CN1337955A - Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents - Google Patents

Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents Download PDF

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Publication number
CN1337955A
CN1337955A CN99816464A CN99816464A CN1337955A CN 1337955 A CN1337955 A CN 1337955A CN 99816464 A CN99816464 A CN 99816464A CN 99816464 A CN99816464 A CN 99816464A CN 1337955 A CN1337955 A CN 1337955A
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carbon
methyl
imino
nitrophenyl
alkyl
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B·R·迪克松
C·M·巴吉
C·R·布伦南
D·R·布里特利
W·H·布洛克
J·陈
W·L·科利贝
R·达利
J·S·约翰森
H·C·E·克鲁恩德
W·F·拉斯罗普
P·刘
C·A·马斯
A·M·雷德曼
W·J·斯科特
K·乌尔巴恩斯
D·J·沃拉宁
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Bayer Corp
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Miles Inc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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    • C07—ORGANIC CHEMISTRY
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
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    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Steroid Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

This invention relates to 2-arylimino heterocycles, including 2-arylimino-1, 3-thiazolidines, 2-arylimino-2, 3, 4, 5-tetrahydro-1, 3-thiazines, 2-arylimino-1, 3-thiazolidin-4-ones, 2-arylimino-1, 3-thiazolidin-5-ones, and 2-arylimino-1, 3-oxazolidines, and their use in modulating progesterone receptor mediated processes, and pharmaceutical compositions for use in such therapies.

Description

Be used as the 2-aryl imino-heterocycle and the composition that comprises them of the replacement of PgR bound drug
The field:
The present invention relates to heterocyclic drug, and more particularly, relate to 2-aryl imino-heterocycle, comprise their medicinal compositions and their purposes in regulating the PgR mediated process.
Background:
The medicine that is incorporated into PgR can be used for multiple indication, comprises the indication that those show in following paragraph:
A1) for strengthening the bone forming in the bone debilitating disease, be used to prevent and/or treat osteopenia or osteoporosis (Manzi etc., J.Soc.Gynecol.Invest., 1,302 (1994); Scheven etc., Biochem.Biophys.Res.Commun., 186,54 (1992); Verhaar etc., Bone, 15,307 (1994)); Ontjes is about " calcium and phosphorus in health care and the disease ", Anderson and Garner (editor), CRC press, 207 (1996); Scheven etc., Biochem.Biophys.Res.Commun., 186,54 (1992)), comprise the osteoporosis (Picardo etc., Drug Safety 15,347 (1996)) of corticosteroid-induced, postclimacteric osteoporosis or Beh et's disease;
A2) as the medicine that strengthens union of fracture;
B1) as women's anti-early pregnancy drug (Cadepond etc., Annu.Rev.Med., 48,129 (1997); Heikinheimo Clin.Pharmacokinet., 33,7 (1997); Li etc., Adv.Contracept., 11,285 (1995); Spitz etc., Adv.Contracept., 8,1 (1992); Spitz etc., Annu.Rev.Pharmacol.Toxicol., 36,47 (1996));
B2) be used to prevent uterine endometrium to implant (Cadepond etc., Annu.Rev.Med., 48,129 (1997));
B3) be used for induced labor (Heikinheimo Clin.Pharmacokinet., 33,7 (1997); Karalis etc., Ann.N.Y.Acad.Sci., 771,551 (1995)), comprise situation (Heikinheimo, Clin.Pharmacokinet., 33,7 (1997) of foetal death; Cadepond etc., Annu.Rev.Med., 48,129 (1997));
B4) be used for the treatment of corpus luteum and lack (Pretzsh etc., Zentralbl.Gynaekol., 119 (augmenting 2), 25 (1997); Bezer etc. are about " Molecular and Cellular Aspects ofPeriimplantation Processes ", Dey (editor), Springer-Verlag, the 27th page (1995));
B5) for the identification that strengthens gestation with keep (Bezer etc., about " Molecular andCellular Aspects of Periimplantation Processes ", Dey (editor), Springer-Verlag, the 27th page (1995));
B6) to antipregnancy preeclampsia, eclampsia and premature labor (Yallampalli etc., WO97/34,922);
B7) treatment infertility comprises promoting spermatogeny, induce acrosomal reaction, make oocyte maturation and making Oocyte in Vitro fertilization (Baldi etc., J.Steroid Biochem.Mol.Biol., 53,199 (1995); Baldi etc., Trends Endocrinol.Metab., 6,198 (1995); Blackwell etc., Colloq.INSERM, 236,165 (1995); Blackmore etc., Cell.Signalling, 5,531 (1993); Cork etc., Zygote, 2,289 (1994); Meizel, Biol.Reprod., 56,569 (1997));
C1) treatment dysmenorrhoea (Coll Capdevila etc., Eur.J.Contracept.Reprod.HealthCare, 2,229 (1997); Adashi etc., Keio J.Med., 44,124 (1995));
C2) hemorrhage (Coll Capdevila etc., Eur.J.Contracept.Reprod.Health Care, 2,229 (1997) of treatment dysfunction temper palace; Adashi etc., Keio J.Med., 44,124 (1995));
C3) treatment ovarian hyperandrogenism (Schaison etc., Androg.Excess Disord.Women, 715 (1997));
C4) treatment ovary aldosteronism (Adashi etc., Keio J.Med., 44,124 (1995));
C5) treatment premenstrual syndrome and/or premenstrual tension (Mortola, Curr.Opin.Endocrinol.Diabetes, 2,483 (1995)); Adashi etc., Keio J.Med., 44,124 (1995));
C6) treatment is through preceding (perimenstrual) behavior disorder (Constant etc., Hormone Res., 40,141 (1993));
C7) treatment climacterium (climeracteric) disorder, i.e. menopause changes (Adashi etc., Keio.J.Med., 44,124 (1995)), comprises hot flush (Sarrel, Int.J.Fertil.Women ' s Med., 42,78 (1997); B  ckstr m etc., Ciba Found.Symp., 121,171 (1995)), emotional change (B  ckstr m etc., Ciba Found.Symp., 121., 171 (1995)), sleep disordered (Sarrel, Int.J.Fertil.Women ' s Med., 42,78 (1997)) and vagina drying (Sarrel, Int.J.Fertil.Women ' s Med., 42,78 (1997));
C8) enhancing women's property susceptibility (Dei etc., Eur.J.Contracept.Reprod.Health Care, 2 (4), 253 (1997); McCarthy etc., Trends Endocrinol.Metab., 7,327-333 (1996); Mani etc., Horm.Behav., 31,244 (1997)) and the male sex's property susceptibility (Johnson etc., about " Essential Reproduction ", the 2nd edition, BlackwellScientific Pub., London the 177th page (1984));
C9) treatment postmenopause urine incontinence (M  kinen etc., Maturitas, 22,233 (1995); Batra etc., J.Urology, 138,1301 (1987));
C10) improve sensation and motor function (B  ckstr m etc., Ciba Found.Symp., 121,171 (1995));
C11) improve short-term memory (B  ckstr m etc., Ciba Found.Symp., 121,171 (1995));
C12) treatment postpartum depression (Dalton, Practitioner, 229,507 (1985));
C13) treatment reproduction atrophy (Sarrel, Int.J.Fertil.Women ' s Med., 42,78 (1997));
C14) the prevention of postoperative adhesion forms (Ustun, Gynecol.Obstet.Invest., 46,202 (1998));
C15) regulate uterus immunologic function (Hansen etc., J.Reprod.Fertil.49 (augmenting), 69 (1995));
C16) prevention myocardial infarction (Sarrel, Int.J.Fertil.Women ' s Med., 42,78 (1997));
D1) Hormone Replacement Therapy (Casper etc., J.Soc.Gynecol.Invest., 3,225 (1996));
E1) the treatment cancer comprises mammary cancer (Cadepond etc., Annu.Rev.Med., 48,129 (1997); Pike etc., Endocr.-Relat.Cancer, 4,125 (1997)), uterus carcinoma (Heikinheimo Clin.Pharmacokinet., 33,7 (1997)), ovarian cancer (Pike etc., Endocr.-Relat.Cancer, 4,125 (1997); Hughes, WO 98/10,771) and carcinoma of endometrium (Satyaswarpoop, Contrib.Oncol., 50,258 (1995); Pike etc., Endocr.-Relat.Cancer, 4,125 (1997));
E2) treatment endometriosis (Cadepond etc., Annu.Rev.Med., 48,129 (1997); Heikinheimo, Clin.Pharmacokinet., 33,7 (1997); Edmonds.Br.J.Obstet.Gynaecol., 103. (augmenting 14), 10 (1996); Adashi etc., Keio J.Med., 44,124 (1995));
E3) treatment fibroma uteri (Cadepond etc., Annu.Rev.Med., 48,129 (1997); Adashi etc., Keio J.Med., 44,124 (1995));
F1) treatment hirsutism (Orentreich etc., US 4684635; Azziz etc., J.Clin.Endocrinol.Metab., 80,3406 (1995));
F2) suppress natural on-off cycles of hair growth (Houssay etc., Acta Physiol.Latinoam., 28,11 (1978));
G1) as male contraceptive pill (Hargreave etc., Int.Congr., Symp.Semin.Ser., 12,99 (1997); Meriggiola etc., J.Androl., 18,240 (1997));
G2) as aborticide (Michna etc., Pharm.Ztg., 141,11 (1996)); With
H1) promote mylin to repair (Baulieu etc., Cell.Mol.Neurobiol., 16,143 (1996); Baulieu etc., Mult.Scler., 3,105 (1997); Schumaker etc., Dev.Neurosci., 18,6 (1996); Koenig etc., Science, 268,1500 (1995)).
At present, Progesterone or progestogen adapt to separately or with the oestrogenic hormon associating clinically: be used for contraception (Merck handbook; Merck ﹠ Co., Inc. (1992)); Be used for the treatment of because gastrointestinal hemorrhage (the Merck handbook that arteriovenous malformotion causes; Merck ﹠ Co., Inc. (1992)); Be used for the treatment of by spanomenorrhea or through closing concurrent recurrence stress fracture of the metatarsal (Merck handbook; Merck ﹠ Co., Inc. (1992)); Be used for the treatment of premenstrual syndrome (PMS, premenstrual tension, Merck handbook; Merck ﹠ Co., Inc. (1992)); Be used for through Hormone Replacement Therapy without offspring (Merck handbook; Merck ﹠ Co., Inc. (1992)); Be used for the treatment of hot flush and consequent insomnia and tired (Merck handbook between climacteric; Merck ﹠ Co., Inc. (1992)); Be used for the treatment of hemorrhage (the Merck handbook in dysfunction temper palace when unexpected gestation; Merck ﹠ Co., Inc. (1992)); Be used to suppress endometriosis (Merck handbook; Merck ﹠ Co., Inc. (1992)), mammary cancer (Merck handbook; Merck ﹠ Co., Inc. (1992)), carcinoma of endometrium (Merck handbook; Merck ﹠ Co., Inc. (1992)) or CLI (Merck handbook; Merck ﹠ Co., Inc. (1992)).For example, medroxyprogesterone, a kind of Progesterone, separately or with oestrogenic hormon unite be applicable to the relevant moderate of preventing osteoporosis disease, treatment vulva and/or vaginal atrophy, treatment and menopause to severe vasomotor symptoms, treatment secondary amenorrhea, treatment because the abnormal uterine bleeding that the hormone imbalances that organ pathology lacks causes, prevention is pregnant or inoperable as adjuvant therapy and palliative treatment, that recur and carcinoma of endometrium or kidney (Merck handbook transfer; Merck ﹠ Co., Inc. (1998)).
General introduction
The invention provides non-steroidal 2-aryl imino--and 2-heteroaryl imino--heterogeneous ring compound, they have affinity to PgR, therefore can as progestogen and/or antiprogestin works and the process of regulating the PgR mediation thus.
The present invention relates to the to have formula compound and the pharmacy acceptable salt thereof of (I) Wherein R is the aryl of 6-14 carbon; Or
3-10 carbon and contain the heteroatomic heteroaryl that 1-3 is selected from N, O and S, condition is that R is not cumarone or thionaphthene; R 1For
The alkyl of 1-10 carbon;
3-12 carbon and contain 1-3 the ring cycloalkyl;
4-7 carbon and contain 1-3 ring and the individual heteroatomic Heterocyclylalkyl that is selected from N, O and S of 1-3;
The alkenyl of 2-10 carbon;
5-12 carbon and contain 1-3 the ring cycloalkenyl group; Or
The alkynyl of 3-10 carbon; R 2, R 3And R 4Independently be selected from
H；
The alkyl of 1-10 carbon;
The cycloalkyl of 3-12 carbon;
The alkenyl of 2-10 carbon;
The cycloalkenyl group of 5-12 carbon;
The aryl of 6-13 carbon;
3-9 carbon and contain the heteroatomic heteroaryl that 1-3 is selected from N, O and S;
CO 2R 5Wherein
R 5Be the alkyl of 1-4 carbon, the haloalkyl of a 1-4 carbon, the cycloalkyl of a 3-6 carbon or the halogenated cycloalkyl of 3-6 carbon;
Halogen; With
=O, the expression radicals R 2, R 3And R 4In two; X is O or S (O) yWherein
Y is 0,1 or 2; N is 2,3,4 or 5; P is non-H substituent R 2, R 3And R 4Sum; T is the substituting group that is selected from following group:
The alkyl of 1-4 carbon;
The alkoxyl group of 1-4 carbon;
The aryl of 6-10 carbon;
CO 2H；
CO 2R 5；
The alkenyl of 2-4 carbon;
The alkynyl of 2-4 carbon;
C(O)C 6H 5；
C (O) N (R 6) (R 7); Wherein:
R 6Alkyl for H or 1-5 carbon; With
R 7Alkyl for H or 1-5 carbon;
S (O) Y 'R 8Wherein
Y ' is 1 or 2; With
R 8Alkyl for 1-5 carbon;
SO 2F；
CHO；
OH；
NO 2；
CN；
Halogen;
OCF 3；
The N-oxide compound;
O-C (R 9) 2-O; This oxygen is connected in the ortho position on the R;
And wherein
R 9Alkyl for H, a halogen or 1-4 carbon;
C (O) NHC (O), this carbon is connected in the ortho position on the R; With
C (O) C 6H 4, this carbonyl carbon and carbonyl adjacent ring carbon are connected in the ortho position on the R; T is 1-5;
Condition be when substituting group part T be the alkyl of 1-4 carbon, the alkoxyl group of a 1-4 carbon, aryl, the CO of a 6-10 carbon 2R 5, the alkenyl of a 2-4 carbon, the alkynyl of a 2-4 carbon, C (O) C 6H 5, C (O) N (R 6) (R 7), S (O) Y 'R 8, O-C (R 9) 2-O or C (O) C 6H 4The time, T is optional so can have secondary (secondary) substituting group that is selected from following group, comprising: alkoxyl group, the CO of the alkyl of 1-4 carbon, a 1-4 carbon 2R 5, CO 2H, C (O) N (R 6) (R 7), CHO, OH, NO 2, CN, halogen, S (O) yR 8Or=O, described secondary substituent number is 1 or 2 except that halogen, it can use at most can reach the perhalogeno level; G is the substituting group that is selected from following group:
Halogen;
OH；
OR 5；
=O represents two substituting group G;
The alkyl of 1-4 carbon;
The alkenyl of 1-4 carbon;
The cycloalkyl of 3-7 carbon;
3-5 carbon and 1-3 heteroatomic Heterocyclylalkyl that is selected from N, O and S;
The cycloalkenyl group of 5-7 carbon;
4-6 carbon and 1-3 heteroatomic heterocycloalkenyl that is selected from N, O and S;
CO 2R 5；
C(O)N(R 6)(R 7)；
The aryl of 6-10 carbon;
3-9 carbon and 1-3 heteroatomic heteroaryl that is selected from N, O and S;
NO 2；
CN；
S(O) yR 8；
SO 3R 8With
SO 2N (R 6) (R 7); G is 0-4, and except that halogen, it can use at most can reach the perhalogeno level;
Condition is when substituting group G is the heterocycloalkenyl of the cycloalkenyl group of Heterocyclylalkyl, a 5-7 carbon of cycloalkyl, a 3-5 carbon of alkenyl, a 3-7 carbon of alkyl, a 1-4 carbon of 1-4 carbon or 4-6 carbon, G chooses the secondary substituting group that can have the halogen that can reach the perhalogeno level at most wantonly so, and when substituting group G is aryl or heteroaryl, G can choose wantonly and have the alkyl that independently is selected from 1-4 carbon and the secondary substituting group of halogen so, described secondary substituent number can reach 3 at most to moieties, and can reach the perhalogeno level at most to halogen; Q is the substituting group that is selected from following group
The alkyl of 1-4 carbon;
The haloalkyl of 1-4 carbon;
The cycloalkyl of 3-8 carbon;
The alkoxyl group of 1-8 carbon;
The alkenyl of 2-5 carbon;
The cycloalkenyl group of 5-8 carbon;
The aryl of 6-10 carbon;
3-9 carbon and contain the heteroatomic heteroaryl that 1-3 is selected from N, O and S;
CO 2R 5；
=O represents two substituting group Q;
OH；
Halogen;
N(R 6)(R 7)；
S(O) yR 8；
SO 3R 8With
SO 2N (R 6) (R 7); Q is 0-4
Condition is when substituting group Q is aryl or heteroaryl, Q is optional so can have the alkyl that independently is selected from 1-4 carbon and the secondary substituting group of halogen, described secondary substituent number can reach 3 at most to moieties, and can reach the perhalogeno level at most to halogen; With other condition be:
A) (Q) qR 1, (Q) qR 2, (Q) qR 3(Q) qR 4In two can connect, and form with the atom that they connected and to contain 0-2 and be selected from the heteroatomic 3-8 unit's spiral shell of N, O and S or the non-aromatic ring of non-spiral shell;
B) when n=2 or 3, R 2, R 3And R 4In at least one is not H;
C) work as n=2, and during X=O, if t=1, T is selected from above substituting group T clauses and subclauses so, except that alkyl, and 1, the 4-position of 3-oxazolidine ring must have a substituting group;
D) work as n=3, and during X=O, if t is equal to or greater than 1, at least one T is selected from above substituting group T clauses and subclauses so, except that alkyl and alkoxyl group;
E) when n=2 or 3, and when X=O or S, R so 1, R 2, R 3And R 4In non-hydrogen atom add up at least 5;
F) work as n=2, X=O, 1, the 4-bit strip of 3-oxazolidine ring has a carbonyl, and R is when its 2-position and 4-bit strip have halogen, and the 5-bit strip of R has H so;
G) when n=2 and X=O, only when the 5-of described ring bit strip has at least one non-H substituting group, 1, the 4-position of 3-oxazolidine ring can have a carbonyl;
H) work as n=2, X=S (O) yThe time, the 4-bit strip of 1,3-thiazoles alkane ring has a carbonyl, R 1The methyl that be to replace, and G is when being phenyl, so described phenyl has secondary substituting group.
