and a double wire resistance, B2 is a hydrogen atom or a hydroxyl group protection j&f, nriO, 1 or 2, provided that R is acetamidoethyl or acetamido When it is an ethynyl group and P represents a hydrogen atom or a sulfonic acid group, n represents 2. 5, 6 represented by J
-Vsucaypabenem-3-carboxylic acid derivative or a bottle thereof. (2) Formula [In the formula, B2 is a water bulk atom or a hydroxyl group t, B3
is hydrogen or power, and X represents a leaving group. ] or a salt thereof and the compound represented by the formula %formula%(0) [wherein Hl is a hydrogen ashing group or a multivolume ring [, n is 0
, 1 or 2] 5゜6-, which is represented by the formula [the symbols in the formula are Mayuki and 14 dishes], which is characterized by the sound reaction.
V-supower μpapenem-3-carboxylic acid W! Mll property method of f14 body or its salt