I) work as n=4, X=S and G are CO 2R 5The time, R so 5Contain at least two carbon.
The present invention also relates to it and comprise medicinal compositions as above disclosed formula (I) compound and pharmaceutically acceptable carrier.
The ability that works as progestogen and/or antiprogestin that the result of the affinity of PgR and their is produced as them, thereby regulate the process of PgR mediation, the related compound of compound of the present invention and some prior arts is considered to be used for the purpose listed in background parts.
Definition that what deserves to be mentioned is that group compound (formula II) that uses in the methods of treatment that requires is more extensive than that group compound of formula I definition, because methods of treatment can be used the compound of some prior arts, before they were not realized as yet and are used for this purpose.
Therefore, the present invention relates in addition and treats Mammals to obtain the method for effect, and wherein said effect is:
A1) bone forming in the enhancing bone debilitating disease is used for the treatment of or prevention of osteoporosis reduces or osteoporosis;
A2) strengthen union of fracture;
B1) as the activity of women's anti-early pregnancy drug;
B2) the prevention uterine endometrium is implanted;
B3) induced labor;
B4) the treatment corpus luteum lacks;
B5) strengthen the identification of gestation and keeping;
B6) to antipregnancy preeclampsia, eclampsia and premature labor;
B7) treatment infertility comprises promoting spermatogeny, induce acrosomal reaction, make oocyte maturation or making the Oocyte in Vitro fertilization;
C1) treatment dysmenorrhoea;
C2) treatment dysfunction temper palace is hemorrhage;
C3) treatment ovarian hyperandrogenism;
C4) treatment ovary aldosteronism;
C5) alleviate premenstrual syndrome and alleviation premenstrual tension;
C6) alleviation is obstacle through moving ahead;
C7) treatment climacteric disturbances comprises that menopause changes emotional change, sleep disordered and vagina drying;
C8) strengthen women's property susceptibility and the male sex's property susceptibility;
C9) treatment postmenopause urine incontinence;
C10) improve sensation and motor function;
C11) improve short-term memory;
C12) alleviate postpartum depression;
C13) treatment reproduction atrophy;
C14) the prevention of postoperative adhesion forms;
C15) regulate the uterus immunologic function;
C16) prevention myocardial infarction;
D1) Hormone Replacement Therapy;
E1) the treatment cancer comprises mammary cancer, uterus carcinoma, ovarian cancer and carcinoma of endometrium;
E2) treatment endometriosis;
E3) treatment fibroma uteri;
F1) treatment hirsutism;
F2) suppress natural on-off cycles of hair growth;
G1) as the activity of male contraceptive pill;
G2) as the activity of aborticide; With
H1) promote mylin to repair; It comprises formula (II) compound and the pharmacy acceptable salt thereof that gives described Mammals significant quantity
Figure A9981646400331
Wherein R is
The aryl of 6-14 carbon; Or
3-10 carbon and contain the heteroatomic heteroaryl that 1-3 is selected from N, O and S, condition is that R is not cumarone or thionaphthene; R 1For
The alkyl of 1-10 carbon;
3-12 carbon and contain 1-3 the ring cycloalkyl;
4-7 carbon and contain 1-3 ring and the individual heteroatomic Heterocyclylalkyl that is selected from N, O and S of 1-3;
The aryl of 6-10 carbon;
3-9 carbon and contain 1-3 ring and contain the heteroatomic heteroaryl that 1-3 is selected from N, O and S;
The alkenyl of 2-10 carbon;
5-12 carbon and contain 1-3 the ring cycloalkenyl group; Or
The alkynyl of 3-10 carbon; R 2, R 3And R 4Independently be selected from
H；
The alkyl of 1-10 carbon;
The cycloalkyl of 3-12 carbon;
The alkenyl of 2-10 carbon;
The cycloalkenyl group of 5-12 carbon;
The aryl of 6-13 carbon;
3-9 carbon and contain the heteroatomic heteroaryl that 1-3 is selected from N, O and S;
CO 2R 5Wherein
R 5Be the alkyl of 1-4 carbon, the haloalkyl of a 1-4 carbon, the cycloalkyl of a 3-6 carbon or the halogenated cycloalkyl of 3-6 carbon;
Halogen; With
=O, the expression radicals R 2, R 3And R 4In two; X is O or S (O) yWherein
Y is 0,1 or 2; N is 2,3,4 or 5; P is non-H substituent R 2, R 3And R 4Sum; The number of two keys in the s representative ring, and be 0,1 or 2; T is the substituting group that is selected from following group:
The alkyl of 1-4 carbon;
The alkoxyl group of 1-4 carbon;
The aryl of 6-10 carbon;
CO 2H；
CO 2R 5；
The alkenyl of 2-4 carbon;
The alkynyl of 2-4 carbon;
C(O)C 6H 5；
C (O) N (R 6) (R 7); Wherein
R 6Alkyl for H or 1-5 carbon; With
R 7Alkyl for H or 1-5 carbon;
S (O) Y 'R 8Wherein
Y ' is 1 or 2; With
R 8Alkyl for 1-5 carbon;
SO 2F；
CHO；
OH；
NO 2；
CN；
Halogen;
OCF 3；
The N-oxide compound;
O-C (R 9) 2-O; This oxygen is connected in the ortho position on the R;
And wherein
R 9Alkyl for H, a halogen or 1-4 carbon;
C (O) NHC (O), this carbon is connected in the ortho position on the R; With
C (O) C 6H 4, this carbonyl carbon and carbonyl adjacent ring carbon are connected in the ortho position on the R; T is 1-5;
Condition be when substituting group part T be the alkyl of 1-4 carbon, the alkoxyl group of a 1-4 carbon, aryl, the CO of a 6-10 carbon 2R 5, the alkenyl of a 2-4 carbon, the alkynyl of a 2-4 carbon, C (O) C 6H 5, C (O) N (R 6) (R 7), S (O) Y 'R 8, O-C (R 9) 2-O or C (O) C 6H 4The time, T is optional so can have the secondary substituting group that is selected from following group, comprising: the alkyl of 1-4 carbon, the alkoxyl group of 1-4 carbon, CO 2R 5, CO 2H, C (O) N (R 6) (R 7), CHO, OH, NO 2, CN, halogen, S (O) yR 8Or=O, described secondary substituent number is 1 or 2 except that halogen, it can use at most can reach the perhalogeno level; G is the substituting group that is selected from following group
Halogen;
OH；
OR 5；
=O represents two substituting group G;
The alkyl of 1-4 carbon;
The alkenyl of 1-4 carbon;
The cycloalkyl of 3-7 carbon;
3-5 carbon and 1-3 heteroatomic Heterocyclylalkyl that is selected from N, O and S;
The cycloalkenyl group of 5-7 carbon;
4-6 carbon and 1-3 heteroatomic heterocycloalkenyl that is selected from N, O and S;
CO 2R 5；
C(O)N(R 6)(R 7)；
The aryl of 6-10 carbon;
3-9 carbon and 1-3 heteroatomic heteroaryl that is selected from N, O and S;
NO 2；
CN；
S(O) yR 8；
SO 3R 8With
SO 2N (R 6) (R 7); G is 0-4, and except that halogen, it can use at most can reach the perhalogeno level;
Condition is when substituting group G is the heterocycloalkenyl of the cycloalkenyl group of Heterocyclylalkyl, a 5-7 carbon of cycloalkyl, a 3-5 carbon of alkenyl, a 3-7 carbon of alkyl, a 1-4 carbon of 1-4 carbon or 4-6 carbon, G chooses the secondary substituting group that can have the halogen that can reach the perhalogeno level at most wantonly so, and when substituting group G is aryl or heteroaryl, G can choose wantonly and have the alkyl that independently is selected from 1-4 carbon and the secondary substituting group of halogen so, described secondary substituent number can reach 3 at most to moieties, and can reach the perhalogeno level at most to halogen; Q is the substituting group that is selected from following group:
The alkyl of 1-4 carbon;
The haloalkyl of 1-4 carbon;
The cycloalkyl of 3-8 carbon;
The alkoxyl group of 1-8 carbon;
The alkenyl of 2-5 carbon;
The cycloalkenyl group of 5-8 carbon;
The aryl of 6-10 carbon;
3-9 carbon and contain the heteroatomic heteroaryl that 1-3 is selected from N, O and S;
CO 2R 5；
=O represents two substituting group Q;
OH；
Halogen;
N(R 6)(R 7)；
S(O) yR 8；
SO 3R 8With
SO 2N (R 6) (R 7); Q is 0-4
Condition is when substituting group Q is aryl or heteroaryl, Q is optional so can have the alkyl that independently is selected from 1-4 carbon and the secondary substituting group of halogen, described secondary substituent number can reach 3 at most to moieties, and can reach the perhalogeno level at most to halogen; With other condition be (Q) qR 1, (Q) qR 2, (Q) qR 3(Q) qR 4In two can connect, and form with the atom that they connected and to contain 0-2 and be selected from the heteroatomic 3-8 unit's spiral shell of N, O and S or the non-aromatic ring of non-spiral shell.Detailed description of the preferred embodiments
In above general introduction, extensive definition (I) compound.In formula (I) compound, following group advantageous applications:
R is preferably phenyl or pyridyl.
R 1Be preferably alkyl, a 3-12 carbon of 1-10 carbon and contain 1-3 ring cycloalkyl, a 2-10 carbon alkenyl, a 5-12 carbon and contain 1-3 the cycloalkenyl group that encircles or the alkynyl of 3-10 carbon.R 1More preferably the alkyl of 1-10 carbon, a 3-12 carbon and contain 1-3 ring cycloalkyl, a 2-10 carbon alkenyl or 5-12 carbon and contain 1-3 cycloalkenyl group that encircles.
R 2, R 3And R 4Be preferably cycloalkyl, a 2-10 carbon of alkyl, a 3-12 carbon of H, a 1-10 carbon alkenyl, a 5-12 carbon cycloalkenyl group or=O, wherein carbonyl is represented R 2, R 3And R 4In two.R 2, R 3And R 4The more preferably alkenyl of the cycloalkyl of the alkyl of H, a 1-10 carbon, a 3-12 carbon, a 2-10 carbon or the cycloalkenyl group of 5-12 carbon.
X is preferably O or S (O) y, wherein y is 0,1 or 2.
Subscript n, the number of carbon on the representative ring is preferably 2 or 3.
Subscript p represents non-H substituent R 2, R 3And R 4Sum, be preferably 1 or 2.
T is for preferentially being selected from the alkyl of 1-4 carbon, the alkoxyl group of a 1-4 carbon, the alkenyl of a 2-4 carbon, alkynyl, the NO of a 2-4 carbon 2, CN and halogen substituting group.T is the alkyl, alkenyl, the NO of a 2-4 carbon of 1-4 carbon more preferably 2, CN or halogen.
Subscript t, the number of expression substituting group T is 1-5, more preferably 1-3.
When substituting group part T is the alkynyl of the alkenyl of alkoxyl group, a 2-4 carbon of alkyl, a 1-4 carbon of 1-4 carbon or 2-4 carbon, T is optional so can have the secondary substituting group that preferentially is selected from following group, comprising: alkoxyl group, the CO of the alkyl of 1-4 carbon, a 1-4 carbon 2R 5, CO 2H, C (O) N (R 6) (R 7), CHO, OH, NO 2, CN, halogen, S (O) yR 8With=O, described secondary substituent number is 1 or 2 except that halogen, it can use at most can reach the perhalogeno level.
As using in this application, term " secondary substituting group " means the substituting group on the substituting group, but not as in the degree of the replacement on definition carbon employed " second stage ".
As using in this application, term " haloalkyl " and " halogenated cycloalkyl " are used for referring to it can comprise the group that can reach the halogen atom of perhalogeno level with any number at most.
G preferentially is selected from halogen, OR 5, the alkyl of a 1-4 carbon, the alkenyl of a 1-4 carbon, the cycloalkyl of a 3-7 carbon, the cycloalkenyl group of a 5-7 carbon, the aryl and the CN of a 6-10 carbon.G is alkyl, the alkenyl of a 1-4 carbon, the cycloalkyl of a 3-7 carbon, the cycloalkenyl group of a 5-7 carbon or the aryl of 6-10 carbon of halogen, a 1-4 carbon more preferably.
Subscript g, the number of expression substituting group G except that halogen, is 0-4,0-2 more preferably, it can use at most can reach the perhalogeno level.
Q preferentially is selected from the alkyl of 1-4 carbon, the haloalkyl of a 1-4 carbon, the cycloalkyl of a 3-8 carbon, the alkoxyl group of a 1-8 carbon, the alkenyl of a 2-5 carbon, cycloalkenyl group, the CO of a 5-8 carbon 2R 5,=O, OH, halogen, N (R 6) (R 7) and S (O) yR 8Q is the alkyl, the haloalkyl of a 1-4 carbon, the cycloalkyl of a 3-8 carbon, the alkoxyl group of a 1-8 carbon, the alkenyl of a 2-5 carbon, the cycloalkenyl group or the halogen of a 5-8 carbon of 1-4 carbon more preferably.
The present invention also comprises the pharmacy acceptable salt of formula I compound.Suitable pharmacy acceptable salt to those skilled in the art be know and comprise following inorganic and organic acid alkali salt: for example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, sulfonic acid, acetate, trifluoroacetic acid, oxysuccinic acid, tartrate, Citric Acid, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, toluylic acid and amygdalic acid.In addition, pharmacy acceptable salt comprises the hydrochlorate of mineral alkali, for example contains alkali metal cation (for example, Li +, Na +Or K +) salt, alkaline earth metal cation (for example, Mg 2+, Ca 2+Or Ba 2+) the hydrochlorate of salt, ammonium cation and organic bases, comprise ammonium and quaternary ammonium cation that aliphatic series and aromatics replace, for example those triethylamines, N from protonated or all alkylization, N dimethylamine, N, N-dicyclohexylamine, pyridine, N, N-dimethyl aminopyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN) and 1, the salt of 8-diazabicyclo [5.4.0] 11-7-alkene (DBU).
Multiple formula I compound has asymmetric carbon and therefore can exist with racemize and optical activity form.The method of enantiomer separation and non-enantiomer mixture is known those skilled in the art.The present invention includes and have any racemize or the optical activity form of PgR in conjunction with the compound described in the active formula I.
The ring expansion homologue of the most preferred 2-imino-of the present invention-1,3-thiazoles alkane and 2-imino--1,3-thiazoles alkane is as follows: (4S)-and 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-sec.-propyl-1,3-thiazoles alkane; (4S)-and 2-(2-methyl-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane; (4S)-2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-(trifluoromethyl)-1,3-thiazoles alkane; (4S)-2-(2-methyl-4-nitrophenyl imino-)-3-cyclopentyl-4-isobutyl--1,3-thiazoles alkane; (4S)-2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-sec.-propyl-1,3-thiazoles alkane; (4S)-2-(2-methyl-4-nitrophenyl imino-)-3-cyclopentyl-4-sec.-propyl-1,3-thiazoles alkane; (4R)-and 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-sec.-propyl tetrahydrochysene-2H-1, the 3-thiazine; (4S)-2-(4-nitro-1-naphthyl imino-)-3-cyclopentyl-4-((1R)-1-hydroxyethyl)-1,3-thiazoles alkane; 2-(4-cyano group-2-aminomethyl phenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane; 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.2-(4-cyano-phenyl-imino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane; 2-(4-cyano group-2-aminomethyl phenyl imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane; 2-(4-cyano group-2,3-3,5-dimethylphenyl imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane; 2-(4-cyano group-2-aminomethyl phenyl imino-)-1-(1-ethyl-1-propyl group)-3-thia-1-azaspiro [4.4] nonane; 2-(4-cyano group-1-naphthyl imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane; 2-(2-methyl-4-nitrophenyl imino-)-1-(third-2-alkene-1-yl)-3-thia-1-azaspiro [4.4] nonane; 2-(2-methyl-4-nitrophenyl imino-)-1-sec.-propyl-3-thia-1-azaspiro [4.4] nonane; 2-(2-methyl-4-nitrophenyl imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane; 2-(2-methyl-4-nitrophenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane; 2-(3-methyl-4-nitrophenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane; 2-(2-methyl-4-nitrophenyl imino-)-1-cyclohexyl-3-thia-1-azaspiro [4.4] nonane; 2-(2,3-dimethyl-4-nitrophenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane; And 2-(4-cyano group-2,3-3,5-dimethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.
The most preferred thiazolidin-4-one of the present invention is as follows: 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--1,3-thiazoles alkane-4-ketone; 2-(3-methyl-4-nitrophenyl imino-)-3-isobutyl--1,3-thiazoles alkane-4-ketone; 2-(2-methyl-4-nitrophenyl imino-)-3-benzyl-1,3-thiazoles alkane-4-ketone; 2-(3-methyl-4-nitrophenyl imino-)-3-benzyl-1,3-thiazoles alkane-4-ketone; 2-(2-methyl-4-nitrophenyl imino-)-3-(2-methyl-1-butene base)-1,3-thiazoles alkane-4-ketone; 2-(3-methyl-4-nitrophenyl imino-)-3-(2-methyl-1-butene base)-1,3-thiazoles alkane-4-ketone; 2-(2-methyl-4-nitrophenyl imino-)-3-(1-cyclohexyl-1-ethyl)-1,3-thiazoles alkane-4-ketone; 2-(3-methyl-4-nitrophenyl imino-)-3-(1-cyclohexyl-1-ethyl)-1,3-thiazoles alkane-4-ketone; 2-(2-methyl-4-nitrophenyl imino-)-3-(2-ethyl-1-butyl)-1,3-thiazoles alkane-4-ketone; 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--5-methylene radical-1,3-thiazoles alkane-4-ketone; And 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--5-methyl isophthalic acid, the 3-thiazolidin-4-one.
Zui You Xuan De oxazolidine of the present invention is as follows: 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4,4-dimethyl-1,3-oxazolidine; 1-cyclopentyl-2-(4-cyano group-2-ethylphenyl imino-)-3-oxa--1-azaspiro [4.4] nonane; 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-oxa--1-azaspiro [4.4] nonane; With 1-cyclohexyl-2-(2-methyl-4-nitrophenyl imino-)-3-oxa--1-azaspiro [4.4] nonane.
Medicine of the present invention can use separately or with other therapy simultaneously.For example, when as when in A1 or A2, using, this medicine can with the analogue of calcium source, vitamins D or vitamins D and/or anti-absorb therapy for example controversies in hormone replacement in the elderly, adopt the fluorine source treatment, adopt the treatment of thyrocalcitonin or calcitonin-like or adopt diphosphonate for example the treatment of Alendronate use simultaneously.When as when in B1 to B7, using, medicine can with therapy for example controversies in hormone replacement in the elderly use simultaneously.When as when in C1 to C16, E1 to E3 or F1 or F2, using, medicine can for example controversies in hormone replacement in the elderly and/or GuRH-A use simultaneously with therapy.When as when in G1 or G2, using, medicine can with therapy for example male sex hormone use simultaneously.
The inventive method is intended for use to treat the disease of PgR mediation in people and other Mammals.
Can the dosage unit preparations oral administration, skin, non-enteron aisle, injection, suction or spraying or hypogloeeis, rectum or vagina give described compound.Term " gives " to comprise vein, intraarticular, intramuscular, the injection of subcutaneous and non-enteron aisle and uses infusion techniques through injection.Skin gives to comprise topical application or transdermal administration.If one or more compounds can with one or more atoxic pharmaceutically acceptable carriers and requirement, with other activeconstituents administration.
According to any suitable method that is used to prepare medicinal compositions known in the art, can prepare the composition that plan orally uses.Such composition can comprise one or more reagent that are selected from thinner, sweeting agent, correctives, tinting material and sanitas so that good to eat preparation to be provided.
Tablet comprises and is suitable for preparing the activeconstituents of the atoxic pharmaceutically acceptable mixed with excipients of tablet.These vehicle can be for example inert diluent such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate, granulating agent and disintegrating agent such as W-Gum or alginic acid and tackiness agent such as Magnesium Stearate, stearic acid or talcum powder.That tablet can be dressing not or their available known technology dressings, so as in gi tract, to postpone disintegration and absorb and long-time thus in continuous action is provided.For example, serviceable time time-delay material such as glyceryl monostearate or distearin.These compounds also can be with the form preparation of solid, release rapidly.
The preparation that orally uses also can be used as hard gelatin capsule and presents, wherein activeconstituents mixes with inert solid diluent such as lime carbonate, calcium phosphate or kaolin, or present wherein activeconstituents and water or oily medium such as peanut oil, whiteruss or mixed with olive oil as soft gelatin capsule.
Also can use the water suspension that contains with the active substance of the mixed with excipients that is suitable for preparing water suspension.Such vehicle is suspension agent such as Xylo-Mucine, methylcellulose gum, hydroxypropyl-methylcellulose gum, sodiun alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; Dispersion agent or wetting agent can be the condensation product such as the polyoxyethylene stearic acid ester of naturally occurring phosphatide such as Yelkin TTS or alkylene oxide and lipid acid, or the condensation product of oxyethane and long chain aliphatic alcohol is as 17 carbon vinyloxy group hexadecanols, or oxyethane and be derived from lipid acid and the condensation product of the part ester of hexitol such as polyoxyethylene sorbitol monoleate or oxyethane and be derived from lipid acid and the condensation product of the part ester of hexitan such as polyethylene dehydrated sorbitol mono-fatty acid ester.Water suspension also can contain one or more sanitass such as ethyl p-hydroxybenzoate or n-propyl, one or more tinting materials, one or more correctivess and one or more sweeting agents such as sucrose or asccharin.
But provide and dispersion agent or wetting agent, suspension agent and one or more sanitas blended activeconstituentss by adding dispersion powder and the granule that entry is suitable for preparing water suspension.By above those already mentioned suitable dispersion agent or wetting agent and suspension agents of illustrating.The vehicle that also can have other, for example sweeting agent, correctives and tinting material.
Described compound also can exist by the on-aqueous liquid dosage form, oil suspension for example, it can be by being suspended in activeconstituents vegetables oil such as peanut oil, sweet oil, sesame oil or peanut oil (peanut oil), or be suspended in mineral oil such as the whiteruss and prepare.Oil suspension can comprise thickening material such as honeybee is cured, paraffinum durum or Cetyl Alcohol.Also can add those materials of sweeting agent such as above elaboration and correctives so that good to eat oral preparations to be provided.These compositions can come anticorrosion through adding antioxidant such as xitix.
Medicinal compositions of the present invention also can the oil-in-water emulsion form exist.Oil phase can be the mixture of vegetables oil such as sweet oil or peanut oil or mineral oil such as whiteruss or these materials.Examples of suitable emulsifiers can be naturally occurring natural gum such as gum arabic or tragacanth gum, naturally occurring phosphatide such as soybean, Yelkin TTS and is derived from lipid acid and the ester of hexitan or part ester, the for example condensation product of dehydrated sorbitol mono-fatty acid ester and described part ester and oxyethane, for example polyoxyethylene sorbitan monoleate.Described milk sap also can comprise sweeting agent and correctives.
With sweeting agent such as glycerine, propylene glycol, sorbyl alcohol or sucrose, but obtain syrup agent and elixir.Such preparation also can comprise demulcen, sanitas and correctives and tinting material.
The suppository form that compound also can be used for rectum or vagina administration gives.By medicine is mixed with suitable non-irritating excipient, can prepare these compositions, this vehicle be solid under normal temps but is liquid under rectum or vagina temperature, thus in rectum or vagina fusion to discharge medicine.Such material comprises theobroma oil and polyoxyethylene glycol,
Use method known to those skilled in the art, but also transdermal administration compound of the present invention (referring to for example: Chien; " Transdermal Controlled Systemic Medications "; Marcel Dekker company; 1987.Lipp etc., WO on March 3rd, 94/04157,1994).For example, solution or the suspensoid of formula I compound in choosing the suitable volatile solvent that contains penetration enhancers wantonly can be united with other additive well known by persons skilled in the art, for example substrate material and sterilant.After the sterilization,, can be formulated as formulation to the mixture that generates according to currently known methods.In addition, under with emulsifying agent and water treatment, the solution or the suspensoid of formula I compound can be formulated as lotion or salve.
The The suitable solvent that is used to process transdermal delivery system to those skilled in the art for known, and comprise lower alcohols such as ethanol or Virahol, rudimentary ketone such as acetone, low-carbon carboxylate such as ethyl acetate, polarity ethers such as tetrahydrofuran (THF), rudimentary hydro carbons such as hexane, hexanaphthene or benzene, or halogenated hydrocarbon such as methylene dichloride, chloroform, Refrigerant R 113 or trichlorine fluoroethane.The suitable solvent can comprise that also one or more are selected from the mixture of the material of lower alcohols, rudimentary ketone, low-carbon carboxylate, polarity ethers, rudimentary hydro carbons, halogenated hydrocarbon.
The suitable infiltration enhancing substance that is used for transdermal delivery system is known to those skilled in the art, and comprises for example monohydroxy or poly-hydroxy alcohols such as ethanol, propylene glycol or phenylcarbinol, saturated or unsaturated C 8-C 18Fatty Alcohol(C12-C14 and C12-C18) such as lauryl alcohol or hexadecanol, saturated or unsaturated C 8-C 18Lipid acid such as stearic acid, have the methyl esters that can reach the saturated of 24 carbon or unsaturated aliphatic ester such as acetate, caproic acid, lauric acid, tetradecanoic acid, stearic acid or palmitinic acid at most, ethyl ester, propyl ester, isopropyl ester, positive butyl ester, secondary butyl ester, isobutyl ester, the tert-butyl ester or direactive glyceride, have and to reach the saturated of 24 carbon or unsaturated dicarboxylic acid diester such as Wickenol 116, diisobutyl adipate, Wickenol 117, isopropyl maleate or fumaric acid diisopropyl ester altogether at most.Infiltration enhancing substance in addition comprises phosphatidyl derivant Yelkin TTS or kephalin, terpene, amides, ketone, ureas and derivative thereof, and ethers such as Isosorbide dimethyl ether and diethylene glycol monoethyl ether.Suitable infiltration strengthens preparation and comprises that also one or more are selected from monohydroxy or polyhydroxy-alcohol, saturated or unsaturated C 8-C 18Fatty Alcohol(C12-C14 and C12-C18), saturated or unsaturated C 8-C 18Lipid acid, have and to reach the saturated of 24 carbon or unsaturated aliphatic ester at most, have the mixture that can reach the material of the saturated of 24 carbon or unsaturated dicarboxylic acid diester, phosphatidyl derivant, terpene, amides, ketone, ureas and its derivative and ethers altogether at most.
The suitable bond material that is used for transdermal delivery system is known to those skilled in the art and comprises polyacrylic ester, polysiloxane, polyurethane(s), block polymer, styrene-butadiene copolymer and natural and synthetic rubber.Ether of cellulose, deutero-polyethylene and silicate also can be used as matrix components.Can add for example tackifying resin or oily of other additive to increase the viscosity of matrix.
For all operational versions of formula I compound disclosed herein, the oral dosage scheme will be preferably 0.01 to 200mg/Kg TBW every day.Be used for through injection comprise vein, intramuscular, subcutaneous and non-enteron aisle drug administration by injection every day dosage and the use of infusion techniques will be preferably 0.01 to 200mg/Kg TBW.The rectal dose scheme will be preferably 0.01 to 200mg/Kg TBW every day.The vagina dosage will be preferably 0.01 to 200mg/Kg TBW every day.The local dose scheme will be preferably 0.1 to 200mg every day, administration every day one to four time.To preferably need keep 0.01 to 200mg/Kg dosage every day through skin concentration.The inhalation dose scheme will be preferably 0.01 to 10mg/Kg TBW every day.
Those skilled in the art will recognize that the administration concrete grammar will decide according to multiple factor, when giving medicine, think that all of these factors taken together is conventional factor.Yet, people also will understand the concrete dosage level of any given patient and will decide according to multiple factor, include but is not limited to activity, patient's age, patient's body weight, patient's general health situation, patient's sex, patient's diet, administration time, route of administration, discharge rate, drug regimen and the severity of disease of being treated of the particular compound of using.Those skilled in the art will recognize that the best course of treatment of treatment in addition, promptly treat pattern and formula I compound or their pharmacy acceptable salt administration number of times every day for the fate of determining and to use the conventional treatment test to determine by those skilled in the art.
More than and below the whole disclosure of all applications, patents and publications quoted be attached to herein by reference.
Use known chemical reactions and method, preparation method by following demonstration and by other reaction and method well known by persons skilled in the art, from known compound (or from starting raw material, it can generate from known compound successively) but preparation I compound.Yet,, present following general preparation method and help the synthetic The compounds of this invention of implementer with the more detailed specific embodiment that is presented in the experimental section.Embodiment only should not be construed as limiting the invention by any way for illustrating purpose and not planning yet.The abbreviation table
As used herein, following term has indicated implication.
AcOH acetate
Anh is anhydrous
The BOC tert-butoxycarbonyl
Conc is dense
Dec decomposes
DBU 1,8-diazabicyclo [5.4.0] 11-7-alkene
The DIBAL diisobutyl aluminium hydride
DME 1, the 2-glycol dimethyl ether
DMF N, dinethylformamide
The DMSO dimethyl sulfoxide (DMSO)
The EtOAc ethyl acetate
EtOH ethanol (100%)
Et 2The O ether
Et 3The N triethylamine
KMnO 4Potassium permanganate
Magnosil ??MgSiO 3·xH 2O
M-CPBA 3-chloro peroxybenzoic acid
MeOH methyl alcohol
Pet.ether sherwood oil (boiling range 30-60 ℃)
The THF tetrahydrofuran (THF)
The logical method of TFA trifluoroacetic acid preparation
Use known operation method (Katritzky etc., Comprehensive HeterocyclicChemistry; Permagon press: Oxford, UK (1984) .March.AdvancedOrganic Chemistry, the 3rd edition; John Wiley: New York (1985)), can synthesize arylamine, aromatic isocyanate, aromatic yl different sulfur cyanic acid ester, asymmetric aryl thiourea, aromatic isocyanate dichloride and 2-aryl imino--1, the 3-heterocycle.For example, aromatic isocyanate (2) can be obtained from the reaction of phosgene or phosgene Equivalent such as carbonyl dimidazoles, two phosgene or triphosgene, and aromatic yl different sulfur cyanic acid ester (3) (flow process I) can be obtained from the reaction of arylamine and thio phosgene or thio phosgene Equivalent such as thio-carbonyldiimidazole.Also can buy on the market and obtain many aromatic isocyanates and aromatic yl different sulfur cyanic acid ester.Then the reaction of aromatic yl different sulfur cyanic acid ester and primary amine obtain thiocarbamide 4 (Hahn etc., Han ' guk Nonghwa Hakhoechi 1997 and, 139; D ü rr US patent 4,079,144; Enders US patent 4,148,799).Flow process I
Figure A9981646400471
As showing among the flow process II, for example alpha-brominated ketone 5 reactions of thiocarbamide and α-Lu Daitong obtain thiazoline (6) (Hahn etc., Han ' guk Nonghwa Hakhoechi 1997,40,139 after the dehydration; D ü rr US patent 4,079,144; Enders US patent 4,148,799).Flow process II
Figure A9981646400481
Similarly, thiocarbamide and alpha-halogen carboxylic acid halides (Giri etc., Asian J.Chem.1992,4,785; Lakhan etc., Agric.Biol.Chem.1982,46,557), alpha-halogen acid (Dogan etc., Spectrosc.Lett.1983,16,499; Seada etc., Indian J.Heterocycl.Chem.1993,3,81) and alpha-halogen ester (Seada etc., Indian J.Heterocycl.Chem.1993,3,81) reaction, obtain 4-thiazolidone (10).Flow process III
Figure A9981646400482
Aromatic yl different sulfur cyanic acid ester (3) also with allyl amine (Tsoi etc., Zh.Org.Khim.1983,19,2605) and propargyl amine (Azerbaev etc., Khim.Geterotsikl.Soedin.1972,471) reaction, form corresponding thiocarbamide, it obtains the thiazolidine (flow process IV) that 5-replaces under acid treatment.Flow process IV
Figure A9981646400491
Aromatic yl different sulfur cyanic acid ester also can form N-hydroxyalkyl thiocarbamide 18 (flow process V) with azanol (17) reaction.Use the acid treatment thiocarbamide then, obtain 2-imino--1,3-heterocycle 19 (Jen etc., J.Med.Chem.1975,18,90; Tyukhteneva etc., Khim.Geterotsikl.Soedin.1985,12,1629; Olszenko-Piontkowa etc., Org.Prep.Proced.Int.11971,3,27).Hydroxyalkyl thiocarbamide 18 and SOCl 2Reaction obtains alkyl chloride base analogue 20, with under the alkaline purification, makes its cyclization obtain heterocycle 19 (Cherbuliez etc., Helv.Chim.Acta.1967,50,331; Felix etc., US patent 4,806,653).Flow process V
Figure A9981646400501
Perhaps, as showing among the flow process VI, with HgO or alkylating reagent for example methyl iodide handle N-hydroxyalkyl thiocarbamide 18, with after alkaline purification obtains corresponding oxygen heterocyclic ring (Jen etc., J.Med.Chem.1975,18,90; Ignatova etc., Khim.Geterotsikl.Soedin.1974,354).Flow process VI
It is reported that chloro alkyl lsothiocyanates and arylamine reaction obtain corresponding sulfur-bearing 2-phenylimino-1,3-heterocycle (Sagner etc., US patent 3,651,053; The same US patent 3,737,536).Flow process VII
Arylamine and formylation source be the arboxylic acid anhydride reactant for example, forms formanilide 25, its can oxidizedly be converted into then aryl isocyanides dichloride (Ferchland etc., DE 3,134,134; For summary, referring to Kuehle etc., Angew.Chem.1967,79,663).Aryl isocyanides dichloride (26) and azanol (27) reaction obtain containing oxygen 2-phenylimino-1,3-heterocycle 30 (Wollweber US patent 3,787,575; The same US patent 3,686,199) and 28 reactions of aryl isocyanides dichloride (26) and oxyamide, obtain thiazolidone 31.In addition, show aryl isocyanides dichloride and amineothiot (29) reaction, obtained sulfur-bearing 2-phenylimino-1,3-heterocycle 32 (Thibault French Patent 1,510,015).Flow process VIII In the presence of alkali, use CS 2Handle azanol and will generate 1,3-sulphur azepine-2-thioketones (flow process IX).It is reported thioketones 34 and SOCl 2Reaction obtains the unsettled imidate 35 of moisture absorption, with arylamine it is handled, and obtains sulfur-bearing 2-imino--1,3-heterocycle (Hanefeld etc., Arch.Pharm.1985,318,60; The same 1988,321,199).Flow process IX
Contain oxygen and sulfur-bearing 2-imino--1, the 3-heterocycle can further be processed.Therefore, for example, as showing among the flow process X, generally in the presence of alkali, handle the unsubstituted 2-phenylimino-1 of N3-with electrophilic reagent, the 3-heterocycle obtains the product (Ambartsumova etc. that N3-replaces, Chem.Heterocycl.Compd.1997,33,475; Mizrakh etc., Khim.Geterotsikl.Soedin.1990,563; Olszenko-Piontkowa etc., Org.Prep.Proced.Int.11971,3,27).Flow process X
In addition, as showing among the flow process XI, sulfur-bearing 2-imino--1,3-heterocycle can be oxidized to sulfoxide or sulfone (Chizhevskaya etc., Khim.Geterotsikl.Soedin.1971,96; Pandey etc., J.Indian.Chem.Soc.1972,49,171).Flow process XI
Figure A9981646400532
Detailed experimental technique
In following detailed synthetic method, provide the detailed preparation embodiment of The compounds of this invention.In the table of subsequently compound, each compound synthetic conversely with reference to the preparation process of these embodiment.Embodiment
Except as otherwise noted, all are reflected under the positive pressure of exsiccant argon gas or exsiccant nitrogen, in the glassware of flame drying or oven drying, carry out, and magnetic agitation.Shift responsive liquid and solution by syringe or ingress pipe, and import in the reaction vessel by the rubber partition.Other reagent of commodity in use level and solvent, and be not further purified.
Unless otherwise indicated, term " decompression concentrates down " refers to and is approximately using the Buchi rotatory evaporator under the 15mmHg.Use Aldrich Kugelrohr device, carry out ball ball (bulbto bulb) is concentrated, and in these cases, temperature refers to Heating temperature.All temperature with degree centigrade (℃) report and not proofreading and correct.Except as otherwise noted, all parts and per-cent are volume ratio.
Thin layer chromatography (TLC) is at Whatman Carry out on the silica gel 60AF-254 250 μ m plates of the glass of coating bottom in advance.The colour developing of plate is finished by following one or more technology: (a) UV-irradiation, (b) be exposed to iodine vapor, (c) plate is immersed in the solution of 10% phospho-molybdic acid in ethanol and postheating, (d) plate is immersed in the cerous sulfate solution and postheating, and/or (e) plate is immersed in the acid ethanol solution of 2,4 dinitrophenyl hydrazine and postheating.Use 230-400 order EM Science Silica gel carries out column chromatography (flash chromatography method).Use is from the SiO of the casting in advance of Harrison Research Chromatotron 2Plate (Alltech ), be rotated chromatography.
Use the automatic fusing point device of Thomas-Hoover fusing point device or Mettler FP66 to measure fusing point (mp) and not correction.Use Mattson 4020 Galaxy Series spectrophotometers to obtain Fourier transform infrared spectroscopy.
Use General Electric GN-Omega 300 (300MHz) spectrograph, use Me 4Si (δ 0.00) or residual protonated solvent (CHCl 3δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard substance, the measurement proton ( 1H) nuclear magnetic resonance spectrum (NMR).Use General Electric GN-Omega 300 (75MHz) spectrograph, with solvent (CDCl 3δ 77.0; MeOD-d 3δ 49.0; DMSO-d 6δ 39.5) as standard substance, measurement carbon ( 13C) NMR spectrum.
Obtain Low Resolution Mass Spectra (MS) and high resolution mass spectrum (HRMS) as electron-bombardment (EI), chemi-ionization (CI) or as fast atom bombardment MS (FAB).The Hewlett Packard 5989A mass spectrograph that use is equipped with the vacuum measurement that is used for the sample importing to resolve the chemi-ionization probe obtains electron impact mass spectra (EI-MS).Ion source maintains under 250 ℃.Carry out electron impact ionization with the electron energy of 70eV and the trap electric current of 300 μ A.Use Kratos Concept 1-H spectrograph, obtain liquid-cerium second ion mass spectroscopy (FAB-MS), it is the last word of fast atom bombardment.Use Hewlett Packard MS-Engine (5989A), with methane or ammonia as reagent gas (1 * 10 -4Holder to 2.5 * 10 -4Holder), obtain chemical ionization mass spectrometry (CI-MS).Directly insert and resolve chemi-ionization (DCI) probe (Vaccumetrics company) and in 10 seconds, keep sample up to all traces disappear (～1-2 minute) from 0-1.5amps ramp and under 10amps.With each scanning 2 seconds, from the 50-800amu scanning spectrum.Use is equipped with Hewlett Packard 1100 HPLC of four-stage pump, variable-wavelenght detector, C-18 post and has the Finnigan LCQ ion trap mass spectrometer of electro-spray ionization, obtains HPLC-electrospray ionization mass spectrum (HPLC ES-MS).According to the ion populations in described source, use the variable ionization time, from the 120-800amu scanning spectrum.Use is equipped with HP-1 methyl silicone post (0.33mM coating; Hewlett Packard 5890 gas chromatographs and the Hewlett Packard5971 mass selective detector (ionization energy 70eV) of 25m * 0.2mm) obtain gas chromatography-ion selectivity mass spectrum (GC-MS).
By Robertson Microlit laboratory, Madison NJ carries out ultimate analysis.NMR spectrum, LRMS, ultimate analysis and the HRMS of compound are consistent with specified structure.
Below the preparation embodiment of The compounds of this invention is provided in the detailed synthetic method.In the table of subsequently compound, each compound synthetic conversely with reference to the preparation process of these embodiment.A. the synthetic A1a. of imines precursor is from the logical method of the synthetic aniline of oil of mirbane.Synthesizing of 4-cyano group-2-aminotoluene.
Figure A9981646400551
Such (J.Med.Chem. (1991), 34,3295) as previously described, synthetic 4-cyano group-2-aminotoluene: (2.0g 12.34mmol) drips SnCl in the solution in acetate (20L) to 3-methyl-4-nitrobenzonitrile 2(9.6g, 49.38mmol) solution in dense HCl (20mL).Stir after 3 hours, under 0 ℃, mixture is joined saturated NH carefully 4In the OH solution (120mL).(4 * 30mL) extract the mixture that generates with EtOAc.Use H 2The organic layer that O (30mL) and saturated NaCl solution (30mL) order washing merge, dry (Na 2SO 4), and decompression concentrates down.Through flash chromatography method (10%EtOAc/ hexane) purifying resistates, obtain 4-cyano group-2-aminotoluene (1.48g, 92%): TLC (30%EtOAc is in hexane) R into white solid f0.23.This material is not further purified and uses.A2a. synthesizing of lsothiocyanates led to method.Synthesizing of 4-nitro-2-n-propyl lsothiocyanates. Step 1
To 2-n-propyl aniline (8.91g, 66mmol) and Et 3(14mL is 106mmol) at CH for N 2Cl 2Drip in the solution (60mL) diacetyl oxide (10.9mL, 99mmol).At room temperature, the mixture stirring that generates is spent the night, use 1N HCl solution (40mL) to handle then.Use CH 2Cl 2(2 * 30mL) extract acidic mixture.Use H 2O (40mL), 1N NaOH solution (40mL), H 2The organic layer that O (40mL) and saturated NaCl solution (40mL) order washing merge, dry (Na 2SO 4), and decompression concentrates down.Powder through crystallization process (EtOAc) purifying generates obtains the 2-n-propyl monoacetylaniline (7.85g, 67%) into white needle.TLC (30%EtOAc/ hexane) R f0.37.
Figure A9981646400562
Step 2
Under-5 ℃, (1.15g 6.50mmol) adds NaNO in the solution in TFA (20mL) to 2-n-propyl monoacetylaniline 2(0.55g, 6.50mmol).Under-5 ℃, mixture was stirred 3 hours, use H then 2O (30mL) handles.(3 * 20mL) extract the aqueous solution that generates with EtOAc.With 1N NaOH solution (30mL), H 2The organic layer that O (30mL) and saturated NaCl solution (40mL) washing merge, dry (Na 2SO 4), and decompression concentrates down.Be dissolved in resistates in the dense HCl solution (30mL) and 100 ℃ of following heated overnight.With ice bath the mixture that generates is cooled to 0 ℃, carefully is adjusted to pH10 with 50%NaOH solution then.(4 * 30mL) extract alkaline mixt with EtOAc.Use H 2The organic layer that O (30mL) and the washing of saturated NaCl solution (40mL) order merge, dry (Na 2SO 4), and decompression concentrates down.Through flash chromatography method (5%EtOAc/ hexane) purifying resistates, obtain 2-n-propyl-4-nitro monoacetylaniline (0.56g, 48%): TLC (20%EtOAc/ hexane) R into yellow solid f0.47.
Figure A9981646400571
Step 3
To 2-n-propyl-4-nitro monoacetylaniline (0.56g, 0.31mmol) drip in the solution in toluene (30mL) thiophosgene (0.24mL, 0.31mmol).Under reflux temperature, mixture heating up is spent the night, be cooled to room temperature and decompression then and concentrate down.Through flash chromatography method (1%EtOAc/ hexane) purifying resistates, obtain 2-propyl group-4-nitrophenyl lsothiocyanates (0.65g, 95%): TLC (20%EtOAc/ hexane) R into yellow oil f0.82.A2b. synthesizing of lsothiocyanates led to method.Synthesizing of 4-cyano group-2-ethylphenyl lsothiocyanates.
Figure A9981646400572
By syringe, (75g 0.51mol) slowly adds thiophosgene (43mL, 0.56mol, 1.1 equivalents) in the solution in toluene (1L) to 4-amino-3-ethyl benzonitrile.In 5 minutes, form the viscid soup compound.Reaction mixture is heated to reflux temperature and viscosity reduces.Under reflux temperature,, make it to be cooled to room temperature then with reaction mixture heating 5 hours.Decompression concentrates the mixture that generates and uses CH down 2Cl 2(600mL) handle resistates and decompression and concentrate down, obtain 4-cyano group-2-ethylphenyl lsothiocyanates (98g, 100%) into light brown crystalline solid: 1H NMR (DMSO-d 6) δ 1.18 (t, J=7.4Hz, 3H), 2.69 (q, J=7.4Hz, 2H), 7.55 (d, J=7.0Hz, 1H), 7.75 (d, J=7.0Hz, 2H), 7.84 (s, 1H); MS (CI-MS) m/z 189 ((M+H) +).A2c. synthesizing of lsothiocyanates led to method.2,4-dimethyl-3-cyano group-5-pyridyl lsothiocyanates synthetic.
Figure A9981646400581
At room temperature, with 6-amino-3-cyano group-2, (0.1g is 0.68mmol) at CH for the 4-lutidine 2Cl 2Suspension (1mL) joins the CaCO that vigorous stirring 3(0.41g is 4.11mmol) at 1: 2 water: CH 2Cl 2In the mixture in the mixture (amounting to 9mL).Reaction mixture is cooled to 0C and drip thiophosgene (0.09g, 0.78mmol).The mixture that generates is warmed to room temperature and stirs and spend the night.Use CH 2Cl 2(3 * 10mL) the anti-water layers that generate that extract.The organic layer that water (10mL) washing merges, dry (MgSO 4) and reduce pressure concentrated down.Through chromatography (SiO 2, the 10%EtOAc/ hexane) and the purifying resistates, obtain 2,4-dimethyl-3-cyano group-6-pyridyl lsothiocyanates (0.12g, 91%): CI-MS m/z 190 ((M+H)+).A2d. synthesizing of lsothiocyanates led to method.2,3-dimethyl-4-nitrophenyl lsothiocyanates synthetic.
Figure A9981646400582
To 2, add thiophosgene (0.3mL, 1.3 equivalents) in the solution of 3-dimethyl-4-N-methyl-p-nitroaniline (0.5g, 1.0 equivalents) in toluene (50mL) and in following reaction mixture heated overnight of reflux temperature.Decompression concentrates down the mixture that generates and through column chromatography (25%CH 2Cl 2/ hexane) purifying resistates obtains being 2 of faint yellow solid, 3-dimethyl-4-nitrophenyl lsothiocyanates (0.30g, 48%): 1H NMR (CDCl 3) δ 2.39 (s, 3H), 2.41 (s, 3H), 7.20 (d, J=8.4Hz, 1H); CI-MS (CI-MS) m/z 200 ((M+H) +).A2e. synthesizing of lsothiocyanates led to method.2,3-dimethyl-6-nitrophenyl lsothiocyanates synthetic.
Figure A9981646400591
To 2, add thiophosgene (2.5mL, 1.8 equivalents) in the solution of 3-dimethyl-6-N-methyl-p-nitroaniline (3.0g, 1.0 equivalents) in toluene (150mL) and under reflux temperature with the reaction mixture heated overnight.Decompression concentrates down the mixture that generates and through column chromatography (10%CH 2Cl 2/ hexane) purifying resistates obtains being 2 of faint yellow solid, 3-dimethyl-6-nitrophenyl lsothiocyanates (3.63g, 95%): 1H NMR (CDCl 3) δ 2.39 (s, 3H), 2.40 (s, 3H), 7.17 (d, J=8.4Hz, 1H), 7.83 (d, J=8.7Hz, 1H).A3a. synthesizing of aryl isonitrile dichloride led to method.Synthesizing of 4-cyano group-2-ethylphenyl isocyanides dichloride.
Figure A9981646400592
Step 1
Diacetyl oxide (235mL, 2.5mol, 2.6 equivalents) joined in the formic acid (118mL, 3.1mol, 3.2 equivalents) and 60 ℃ following solution heating that generates 2 hours.After reactant is cooled to room temperature, is no more than 45 ℃ of such speed with temperature of charge and adds 4-amino-3-ethyl benzonitrile (140g, 0.96mol) solution in anhydrous THF (700mL) (about 20 minutes).When the solution that generates is cooled to room temperature, its decompression is concentrated down, handle with EtOH (600mL), and decompression is concentrated once more down, obtains being filbert solid 4-cyano group-2-ethyl n-formylaniline (167g, 100%): 1H NMR (CDCl 3) δ 1.13 (t, J=7.3Hz, 3H), 2.48 (q, J=7.3Hz, 2H), 7.65 (d, J=8.5Hz, 1H), 8.35 (d, J=8.5Hz, 1H), 8.37 (s, 1H), 9.89 (brs, 1H).
Figure A9981646400601
Step 2
By syringe, to being cooled to 4-cyano group-2-ethyl n-formylaniline (167g, 0.96mol, 1.0 equivalents) of 0 ℃ at SOCl with ice bath 2Add sulfuryl chloride (112mL, 1.4mol, 1.4 equivalents) in the solution in (525mL, 6.05mol, 6.3 equivalents).Remove cooling bath then and under 50 ℃ with the reactant heated overnight.Decompression concentrates the mixture that generates down, uses CH 2Cl 2(600mL) handle, and decompression concentrates down once more.Resistates is dissolved in Et 2Among the O (800mL) and through Magnosil Pad filters, and obtains the 4-cyano group-2-ethylphenyl isocyanides dichloride (210g, 96%) into oil: 1H NMR (CDCl 3) δ 1.13 (t, J=7.3Hz, 3H), 2.49 (q, 2H, J=7.3Hz), 7.15 (d, J=8.2Hz, 1H), 8.35-8.40 (m, 2H).A3b. synthesizing of aryl isonitrile dichloride led to method.Synthesizing of 2-methyl-4-nitrophenyl isocyanides dichloride.
Figure A9981646400602
Step 1
Diacetyl oxide (400mL, 4.26mol, 2.6 equivalents) joined in the formic acid (200mL, 5.25mol, 3.2 equivalents) and 60 ℃ following solution heating that generates 2.25 hours.After being cooled to room temperature,, temperature of charge adds the 2-methyl-solution (about 30 minute) of 4-N-methyl-p-nitroaniline (152g, 1.64mol, 1.0 equivalents) in anhydrous THF (1.2L) so that being no more than 45 ℃ of such speed.When the solution that generates was cooled to room temperature, decompression was concentrated into it half volume and removes reactant after filtration down, obtains being filbert solid 2-methyl-4-nitro formanilide (295g, 100%): 1H NMR (CDCl 3) δ 2.31 (s, 3H), 8.03 (m, 2H), 8.24 (d, J=8.8Hz, 1H), 8.39 (brs, 1H), 9.94 (brs, 1H). Step 2
With SOCl 2(525mL, 6.05mol, 6.3 equivalents) join 2-methyl-4-nitro formanilide (167g, 0.96mol) in and the solution that generates is cooled to 0 ℃.By syringe, add sulfuryl chloride (112mL, 1.4mol, 1.4 equivalents), remove cooling bath and under 60 ℃ with reactant heating 4 hours, be cooled to ambient temperature overnight then.Decompression is concentrated into reaction mixture half volume and filters the soup compound that generates down.Use 50%Et 2O/ hexane solution washing solid obtains the 2-methyl-4-nitrophenyl isocyanides dichloride (323g, 85%) into yellow solid: 1HNMR (CDCl 3) δ 2.19 (s, 3H), 7.20 (d, J=8.5Hz, 1H), 8.15 (d, J=8.5Hz, 1H), 8.2 (s, 1H).A4a. from the logical method of aniline synthesizing nitryl aniline.2,3-dimethyl-6-N-methyl-p-nitroaniline and 2,3-dimethyl-4-N-methyl-p-nitroaniline synthetic. Step 1
Under 0 ℃, in 30 minutes to 23 dimethyl aniline (1.1mL, 1.00 equivalents) and Et 3N (1.5mL, 1.30 equivalents) is at CH 2Cl 2Add Acetyl Chloride 98Min. (0.73mL, 1.25 equivalents) in the solution (15mL).At room temperature, the reaction mixture stirring is spent the night, use 2N HCl solution (10mL) and CH then 2Cl 2(25mL) handle.(3 * 25mL) extract the mixture that generates with EtOAc.With 2N HCl solution (2 * 25mL), water (2 * 25mL), saturated NaHCO 3Solution (2 * 25mL) and saturated NaCl solution (organism that 2 * 25mL) washings merge, dry (Na 2SO 4), and decompression is concentrated down, obtains being 2 of white solid, 3-dimethyl monoacetylaniline (1.25g, 93%): 1H NMR (CDCl 3) δ 2.05 (s, 3H), 2.15 (s, 3H), 2.25 (s, 3H), 6.95 (d, J=7.5Hz, 1H), 7.02 (apparent t, J=7.5Hz, 1H), 7.35 (d, J=6.9Hz, 1H).
Figure A9981646400621
Step 2
Under 0 ℃, to 2,3-dimethyl monoacetylaniline (14.0g, 1.0 equivalents) is at dense H in 30 minutes 2SO 4Add HNO in the solution (35mL) 3(5.1mL, 1.25 equivalents).At room temperature, the mixture that generates was stirred 15 minutes, use frozen water (500mL) to handle then, form yellow mercury oxide.Remove solid and wash with water, obtain 2,3-dimethyl-6-nitro monoacetylaniline and 2,3-dimethyl-1: 1 mixture of 4-nitro monoacetylaniline (16.0g, 90%): 1HNMR (CDCl 3) δ 2.15 (s, 1.5H), 2.22 (s, 1.5H), 2.37 (s, 1.5H), 2.38 (s, 1.5H), 2.41 (s, 1.5H), 5.93 (brs, 1H), 7.15 (d, J=8.7Hz, 0.5H), 7.63 (d, J=8.7Hz, 0.5H), 7.76 (d, J=8.1Hz, 1H).This mixture is not further purified and promptly is used for next step.
Figure A9981646400631
Step 3
In the solution of the mixture (16.0g, 1.0 equivalents) of nitro monoacetylaniline, add 60%H 2SO 4Solution (150mL).Under reflux temperature,, be cooled to room temperature then and the 2N NaOH solution (100mL) that is used in the frozen water is handled solution heating 1 hour.(3 * 50mL) extract the mixture that generates with EtOAc.With saturated NaHCO 3Solution (2 * 50mL) and saturated NaCl solution (organic layer that 2 * 50mL) washings merge, dry (Na 2SO 4), and decompression concentrates down.Through column chromatography (10%CH 2Cl 2/ hexane) purifying resistates successively obtains 2,3-dimethyl-6-N-methyl-p-nitroaniline (5.5g, 43%), 2,3-dimethyl-4-N-methyl-p-nitroaniline (1.5g, 12%).2,3-dimethyl-6-N-methyl-p-nitroaniline (5.5g, 43%): 1H NMR (CDCl 3) δ 2.05 (s, 3H), 2.20 (s, 3H), 6.15 (brs, 2H), 6.45 (d, J=8.7Hz, 1H), 7.63 (d, J=9.0Hz, 1H); 1HNMR (DMSO-d 6) δ 2.10 (s, 3H), 2.30 (s, 3H), 6.50 (d, J=8.7Hz, 1H), 7.15 (brs, 2H), 7.75 (d, J=9.0Hz, 1H).2,3-dimethyl-4-N-methyl-p-nitroaniline: 1H NMR (CDCl 3) δ 2.10 (s, 3H), 2.45 (s, 3H), 4.05 (brs, 2H), 6.45 (d, J=9.0Hz, 1H), 7.65 (d, J=8.7Hz, 1H); 1H NMR (DMSO-d 6) δ 2.00 (s, 3H), 2.35 (s, 3H), 6.12 (brs, 2H), 6.53 (d, J=9.0Hz, 1H), 7.63 (d, J=9.0Hz, 1H).A5a. synthesizing of iodo aniline led to method.Synthesizing of 4-iodo-2-n-propyl aniline.
Figure A9981646400632
In the solution of 2-n-propyl aniline in MeOH (25mL), add NaHCO 3(5.0g is 59.5mmol) at H 2Solution among the O (25mL).In 70 minutes, add iodine (8.4g, 33.3mmol), holding temperature stirs mixture 30 minutes under 10 ℃ then at 10 ℃ simultaneously in batches.Use H 2The mixture that O (30mL) dilution generates is also used EtOAc (4 * 40mL) extractions.Use 5%Na 2S2O 3Solution (30mL) and saturated NaHCO 3The organic layer that the washing of solution (30mL) order merges, dry (Na 2SO 4), and decompression is concentrated down, obtains 4-iodo-2-n-propyl aniline (9.4g, 98%): TLC (20%EtOAc/ hexane) R f0.43.This material is not further purified and promptly is used for next step.B. form the logical method of the method B1a. of 2-imino-heterocyclic precursor by reducing amino acid derivative synthesizing ethanolamine.Synthesizing of 1-amino-1-(hydroxymethyl) hexanaphthene.
Figure A9981646400641
Step 1
To 1-aminocyclohexane-1-carboxylic acid (10.0g, 70.0mmol) add in the solution in 1M NaOH solution (100mL) benzyl chloroformate (12.0ml, 84.0mmol).Reaction mixture was stirred 2 hours, keep pH9 by adding 1M NaOH solution where necessary simultaneously.Use Et 2(solution that 2 * 100mL) washings generate is adjusted to pH0 to water layer with dense HCl solution to O then and (3 * 150mL) extract solution with EtOAc.Dry (MgSO 4) organic layer and the decompression that merge concentrate down, obtains 1-(benzyloxycarbonyl amino) hexanaphthene-1-carboxylic acid (17.3g, 89%): TLC (25%EtOAc/ hexane) R f0.07.
Figure A9981646400642
Step 2
Under 4 ℃, to 1-(benzyloxycarbonyl amino) hexanaphthene-1-carboxylic acid (4.16g, 15.0mmol) and N-methylmorpholine (1.81mL, 16.5mmol) slowly add chloroformic acid isobutyl (2.14mL in the solution in DME (15mL), 16.5mmol) and reaction mixture stirred 5 minutes, filter then and enter in advance in refrigerative (4 ℃) flask.(0.85g 22.5mmol), immediately adds entry (500mL) to be added in sodium borohydride in the water (7mL).Then reactant is warmed to 20 ℃ and stirred 30 minutes.Use CH 2Cl 2Abstraction reaction mixture and decompression concentrate down, obtain 1-(benzyloxycarbonyl amino)-1-(hydroxymethyl) hexanaphthene (4.0g, 100%): TLC (25%EtOAc/ hexane) R f0.11.
Figure A9981646400651
Step 3
At H 2Under (1 normal atmosphere), with 1-(benzyloxycarbonyl amino)-1-(hydroxymethyl) hexanaphthene (4.0g, 15mmol) and the soup compound of 10%Pd/C (0.40g) in MeOH (75mL) stirred 1 hour, use Celite then Handle.The mixture filtration and the decompression that generate are concentrated down, obtain 1-amino-1-(hydroxymethyl) hexanaphthene.B1b. by the logical method of reducing amino acid derivative synthesizing ethanolamine.(1S)-1-(hydroxymethyl)-3-methyl butyl amine synthetic.
Figure A9981646400652
Step 1
Under-15 ℃, be no more than under 5 ℃ of such speed with the temperature of reactant, (315g 2.4mol) drips SOCl in the suspension in MeOH (3.2L) to (L)-leucine 2(315mL, 4.32mol, 1.8 equivalents).Add finish after, reaction mixture is warmed to room temperature and stirs and spend the night.Decompression concentrates the mixture that generates down and slowly add Et in resistates 2O (3L) generates precipitation.Use the ice bath cooling mixture, use other MeOH (3L) to handle relatively apace then.At 0 ℃ after following 1 hour, collect crystallization and dry, obtain (L)-leucine methyl ester HCl salt (394g, 86%): mp 147-149 ℃ into white crystalline solid; 1H-NMR (CD 3OD) δ 0.78-0.98 (m, 6H), 1.58-1.72 (m, 3H), 3.76 (s, 3H), 3.92 (t, J=7.3Hz, 1H).
Figure A9981646400661
Step 2
Under 5 ℃, be no more than (about 70 minutes) under 15 ℃ of such speed with the temperature of reactant, to (L)-leucine methyl ester HCl salt (254g, 1.4mol), NaHCO 3Add NaBH in (118g, 1.4mol, 1.0 equivalents) and the mixture of water (1.8L) in EtOH (1.8L) in batches 4(159g, 4.2mol, 3.0 equivalents).Add NaBH 4After finishing, remove ice bath and reactant is heated to reflux temperature and spend the night.By ice bath, the mixture that generates is cooled to room temperature.Filter the soup compound that generates and use EtOH (750mL) washing solid.The concentrated down filtrate that merges of decompression is 950mL extremely approximately.(2 * 1L) extract with EtOAc (2.5L) dilution resistates and with 1NNaOH solution.With EtOAc (2 * 750mL) the anti-water layers that extract.Dry (MgSO 4) organism and the decompression that merge concentrate down, obtains (1S)-1-(the hydroxymethyl)-3-methyl butyl amine (112g, 65%) into light yellow oil: 1H NMR (CDCl 3) δ 0.88-0.93 (m, 6H), 1.17 (t, J=7.7Hz, 2H), 1.68-1.80 (m, 2H), 1.82 (brs, 2H), 2.86-2.91 (m, 1H), 3.22 (dd, J=10.7,8.1Hz, 1H), 3.56 (dd, J=10.3,3.6Hz, 1H).B1c. by the logical method of reducing amino acid derivative synthesizing ethanolamine.Synthesizing of 1-hydroxymethyl cyclopentamine.
Figure A9981646400662
Step 1
Temperature with reactant is no more than under 7 ℃ of such speed, drips SOCl to bathing in the suspension of 1-aminocyclopentanecarboxylic acid (675g, 5.23mol, 1.0 equivalents) in MeOH (6.5L) that is controlled under-15 ℃ with ice/MeOH 2(687mL, 9.4mol, 1.8 equivalents).After adding is finished, remove cooling, at room temperature reactant is stirred and spend the night, decompression concentrates down then.Use CH 2Cl 2(1L) handle resistates and decompression and concentrate down, obtain 1-aminocyclopentanecarboxylic acid methyl ester HCl salt (938g, 100%) into white solid: 1H NMR (CD 3OD) δ 1.87-1.94 (m, 8H), 3.83 (s, 3H); NMR (DMSO-d 6) δ 1.67-1.71 (m, 2H), 1.83-1.98 (m, 4H), 2.06-2.14 (m, 2H), 3.73 (s, 3H), 8.81 (brs, 3H).This material is not further purified and promptly is used for next step. Step 2
Use NaHCO 3(145g, 1.73mol, 1.0 equivalents) handle 1-aminocyclopentanecarboxylic acid methyl ester HCl salt (310g, 1.73mol) solution in the solution of EtOH (12.5L) and water (2.5L).With ice bath the mixture that generates is cooled to 5 ℃ and be no more than with temperature of charge that (about 75 minutes) add NaBH in batches under 15 ℃ of such speed then 4(196g, 5.2mol, 3.0 equivalents).NaBH 4After adding is finished, remove ice bath and, be cooled to room temperature, and filter by ice bath reactant heated overnight under reflux temperature.The solid and the decompression that generate with EtOH (750mL) washing concentrate the filtrate that merges down.Use EtOAc (2.5L) to handle the soup compound that generates then.(2 * 750mL) washing organic layers are also with EtOAc (2 * 500mL) the anti-water layers that extract with 1N NaOH solution.Dry (MgSO 4) organic layer and the decompression that merge concentrate down, obtains the 1-hydroxymethyl cyclopentamine (169g, 85%) into low melt wax: 1H NMR (CDCl 3) δ 1.38-1.44 (m, 2H), 1.58-1.69 (m, 4H), 1.70-1.84 (m, 2H), 2.11 (brs, 3H), 3.36 (s, 2H).CI-MS?m/z?116((M+H) +)。B2a. the alkylating logical method of N-that is used for thanomin by substitution reaction.Synthesizing of 2-(isobutylamino)-2-(hydroxymethyl) norbornane.
With with the similar mode of method B1a, the amino norbornane of 2--2-carboxylic acid is converted into 2-amino-2-(hydroxymethyl) norbornane into non-enantiomer mixture.Under 90 ℃, with amino alcohol (0.31g, 2.16mol) and isobutyl bromide (0.23ml, 2.16ml) solution in DMF (3mL) heating is 92 hours, is cooled to room temperature then and at EtOAc (100mL) and saturated NaHCO 3Distribute between the solution (100mL).With saturated NaCl solution (50mL) washing organic layer, dry (MgSO 4), and decompression is concentrated down, obtains 2-(isobutylamino)-2-(hydroxymethyl) norbornane (0.24g, 55%) into non-enantiomer mixture: GC-MS m/z 197 (M +).B2b. the alkylating logical method of N-that is used for thanomin by substitution reaction.Synthesizing of N-hydroxyethyl-N-hexamethylene-1-thiazolinyl methylamine.
Figure A9981646400682
Step 1
Under-78 ℃, to the hexamethylene that is stirring-1-olefinic carboxylic acid methyl ester (4.56g, 32mmol) drip in the solution in THF (100mL) DIBAL (1M in THF, 130mmol, 130mL).Under-78 ℃, mixture was stirred 4 hours, use saturated NaHCO then 3Solution (40mL) is handled.(4 * 20mL) extract water layer and use H with EtOAc 2The organic layer that O (40mL) and saturated NaCl solution (40mL) washing merge, dry (Na 2SO 4) and reduce pressure concentrated down.Remaining hexamethylene-1-thiazolinyl methyl alcohol is not purified is directly used in next step: TLC (30%EtOAc/ hexane) R f0.44.
Figure A9981646400691
Step 2
Under 0 ℃, (3.58g is 32mmol) at CH to hexamethylene-1-thiazolinyl methyl alcohol 2Cl 2Add PPh in the solution (40mL) 3(36mmol, 9.39g) and CBr 4(36mmol, 12.96g).At room temperature, the mixture stirring is spent the night and reduces pressure then to descend to concentrate.With pentane (60mL) dilution resistates and filtration.Decompression is descended concentrated filtrate and through column chromatography (5%EtOAc/ hexane) purifying, is obtained the 1-brooethyl-1-tetrahydrobenzene (3.25g, 57% through two steps) into oil: TLC (30%EtOAc/ hexane) R f0.91. Step 3
Under reflux temperature, 1-brooethyl-1-tetrahydrobenzene (3.25g) and 2-monoethanolamine (6mL) were heated 3 days in the solution in trieline (40mL), be cooled to room temperature, with 1N NaOH solution (30mL) dilution.Use CH 2Cl 2(4 * 20mL) extract water layer and use H 2The organic layer that O (30mL) and saturated NaCl solution (30mL) washing merge, dry (Na 2SO 4) and reduce pressure concentrated down.Resistates through the vacuum distilling purifying, is obtained the N-hydroxyethyl-N-hexamethylene-1-thiazolinyl methylamine (1.78g, 62%) into water white oil: bp 92-94 ℃ (6mmHg).B3a. the alkylating logical method of N-that is used for thanomin by reductive alkylation.(R)-N-isobutyl-Serine methyl ester HCl salt synthetic.
Figure A9981646400693
To (D)-Serine methyl ester HCl salt (2.13g, 13.7mmol) 1, add in the suspension in the 2-ethylene dichloride isobutyric aldehyde (1.5mL, 16.4mmol) and sodium triacetoxy borohydride (4.3g, 20.5mmol).At room temperature, reaction mixture was stirred 24 hours, then at Et 2O (100mL) and saturated NaHCO 3Distribute between the solution (100mL).With saturated NaHCO 3Solution (3 * 100mL) washing organic layers, dry (MgSO 4), and the 1M HCl solution (25mL) that is used in the ether is handled.Decompression concentrates the mixture that generates down, obtains (R)-N-isobutyl-Serine methyl ester HCl salt (2.27g, 79%): NMR (DMSO-d 6) δ 0.94 (dd, J=6.7,3.0Hz, 6H); 1.97-2.11 (m, 1H); 2.76-2.91 (m, 1H); 3.76 (s, 3H); 3.86 (dd, J=12.1,4.1Hz, 1H), 3.99 (dd, J=12.4,3.2Hz, 1H), 4.13-4.21 (m, 1H).B4a. by forming 2-alkyl-1, the 3-oxazolidine reduces the alkylating logical method of N-that is used for thanomin subsequently.Synthesizing of 1-(cyclohexyl amino)-1-(hydroxymethyl) pentamethylene.
Figure A9981646400701
Step 1
Under 4 ℃, to 1-amino-1-(hydroxymethyl) pentamethylene (method B1c; 1.44g, 12.54mmol) at CH 2Cl 2Add in the solution (10mL) TFA (0.097mL, 1.25mmol), pimelinketone (1.30mL, 12.54mmol) and sodium sulfate (2g) and reactant is warmed to 20 ℃.Reactant was stirred 72 hours and water (10mL) and saturated NaHCO 3The washing of solution (20mL) order, dry (MgSO 4), and decompression is concentrated down, obtains 14-azepine-7-oxa-two spiral shells [4.2.5.1] tetradecane (2.38g, 97%): GC-MS m/z 195 (M +).
Figure A9981646400702
Step 2
Under 4 ℃, to LiAlH 4(0.93g, 24.4mmol) and AlCl 3(3.24g 24.4mmol) drips 14-azepine-7-oxa-two spiral shells [4.2.5.1] tetradecane (2.38g, 12.2mmol) solution in THF (15mL) in the solution in THF.The mixture that generates is warmed to 20 ℃ and stirred 45 minutes, is cooled to 4 ℃ then.Slowly add entry (5mL) with the quenching reactant and add the solid that 1N NaOH solution (85mL) generates with dissolving.Use Et 2O (200mL) extracts the solution that generates.Dry (Na 2SO 4) also decompression is concentrated down for organic layer, obtains 1-(cyclohexyl amino)-1-(hydroxymethyl) pentamethylene 1.89g (79%): GC-MS m/z 197 (M +).B4b. by forming 2-alkyl-1, the 3-oxazolidine reduces the alkylating logical method of N-that is used for thanomin subsequently.Synthesizing of N-cyclopentyl-(1,1-dimethyl-2-hydroxyethyl) amine.
Figure A9981646400711
Step 1
Under reflux temperature, with 2-amino-2-methyl-1-propanol (15.0g, 0.168mol), cyclopentanone (14.9mL, 0.168mol, 1.0 equivalent) and the mixture of tosic acid monohydrate (1.6g, 8.4mmol, 0.05 equivalent) in toluene (300mL) stir and to spend the night.Then reaction mixture is cooled to room temperature,, uses saturated NaHCO then with EtOAc (500mL) dilution 3(250mL) washing, dry (Na 2SO 4), and decompression is concentrated down, obtains the 4-azepine-3 into light yellow oil, 3-dimethyl-1-oxaspiro [4.4] nonane (15.5g, 60%): 1H NMR (CDCl 3) δ 1.12 (s, 6H), 1.65 (m, 5H), 1.80 (m, 2H), 1.97 (m, 2H), 3.45 (s, 2H).
Figure A9981646400712
Step 2
Under 0 ℃, be no more than with temperature of charge under 10 ℃ the speed (about 1 hour), to 4-azepine-3, (15.5g 0.10mol) adds NaBH in the solution in EtOH (85mL) to 3-dimethyl-1-oxaspiro [4.4] nonane 4(5.47g, 0.145mol, 1.45 equivalents).Make reaction mixture be warmed to room temperature then, and stirred 18 hours.Water (100mL) is handled the mixture that generates and also is concentrated into pasty state under the decompression.Add the following enriched mixture once more of MeOH (100mL) and decompression.Handle resistates with EtOAc (300mL) and water (150mL).Dry (Na 2SO 4) also decompression is concentrated down for organic layer, obtains N-cyclopentyl-(1, the 1-dimethyl-2-hydroxyethyl) amine (13.0g, 83%) into light yellow oil: 1H NMR (CDCl 3) δ 1.07 (s, 6H), 1.24 (m, 3H), 1.50 (m, 2H), 1.65 (m, 2H), 1.87 (m, 2H), 3.0 (m, 1H), 3.22 (s, 2H); CI-MS m/z158 ((M+H) +).B4c. by forming 2-alkyl-1, the 3-oxazolidine reduces the alkylating logical method of N-that is used for thanomin subsequently.(2S)-4-methyl-2-(isobutylamino) penta-1-alcohol synthetic.
Figure A9981646400721
Step 1
Under reflux temperature, with (1S)-1-(hydroxymethyl)-3-methyl butyl amine (method B1b; 152g, 1.3mol) and the solution heating of isobutyric aldehyde (118mL, 1.3mol, 1.0 equivalents) in toluene (1.5L) up to the water (23.4mL) of in the Rodney Stark couch water trap of Dean, having collected theoretical amount.By distillation reaction mixture is concentrated into about 700mL.The mixture that generates is cooled to room temperature also is concentrated into constant weight under the decompression, obtain (4S)-2-sec.-propyl-4-isobutyl--1,3-oxazolidine (223g, 100%) into light yellow oil: 1H NMR (CDCl 3) δ 0.88-0.99 (m, 12H), 1.18-1.35 (m, 1H), 1.42-1.56 (m, 1H), 1.61-1.79 (m, 4H), 3.08 (t, J=7.4Hz, 1H), 3.20-3.34 (m, 1H), 3.85 (t, J=7.4Hz, 1H), 4.18 (dd, J=7.3,3.4Hz, 1H).
Figure A9981646400722
Step 2
Be no more than (about 2 hours) under 10 ℃ of such speed with temperature of charge, to bathing (the 4S)-2-sec.-propyl-4-isobutyl--1 that is cooled to-13 ℃ with ice/MeOH, (223g 1.3mol) adds NaBH in the solution in EtOH (1.1L) to the 3-oxazolidine in batches 4(70.3g, 1.82mol).Make reaction mixture be warmed to room temperature, stirring is spent the night, and filters through coarse sintered glass funnel then.Solid with EtOH washing generation.Decompression concentrates the filtrate that merges down and also handles resistates with EtOAc (2L) and water (1L).Dry (Na 2SO 4) also decompression is concentrated down for organic layer, obtains (2S)-4-methyl-2-(isobutylamino) penta-1-alcohol (192g, 85%) into the viscid light yellow oil: 1H NMR (CDCl 3) δ 0.90-0.96 (m, 12H), 1.18-1.24 (m, 1H), 1.32-1.39 (m, 1H), and 1.58-1.72 (m, 2H), 2.33 (dd, J=11.1,7.0Hz, 1H), 2.49 (dd, J=11.1,7.0Hz, 1H), and 2.63-2.67 (m, 1H), 3.19 (dd, J=10.3,6.2Hz, 1H), 3.60 (dd, J=10.3,6.2Hz, 1H).B4d. by forming 2-alkyl-1, the 3-oxazolidine reduces the alkylating logical method of N-that is used for thanomin subsequently.Synthesizing of 1-(cyclopentyl amino)-1-(hydroxymethyl) pentamethylene.
Figure A9981646400731
Step 1
Under reflux temperature, with 1-hydroxymethyl cyclopentamine (method B1c; 263g, 2.3mol) and the solution heating azeotropic water removing of cyclopentanone (220mL, 1.3mol, 1.1 equivalents) in toluene (2.7L), up to the water of collecting theoretical amount (41.4mL).Through single flash reaction mixture is concentrated into 700mL, is cooled to then under room temperature and the decompression and is concentrated into constant weight, obtain 6-azepine-12-oxa-two spiral shells [4.1.4.2] tridecane (414g, 100%) into light yellow oil: 1HNMR (CDCl 3) δ 1.55-1.89 (m, 17H), 3.60 (s, 2H). Step 2
Be no more than with temperature under 10 ℃ the speed (about 30 minutes), (124g adds NaBH in batches in solution 0.69mol) to bathe 6-azepine-12-oxa-two spiral shells [4.1.4.2] tridecane among the EtOH (600mL) of being dissolved in that is controlled under-13 ℃ with ice/MeOH 4(38g, 1.0mol, 1.45 equivalents).Making reaction mixture be warmed to room temperature and stir spends the night.Water (500mL) diluted reaction mixture and decompression concentrate down.Between EtOAc (1L) and water (600mL), separate remaining mashed prod.Dry (Na 2SO 4) also decompression is concentrated down for organic layer, obtains 1-(cyclopentyl amino)-1-(hydroxymethyl) pentamethylene (107g, 85%) into white powder: 1H NMR (CDCl 3) δ 1.23-1.28 (m, 2H), 1.46-1.57 (m, 8H), 1.58-1.69 (m, 4H), 1.82-1.86 (m, 2H), 2.94-3.06 (m, 1H), 3.30 (s, 2H).B5a. the logical method that is used for synthesizing ethanolamine by amine and epoxide reaction.Synthesizing of N-(hydroxyethyl)-N-(2-butyl) amine.
Figure A9981646400741
At room temperature, by sleeve pipe, to sec-butylamine (60mL, 0.60mmol) drip in the solution in MeOH (40mL) oxyethane (10mL, 0.20mmol).At room temperature, mixture was stirred 4 hours, decompression concentrates down then.Through vacuum distilling purifying resistates, obtain N-(hydroxyethyl)-N-(2-butyl) amine (16.4g, 70%): bp 109-112 ℃ (6mmHg) into water white oil.B5b. the logical method that is used for synthesizing ethanolamine by amine and epoxide reaction.Synthesizing of N-(3-phenyl-2-hydroxypropyl)-N-isobutylamine.
Figure A9981646400742
With 2,3-epoxypropyl benzene (10g, 74.5mmol) and isobutylamine (5.4g 74.5mmol) mixes then water (2mL) and handles.Under 110 ℃, stir the mixture and spend the night, distillation obtains N-(3-phenyl-2-hydroxypropyl)-N-isobutylamine (6.5g): bp 115-117 ℃ (1mmHg) then.B6a. reduce the logical method that is used for synthetic Propanolamine subsequently by Arndt-Esther homology materialization amino acid.(R)-3-(tertiary butyl amino)-4-methyl amyl alcohol synthetic. Step 1
Under-10 ℃, to N-(tert-butoxycarbonyl)-(L)-Xie Ansuan (4.32g, 19.9mmol) and N-methylmorpholine (23mL, 20.9mmol) add in the solution in DME (30mL) the chloroformic acid isobutyl (2.27mL, 21.0mmol).At room temperature, the mixture that generates was stirred 15 minutes, filter then, and wash solid with cold DME.Filtrate is cooled to-10 ℃, uses CH then 2N 2At Et 2Solution-treated among the O, lasting up to yellow, the mixture that generates is warmed to 20 ℃ and stirred 45 minutes under this temperature, then decompression enriched mixture down.Through chromatography (SiO 2, gradient from hexane to the 30%EtOAc/ hexane) the purifying resistates, obtain (S)-3-(tert-butoxycarbonyl amino)-1-diazo-4-methylpenta-2-one (1.82g, 38%): TLC (10%EtOAc/ hexane) R f0.11.
Figure A9981646400752
Step 2
Under reflux temperature, (1.83g, 7.6mmol) heating of the solution in MeOH (100mL) and adding silver benzoate are at Et with (S)-3-(tert-butoxycarbonyl amino)-1-diazo-4-methylpenta-2-one 3(the 0.50g silver benzoate is at 5mL Et for filtering solution among the N 3Among the N, 0.5mL).Stop (about 5 minutes) at initial gas evolution after, add other silver-colored solution (0.5mL).Repeat this method, no longer cause gas evolution up to adding silver salt.The mixture that generates is cooled to 20 ℃, uses Celite Handle and filter.Decompression is concentrated filtrate down.Resistates is dissolved in Et 2O (100mL) and with 1N HCl solution (100mL), saturated NaHCO 3Solution (100mL) and saturated NaCl solution (50mL) order washing, dry (MgSO 4), and decompression is concentrated down, obtains (R)-3-(tert-butoxycarbonyl amino)-4-methylvaleric acid methyl ester (1.63g, 87%): TLC (10%EtOAc/ hexane) R f0.29. Step 3
With with the similar method of method B8a step 2, (1.62g 6.6mmol), obtains (R)-3-(tert-butoxycarbonyl amino)-4-methyl amyl alcohol (93%) to handle (R)-3-(tert-butoxycarbonyl amino)-4-methylvaleric acid methyl ester with lithium borohydride.B7a. the logical method that is used for synthetic chloro ethylamine.(1S)-1-(chloromethyl)-3-methyl fourth ammonium is muriatic synthetic.
Figure A9981646400762
Through ice bath cooling (1S)-1-(hydroxymethyl)-3-methyl butyl amine (method B1b; 5.40g, 46.1mmol) at CH 2Cl 2Solution (200mL) is also saturated with HCl gas.Add SOCl 2(4.0mL 55.3mmol), under reflux temperature, with reactant heating 2.5 hours, is cooled to room temperature and decompression then and concentrates down.Use Et 2The O grinding residues obtains (1S)-1-(chloromethyl)-3-methyl fourth ammonium muriate (5.67g, 71%): EI-MS m/z 136 ((M+H) +).B7b. the logical method that is used for synthetic chloro ethylamine.Synthesizing of 1-(chloromethyl)-1-(cyclohexyl amino) pentamethylene HCl salt.
Figure A9981646400771
To contain 1-(cyclohexyl amino)-1-(hydroxymethyl) pentamethylene (method B4a; 1.9g, 9.6mmol) and SOCl 2(0.84mL, 4M HCl solution 11.5mmol) (the P-diox, 40mL) be heated to 70 ℃ 18 hours.The mixture that generates is cooled to room temperature, and also decompression is concentrated down, obtains crude product 1-(chloromethyl)-1-(cyclohexyl amino) pentamethylene HCl salt (2.84g), and it is not further purified and promptly is used for next step reaction.B7c. the logical method that is used for synthetic chloro ethylamine, N-(1-S)-(1-(chloromethyl)-3-methyl butyl)-N-(isobutyl-) amine HCl salt synthetic,
Figure A9981646400772
In 15 minutes, to (2S)-4-methyl-2-(isobutylamino) penta-1-alcohol (method B4c; 256g 1.5mol) and in the solution of toluene (2.5L) adds SOCl 2(167mL).Add SOCl 2After finishing, under 90 ℃, the reactant heated overnight.Then reactant solution is cooled under room temperature and the decompression and concentrates.Dark oily resistates is dissolved in CH 2Cl 2Concentrate (2L) and under the decompression.Make the reddish-brown resistates be dissolved in Et 2O (1L), and in 8 hours, drip hexane (750mL).The soup compound stirring that generates is spent the night, filters, and wash, obtain N-(1-S)-(1-(chloromethyl)-3-methyl butyl)-N-(isobutyl-) amine HCl salt (276g) into dark brown solid with the 40%EtOAc/ hexane solution: 1H NMR (CDCl 3) δ 0.93-1.00 (m, 6H), 1.10-1.12 (m, 6H), 1.85 (m, 4H), 2.24-2.34 (m, 2H), 2.80-2.88 (m, 1H), 2.90-3.02 (m, 1H), 3.50-3.57 (m, 1H), 3.96 (dd, J=12.9,5.6Hz, 1H), 4.10 (dd, J=13.2,3.6Hz, 1H).B7d. the logical method that is used for synthetic chloro ethylamine, 1-(chloromethyl)-1-(cyclopentyl amino) pentamethylene HCl salt synthetic.
Figure A9981646400781
In 15 minutes, to 1-(cyclopentyl amino)-1-(hydroxymethyl) pentamethylene (method B1c; 140g, 0.76mol, 1.0 equivalents) add SOCl in the solution in toluene (1.4L) 2(84mL).Add SOCl 2After finishing, under 60 ℃, with the reaction mixture heated overnight that is warmed to 40 ℃.The solution that generates be cooled to room temperature and with HCl (4N 100mL) handles in the P-diox, and reactant be heated to 60 ℃ 3 hours, at room temperature stir then and spend the night.Decompression down is concentrated into half of initial volume with the mixture that generates, and at this moment, begins to form precipitation.Use Et 2O dilutes the soup compound of generation and it was stirred 4 hours.Filter the precipitation that generates and use Et 2O (2 * 50mL) washings obtain 1-(chloromethyl)-1-(cyclopentyl amino) the pentamethylene HCl salt (125g, 70%) into pale powder: 1H NMR (CDCl 3) δ 1.53-1.66 (m, 4H), 1.76-1.94 (m, 2H), 1.95-2.22 (m, 10H), 2.28-2.34 (m, 2H), 3.40 (s, 2H), 3.63-3.73 (m, 1H).B7e. the logical method that is used for synthetic chloro ethylamine, 1-chloro methyl cyclopentamine HCl salt synthetic.
Figure A9981646400782
To 1-hydroxymethyl cyclopentamine HCl salt (method B1c; 20g, 0.17mol) add in the solution in anhydrous P-diox (65mL) HCl (4M in the P-diox, 65mL, 0.26mol).At room temperature, the solution stirring that generates 20 minutes, drip SOCl then 2(22.7g, 0.19mol).Under 80 ℃, reaction mixture heating 2 days, be cooled to room temperature, and decompression is concentrated down, obtains 1-chloro methyl cyclopentamine HCl salt (29g, 100%): CI-MS m/z 171 ((M+H)+).B8a. the logical method that is used for Synthetic 2-amino-ethyl sulphonate, (1R, 2R)-1-(mesyloxy methyl)-2-(tert.-butoxy) third ammonium is muriatic synthetic.
Figure A9981646400791
Step 1
Use CH 2N 2At Et 2Solution-treated among the O (L)-(1S, 2R)-N-(benzyloxycarbonyl)-(2.15g is 4.4mmol) at CH for O-tertiary butyl Threonine dicyclohexyl amine salt 2Cl 2Solution (50mL), lasting up to yellow.Decompression concentrates the solution that generates down.Resistates is dissolved among the EtOAc (100mL) and with 1N HCl solution (2 * 100mL) and saturated NaCl solution (50mL) order washing, dry (MgSO 4), and decompression is concentrated down, obtain (1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine methyl ester (1.44g, 100%): TLC (25%EtOAc/ hexane) R f0.54. Step 2
To (1S, 2R)-N-(benzyloxycarbonyl)-(1.4g is 4.4mmol) at Et for O-tertiary butyl Threonine methyl ester 2Add LiBH in the solution among the O (20mL) 4At Et 2Saturated solution among the O (9mL) and under reflux temperature reacting by heating mixture 2 hours, be cooled to 20 ℃ then.In the mixture that generates, add entry (5mL), add 1N HCl solution then, emit up to no more gas.With saturated NaCl solution (50mL) washing ether layer, dry (MgSO 4), and decompression is concentrated down, obtain (1R, 2R)-N-(benzyloxycarbonyl)-1-(hydroxymethyl)-2-(tert.-butoxy) propylamine (1.69g, 99%): TLC (25%EtOAc/ hexane) R f0.20.
Figure A9981646400801
Step 3
Under 4 ℃, to (1R, 2R)-N-(benzyloxycarbonyl)-1-(hydroxymethyl)-2-(tert.-butoxy) propylamine (1.6g, 5.4mmol) drip in the solution in anhydrous pyridine (30mL) methylsulfonyl chloride (0.75mL, 9.7mmol).Reaction stirred 5.5 hours is used EtOAc (200mL) dilution then and (4 * 200mL) wash with 1N HCl solution.Dry (MgSO 4) organic layer and the decompression that merge concentrate down, obtain into oil (1R, 2R)-N-(benzyloxycarbonyl)-1-(mesyloxy methyl)-2-(tert.-butoxy) propylamine (2.03g, 100%): TLC (25%EtOAc/ hexane) R f0.31.
Figure A9981646400802
Step 4
To (1R, 2R)-(2.03g 5.5mmol) adds 4M HCl solution (diox to N-(benzyloxycarbonyl)-1-(mesyloxy methyl)-2-(tert.-butoxy) propylamine in the solution in MeOH (50mL); 1.5mL, 6.0mmol) and 10%Pd/C (0.20g).At H 2Under (1 normal atmosphere), the soup compound that generates was stirred 2 hours, use Celite then Handle, filtration and decompression concentrate down, obtain (1R, 2R)-1-(mesyloxy methyl)-2-(tert.-butoxy) third ammonium muriate (1.6g, 100%).B8b. the logical method that is used for Synthetic 2-amino-ethyl sulphonate, N-(2-tosyloxy ethyl)-2-methyl-prop-2-alkene-1-ammonium trifluoroacetate synthetic.
Figure A9981646400811
Step 1
Under 0 ℃, to N-(tert-butoxycarbonyl) glycine tertiary butyl ester (3.97g, 17.2mmol) add hexamethyl two silicon sodiumazide (3.78g in the solution in DMF (70mL), 20.6mmol) and the mixture stirring that generates 25 minutes, make it to be warmed to room temperature then, (2.60mL 25.7mmol) handles the solution that generates with 3-bromo-2-methacrylic, at room temperature stirred 10 minutes, and dilute with EtOAc (300mL).With EtOAc solution with water (4 * 500mL) and saturated NaCl solution (4 * 500mL) order washings, dry (MgSO 4), and decompression is concentrated down, obtains N-(tert-butoxycarbonyl)-N-(2-methyl-prop-2-thiazolinyl) glycine tertiary butyl ester (4.03g, 82%): TLC (10%EtOAc/ hexane) R f0.51.
Figure A9981646400812
Step 2
(0.26g is 0.93mmol) at Et to handle N-(tert-butoxycarbonyl)-N-(2-methyl-prop-2-thiazolinyl) glycine tertiary butyl ester with lithium borohydride (0.011g) 2Solution among the O (3mL) at room temperature stirs then and spends the night.In the mixture that generates, add entry (2mL), drip 1N HCl then and emit up to gas and stop.With organic phase with saturated NaHCO 3Solution (20mL) washing, dry (MgSO 4), and decompression concentrates down.Through chromatography (SiO 2, gradient from the 10%EtOAc/ hexane to the 50%EtOAc/ hexane) the purifying resistates, obtain N-(tert-butoxycarbonyl)-N-(2-hydroxyethyl)-1-amino-2-methyl third-2-alkene (0.113g, 57%): TLC (10%EtOAc/ hexane) R f0.66.
Figure A9981646400821
Step 3
Under-78 ℃, to N-(tert-butoxycarbonyl)-N-(2-hydroxyethyl)-(21.1g is 98mmol) at Et for 1-amino-2-methyl third-2-alkene 2Slowly add in the solution among the O (800mL) potassium tert.-butoxide (1M in the trimethyl carbinol, 103mL, 103mmol).Make that reaction mixture is of short duration to be warmed to-45 ℃, be cooled to-78 ℃ then, and (18.7g is 98.0mmol) at Et with Tosyl chloride 2Solution-treated among the O (100mL).Then the mixture that generates is warmed to-45 ℃ and water (500mL) processing.With saturated NaCl solution (800mL) washing organic phase, dry (MgSO 4), and decompression is concentrated down, obtains N-(tert-butoxycarbonyl)-N-(2-tosyloxy ethyl)-1-amino-2-methyl third-2-alkene (36.4g, 101%): TLC (25%EtOAc/ hexane) R f0.56. Step 4
(15g 55.7mmol) is cooled to 0 ℃ and be dissolved among the TFA (200mL) with solid N-(tert-butoxycarbonyl)-N-(2-tosyloxy ethyl)-1-amino-2-methyl third-2-alkene.Make reaction mixture be warmed to room temperature, decompression concentrates down then.Use Et 2O (500mL) obtains N-(2-tosyloxy ethyl)-2-methyl-prop-2-alkene-1-ammonium trifluoroacetate (16.7g, 78%) with the oily crystallization of remnants.B9a. be used for synthetic 3-chloropropyl-and the logical method of 4-chlorobutyl amine, N-isobutyl--3-chloropropyl amine HCl salt synthetic.
Figure A9981646400823
Step 1
(91g 65.4mmol) adds isobutyric aldehyde (9.0mL, 99.1mmol, 1.5 equivalents) and MgSO in the solution in toluene (100mL) to the 3-aminopropanol 4(7.5g) produce heat.Soup compound was stirred 30 minutes and add other a MgSO 4(7.5g), and the soup compound stirring spend the night.Filtering the mixture and the decompression that generate concentrates down.Decompression concentrates condensation product once more down and merges two parts of resistatess, obtains the 2-sec.-propyl tetrahydrochysene-1 into water white oil, 3-oxazine (5.18g, 61%): 1H NMR (CDCl 3) δ 0.84-0.88 (m, 6H), 1.24-1.29 (m, 1H), 1.51-1.66 (m, 3H), 2.77-2.87 (m, 1H), 3.07-3.13 (m, 1H), 3.60-3.76 (m, 2H), 4.00-4.05 (m, 1H). Step 2
Under 0 ℃, in 15 minutes, to 2-sec.-propyl tetrahydrochysene-1, (4.94g 38.2mmol) adds NaBH in the solution in anhydrous EtOH (100mL) to the 3-oxazole with aliquot 4(2.17g, 57.4mmol, 1.5 equivalents) also at room temperature stir the mixture that generates and spend the night.Decompression concentrates the mixture that generates down, uses EtOAc (150mL) and water (100mL) to handle (careful: gas is emitted) then, and at room temperature stirs 30 minutes.Organic layer with saturated NaCl solution washing generation.With the anti-water layer that merges that extracts of EtOAc (150mL).Dry (Na 2SO 4) organic layer and the decompression that merge concentrate down, obtains the N-isobutyl--3-hydroxypropyl amine (5.04g, 100%) into water white oil: 1H NMR (CDCl 3) δ 0.84 (d, J=6.6Hz, 6H), 1.60-1.71 (m, 3H), 2.36 (d, J=6.6Hz, 2H), 2.80 (dd, J=5.9,5.9Hz, 2H), 3.10-3.30 (brs, 2H), 3.74 (dd, J=5.5,5.5Hz, 2H); 13C NMR (CDCl 3) δ 20.5,28.1,30.6,50.0,57.8,64.1.
Figure A9981646400832
Step 3
(1.01g 7.70mmol) adds SOCl in the solution in toluene (100mL) to N-isobutyl--3-hydroxypropyl amine 2(1.37g, 11.6mmol, 1.5 equivalents) also at room temperature stir the mixture that generates 4 hours.Decompression concentrates the soup compound that generates down, obtains N-isobutyl--3-chloro propyl group amine HCl salt: 1H NMR (CDCl 3) δ 1.12 (s, 9H), 1.28 (t, J=7.0Hz, 3H), 4.24 (q, J=7.0Hz, 2H), 4.55 (s, 1H), 5.00 (s, 2H); 13C NMR (CDCl 3) δ 13.9,27.8,38.2,61.5,67.1,67.3,117.0,167.1,180.7; CI-LRMS m/z (relative abundance) 150 ((M+H) +, 100%).B10a. the logical method that is used for Synthetic 2-chloro thiazolidine salt.(4S)-and 2-chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazoles quinoline is muriatic synthetic.
Figure A9981646400841
Step 1
To (2S)-4-methyl-2-(isobutylamino) penta-1-alcohol HCl salt (method B4c; 0.21g, 1.0mmol) and CS 2Add Cs in (0.30mL, 5.0mmol, 5.0 equivalents) mixture in 2-butanone (20mL) 2CO 3(0.72g, 2.20mmol, 2.2 equivalents) also spend the night in the mixture heating up that following of reflux temperature generates.Decompression concentrates the orange solution of generation down also with EtOAc (25mL) grinding residues.Wash remaining solid with EtOAc (25mL), and decompression concentrates the EtOAc phase that merges down.Resistates is absorbed SiO 2Go up and through MPLC (Biotage 40S silicagel column; The 5%EtOAc/ hexane) purifying obtains (4S)-3 into yellow oil, 4-diisobutyl-1,3-thiazoles alkane-2-thioketones (0.11g, 52%). Step 2
Under 70 ℃, with (4S)-3, (5.0g is 21.6mmol) at SOCl for 4-diisobutyl-1,3-thiazoles alkane-2-thioketones 2(31mL, 0.43mol) the solution heating in is 2.5 hours, is cooled to room temperature and decompression then and concentrates down, obtains being semisolid (4S)-2-chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazoles quinoline muriate: 1H NMR δ 0.99-1.10 (m, 12H), 1.59-1.67 (m, 1H), 1.72-1.84 (m, 1H), 2.00-2.10 (m, 1H), 2.17-2.29 (brm, 1H), 3.61-3.68 (m, 1H), 3.86-3.95 (brm, 2H), 4.50-4.57 (m, 1H), 4.97-5.06 (brm, 1H).This material is dissolved in the ethylene dichloride (180mL) with preparation 0.12M stock solution (the supposition Quantitative yield is the thiazolidine muriate).C. be used for synthetic imino-heterocyclic method C1a. is used for Synthetic 2-imino--1,3-thiazoles alkane by 2-chloro ethylamine and lsothiocyanates reaction logical method.(4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane synthetic.
Figure A9981646400851
By syringe, to being suspended in CH 2Cl 2(1S)-1-(chloromethyl) (15mL)-3-methyl fourth ammonium muriate (method B7a; 1.14g 3.71mmol) (0.72g adds Et in mixture 3.71mmol) with 2-methyl-4-nitrophenyl lsothiocyanates 3N (1.08mL, 7.78mmol).At room temperature, the solution stirring that generates 18 hours.With saturated NaHCO 3Solution washing reaction mixture and decompression concentrate down.Through chromatography (SiO 2, gradient from the 10%EtOAc/ hexane to the 30%EtOAc/ hexane) the purifying resistates, obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane (0.91g, 47%): TLC (25%EtOAc/ hexane) R f0.46.C1b. react the logical method that is used for Synthetic 2-imino--1,3-thiazoles alkane by 2-chloro ethylamine and lsothiocyanates.(4S)-and 2-(4-cyano group-2-ethylphenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane HCl salt synthetic.
Figure A9981646400861
Under 15 ℃, to N-(1-S)-(1-(chloromethyl)-3-methyl butyl)-N-(isobutyl-) amine HCl salt (method B7c; 95g, 0.41mol, 1.08 equivalents) at CH 2Cl 2Add 4-cyano group-2-ethylphenyl lsothiocyanates (method A2b in the solution (1.1L); 72g 0.38mol), adds diisopropyl ethyl amine (200mL, 1.15mol, 3.0 equivalents) subsequently, produces slight exotherm.When reactant cools back room temperature, remove ice bath and reaction stirred 4 hours at room temperature.Use CH then 2Cl 2(500mL) diluting reaction thing is with 1N NaOH solution (3 * 500mL) washings, dry (MgSO 4) and reduce pressure concentrated down.The dark oil (132g) of remnants is dissolved in CH 2Cl 2Filter (5g SiO by silica gel plug (50mL) and by the 5%EtOAc/ hexane solution 2/ g crude product product), obtain oil (120g), it is dissolved in EtOAc (400mL), and also (1M is at Et with HCl solution 2Among the O, 500mL) slowly handle, obtain (4S)-2-(4-cyano group-2-ethylphenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane HCl salt (95g, 66%) into white solid: 1H NMR (CDCl 2) δ 0.96 (d, J=5.9Hz, 3H), 1.02 (d, J=6.3Hz, 3H), 1.12 (m, 6H), 1.23 (t, J=7.7Hz, 3H), 1.46-1.76 (m, 3H), 2.10-2.20 (m, 1H), 2.82 (q, J=7.7Hz, 2H), 3.06-3.14 (m, 2H), 3.55 (dd, J=11.4,7.7Hz, 1H), 4.18-4.25 (m, 1H), 5.02 (dd, J=14.3,8.1Hz, 1H), 7.32 (d, J=8.1Hz, 1H), 7.51 (dd, 1H, J=8.1,1.8Hz, 1H), 7.58 (d, J=1.8Hz, 1H).C1c. react the logical method that is used for Synthetic 2-imino--1,3-thiazoles alkane by 2-chloro ethylamine and lsothiocyanates.(4S)-2-(2-chloro-4-cyano group-6-aminomethyl phenyl imino-)-4-isobutyl--1,3-thiazoles alkane synthetic.
Figure A9981646400871
To 2-chloro-4-cyano group-6-aminomethyl phenyl lsothiocyanates (0.10g, 0.50mmol) and poly-(4-vinylpridine) (0.030g) at CH 2Cl 2In soup compound in add (1S)-1-(chloromethyl)-3-methyl fourth ammonium muriate (method B7a; 0.086g, 0.50mol, 1.0 equivalents) in DMF (2mL) solution and stirred down the mixture that generates 16 hours at 55 ℃, decompression concentrates down then.Through column chromatography (30g, gradient from the 10%EtOAc/ hexane to the 20%EtOAc/ hexane) purifying resistates, obtain (4S)-2-(2-chloro-4-cyano group-6-aminomethyl phenyl imino-)-4-isobutyl--1,3-thiazoles alkane (0.052g, 34%).C1d. react the logical method that is used for Synthetic 2-imino--1,3-thiazoles alkane by 2-chloro ethylamine and lsothiocyanates.(4S)-2-(4-chloro-2-(trifluoromethyl) phenylimino)-3-isobutyl--1,3-thiazoles alkane synthetic.
Figure A9981646400872
With with the similar method of method B7c, N-(hydroxyethyl)-N-isobutylamine is converted into N-(chloro ethyl)-N-isobutyl-ammonium muriate.To N-(chloro ethyl)-N-isobutyl-ammonium muriate (0.10mmol, 0.10M) and poly-(4-vinylpridine) (0.030g) adds 4-chloro-2-(trifluoromethyl) phenyl isothiocyanic acid ester solution in the soup compound in DMF (1.0mL), and (0.25M is in THF, 0.40mL, the mixture that heating generates in sand bath 0.10mmol) and under 55 ℃ 16 hours.Filter the soup compound that generates and the concentrated filtrate down that reduces pressure.(the C-18 post, gradient is from 0.1%TFA/20%CH through preparation type reversed-phase HPLC 3CN/79.9% water is to 0.1%TFA/99.9%CH 3CN) purifying resistates obtains (4S)-2-(4-chloro-2-(trifluoromethyl) phenylimino)-3-isobutyl--1,3-thiazoles alkane (0.020g, 59%).C1e. react the logical method that is used for Synthetic 2-imino--1,3-thiazoles alkane by 2-chloro ethylamine and lsothiocyanates.Synthesizing of 2-(2,4-dimethyl-3-cyano group-6-pyridyl imino-)-3-thia-1-azaspiro [4.4] nonane.
Figure A9981646400881
By syringe, to 1-chloro methyl cyclopentamine HCl salt (method B7e; 0.25g, 1.32mmol) with 2,4-dimethyl-3-cyano group-5-pyridyl lsothiocyanates (method A2c; 0.23g, 1.32mmol), drip Et in the solution in the 2-ethylene dichloride (10mL) anhydrous 1 3N (1mL).Under 50 ℃, the mixture heating up that generates is spent the night, be cooled to room temperature then, and with saturated NaHCO 3Handle.Use CH 2Cl 2(3 * 25mL) extract the mixture that generates.Dry (Na 2SO 4) organic layer and the decompression that merge concentrate down.Through chromatography (SiO 2, the 40%EtOAc/ hexane) and the purifying resistates, obtain 2-(2,4-dimethyl-3-cyano group-6-pyridyl imino-)-3-thia-1-azaspiro [4.4] nonane (0.192g, 51%): CI-MS m/z 287 ((M+H)+).C1f. react the logical method that is used for Synthetic 2-imino--1,3-thiazoles alkane by 2-chloro ethylamine and lsothiocyanates.2-(3-quinolyl imino-)-3,5-diisobutyl-1,3-thiazoles alkane synthetic.
Figure A9981646400891
With with the similar method of method A2c, preparation 3-quinoline lsothiocyanates.To 3-quinoline lsothiocyanates (0.1g, 0.54mmol) and N-(1-S)-(1-(chloromethyl)-3-methyl butyl)-N-(isobutyl-) amine HCl salt (method B7c; 0.113g, 0.54mmol) at anhydrous CH 2Cl 2Drip in the solution (2mL) diisopropyl ethyl amine (0.208g, 1.61mmol).At room temperature, the mixture stirring of generation is spent the night, decompression concentrates down then.Through chromatography (SiO 2, the 30%EtOAc/ hexane) and the purifying resistates, obtain 2-(3-quinolyl imino-)-3,5-diisobutyl-1,3-thiazoles alkane (0.02g, 0.9%): ES-MS m/z 342 ((M+H)+).C2a. be converted into 2-chloro ethylamine is used for Synthetic 2-imino--1,3-thiazoles alkane subsequently with the lsothiocyanates reaction logical method by thanomin.Synthesizing of 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.
Figure A9981646400892
To 1-amino-1-(hydroxymethyl) pentamethylene (method B1c; 20.7g, 180mmol) and HCl (4M adds SOCl in solution 400mL) in the P-diox 2(15.7mL 216mmol) and at 100 ℃ following solution that generates heated 18 hours.Decompression is concentrated reaction mixture down, and (31.4g, 162mmol) with 1,2-ethylene dichloride (400ml) is handled, and uses N-methylmorpholine (49mL, 449mmol) processing subsequently to use 2-methyl-4-nitrophenyl lsothiocyanates then.Under 70 ℃,, be cooled to room temperature and decompression concentrates down the mixture heating up that generates 18 hours.EtOAc with heat handles resistates, filters and reduce pressure to concentrate down.With resistates recrystallization (MeOH), obtain 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane (38.3g, 81%): TLC (25%EtOAc/ hexane) R f0.27.C2b. be converted into 2-chloro ethylamine is used for Synthetic 2-imino--1,3-thiazoles alkane subsequently with lsothiocyanates reaction logical method .1-isobutyl--2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.5] decane synthetic by thanomin.
Figure A9981646400901
With with the similar method of method C2a, 1-amino-1-(hydroxymethyl) hexanaphthene (method B1a) is dissolved in the P-diox (80mL) uses SOCl then 2Handle, handle with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.5] decane (20%), make it to react with similar method of method D2a and isobutyl bromide, obtain 1-isobutyl--2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.5] decane (0.026g, 2%): TLC (20%EtOAc/ hexane) R f0.69.C2c. be converted into 2-chloro ethylamine is used for Synthetic 2-imino--1,3-thiazoles alkane subsequently with the lsothiocyanates reaction logical method by thanomin.2-'s (2-methyl-4-nitrophenyl imino-)-3-isobutyl-spiral shell [1,3-thiazoles alkane-4,2 '-dicyclo [2.2.1] heptane] is synthetic.
Figure A9981646400902
With with the similar method of method C2a, use SOCl 2Handle 2-(isobutylamino)-2-(hydroxymethyl) norbornane (method B2a; 0.24g, 1.2mmol), handle with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(2-isobutyl-spiral shell [1 for oil, 3-thiazolidine-4,2 '-dicyclo [2.2.1] heptane] (0.022g, 5%): TLC (25%EtOAc/ hexane) R f0.72.C2d. be converted into 2-chloro ethylamine by thanomin and be used for Synthetic 2-imino--1 with the lsothiocyanates reaction subsequently, the logical method .3-isobutyl--4-methylene radical-2-of 3-thiazolidine (2-methyl-4-nitrophenyl imino-)-1,3-thiazolidine-5-ketone and (4S)-3-isobutyl--4-methoxycarbonyl-2-(2-methyl-4-nitrophenyl imino-)-1,3-thiazoles alkane HCl salt synthetic.
Figure A9981646400911
With with the similar method of method C2a, use SOCl 2Handle (R)-N-isobutyl-Serine methyl ester HCl salt (method B3a; 2.28g, 10.8mmol), handle with 2-methyl-4-nitrophenyl lsothiocyanates subsequently.Through column chromatography (SiO 2Gradient from hexane to the 10%EtOAc/ hexane) material that generates of purifying, obtain 3-isobutyl--4-methylene radical-2-(2-methyl-4-nitrophenyl imino-)-1,3-thiazolidine-5-ketone (0.028g, 10%), obtain (S)-3-isobutyl--4-methoxycarbonyl-2-(2-methyl-4-nitrophenyl imino-)-1,3-thiazoles alkane HCl salt (0.192g, 56%) subsequently.3-isobutyl--4-methylene radical-2-(2-methyl-4-nitrophenyl imino-)-1,3-thiazoles alkane-5-ketone: TLC (25%EtOAc/ hexane) R f0.40.(S)-3-isobutyl--4-methoxycarbonyl-2-(2-methyl-4-nitrophenyl imino-)-1,3-thiazoles alkane HCl salt: TLC (free alkali, 25%EtOAc/ hexane) R f0.50.C2e. be converted into 2-chloro ethylamine is used for Synthetic 2-imino--1,3-thiazoles alkane subsequently with the lsothiocyanates reaction logical method by thanomin.Synthesizing of 1-cyclohexyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.
With with the similar method of method C2a, make 1-(cyclohexyl amino)-1-(hydroxymethyl) pentamethylene (method B4a; 1.89g, 9.59mmol) and SOCl 2Reaction with 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtains 1-cyclohexyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane (0.44g, 17%): CI-MS m/z 374 ((M+H)+) subsequently.C2f. be converted into 2-chloro ethylamine is used for Synthetic 2-imino--1,3-thiazoles alkane subsequently with the lsothiocyanates reaction logical method by thanomin.2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4,4-dimethyl-1,3-thiazoles alkane synthetic.
Figure A9981646400922
With with the similar method of method B4a, preparation N-isobutyl--1,1-dimethyl-2 hydroxy ethylamine.The HCl bubbling is fed N-isobutyl--1, and (1.45g is 10mmol) in the solution in toluene (20ml), up to saturated for 1-dimethyl-2 hydroxy ethylamine.At room temperature, with SOCl 2(10mmol) be added drop-wise in this solution, at room temperature stirred 1 hour and stirred 1 hour down at 50 ℃.Decompression concentrates the mixture of generation down and resistates is dissolved in CHCl 3(20mL).Methyl-(1.94g 10mmol), at room temperature drips Et to 4-nitro-phenyl lsothiocyanates then to add 2-in the solution that generates 3N (10mmol) is at CHCl 3Solution (10mL).Under reflux temperature, the mixture that heating generates 3 hours, decompression concentrates down then.Resistates is dissolved among the EtOAc (100mL), and washs the solution that generates, dry (MgSO with the 10%NaOH aqueous solution (50mL) and saturated NaCl solution (50mL) order 4) and reduce pressure concentrated down.Through chromatography (9%EtOAc/ sherwood oil) purifying resistates and the solid recrystallization (sherwood oil) that generates, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4,4-dimethyl-1,3-thiazoles alkane (0.6g, 63%): mp97 ℃.In the time of suitably, by free alkali (5mmol) is dissolved in Et 2Up to no longer being settled out more solid, product is converted into HCl salt among the O (50mL) and with this solution of HCl solution-treated of 2N ether.Filter the soup compound that generates and successively use Et 2The solid that O (25mL) and EtOAc (25mL) washing generate.C3a. react the logical method that is used for Synthetic 2-imino--1,3-thiazoles alkane homologue with lsothiocyanates subsequently by hydroxyalkyl amine being converted into the chloro alkylamine.(R)-and 4-sec.-propyl-2-(2-methyl-4-nitrophenyl imino-)-2,3,4,5-tetrahydrochysene-1,3-thiazine synthetic.
Figure A9981646400931
With with the similar method of method C2a, make (R)-3-(tert-butoxycarbonyl amino)-4-methyl amyl alcohol (method B6a) and SOCl 2Reaction with 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtains (R)-4-sec.-propyl-2-(2-methyl-4-nitrophenyl imino-)-2,3,4,5-tetrahydrochysene-1,3-thiazine (100%) subsequently.C4a. be used for Synthetic 2-imino--1 by 2-chloro ethylamine and isocyanate reaction, the logical method of 3-oxazolidine.Synthesizing of 1-cyclohexyl-2-(2-methyl-4-nitrophenyl imino-)-3-oxa--1-azaspiro [4.4] nonane.
To 1-(chloromethyl)-1-(cyclohexyl amino) pentamethylene HCl salt (method B7b; 1.06g, 4.2mmol) and 2-methyl-4-nitrophenyl isocyanic ester (0.75g, 4.2mmol) 1, add in the solution in the 2-ethylene dichloride (10ml) N-methylmorpholine (0.92mL, 8.4mmol).The mixture heating up to 50 that generates ℃ 18 hours, be cooled to 20 ℃ and decompression then and concentrate down.Through chromatography (SiO 2, gradient from hexane to the 10%EtOAc/ hexane) the purifying resistates, obtain 1-cyclohexyl-2-(2-methyl-4-nitrophenyl imino-)-3-oxa--1-azaspiro [4.4] nonane (0.021g, 1.4%): CI-MS m/z 358 ((M+H)+).C5a. be used for the logical method of Synthetic 2-imino-heterocyclic by amino-ethyl sulphonate and isocyanic ester or lsothiocyanates reaction.2-(2-methyl-4-nitrophenyl imino-)-3-(2-methyl-prop-2-thiazolinyl)-1,3-oxazolidine synthetic.
To N-(2-tosyloxy ethyl)-2-methyl-prop-2-alkene-1-ammonium trifluoroacetate (method B8b, step 4; 0.21g methyl-(0.0955g 0.536mmol), adds Et to 4-nitrophenyl isocyanic ester subsequently 0.548mmol) to add 2-in the solution in P-diox (5ml) 3N (0.080mL, 1.15mmol).Under 37 ℃, the mixture stirring that generates is spent the night, be cooled to room temperature and also concentrate under the decompression.Resistates is dissolved in CH 2Cl 2Also water (50ml) washing (50ml).Extract organic layer with 2N HCl solution.Make the water layer alkalization with 1N NaOH solution, and use CH 2Cl 2(50ml) extract.Dry (Na 2SO 4) also decompression is concentrated down for organic phase, obtains 2-(2-methyl-4-nitrophenyl the imino-)-3-(2-methyl-prop-2-thiazolinyl)-1 into yellow oil, 3-oxazolidine (0.020g, 14%): CI-MS m/z 276 ((M+H) +).C5b. be used for the logical method of Synthetic 2-imino-heterocyclic by amino-ethyl sulphonate and isocyanic ester or lsothiocyanates reaction.(4S)-4-(1 (R)-tert.-butoxy ethyl)-3-isobutyl--2-(2-methyl-4-nitrophenyl imino-)-1,3-thiazoles alkane synthetic.
With with the similar method of in method C1a, describing, make (1R, 2R)-1-(mesyloxy methyl)-2-(tert.-butoxy) third ammonium muriate (method B8a; 1.5g, 5.5mmol), obtain 4 (S)-(1 (R)-tert.-butoxy ethyl)-2-(2-methyl-4-nitrophenyl imino-)-1,3-thiazoles alkane (1.2g, 67%) with 2-methyl-4-nitrophenyl lsothiocyanates reaction.With with the similar method of method D2a, make (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-(1 (R)-tert.-butoxy ethyl)-1,3-thiazolidine and isobutyl bromide reaction obtain (4S)-4-(1 (R)-tert.-butoxy ethyl)-3-isobutyl--2-(2-methyl-4-nitrophenyl imino-)-1,3-thiazolidine (0.26g, 56%): TLC (25%EtOAc/ hexane) R f0.67.C6a. be converted into 2-thio-ethyl amine is used for Synthetic 2-imino--1,3-thiazoles alkane subsequently with the reaction of isocyanides dichloride logical method by the chloro ethylamine.(4S)-and 2-(4-cyano group-2-ethylphenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane HCl salt synthetic.
Figure A9981646400961
In the solution of sodium sulfhydrate (69g, 1.2mol, 2.2 equivalents) in water (500mL), add N-(1-S)-(1-(chloromethyl)-3-methyl butyl)-N-(isobutyl-) amine HCl salt (method B7c; 126g, 0.55mol, 1.0 equivalents).At room temperature, the mixture that stirring generates 8 hours adds 4-cyano group-2-ethylphenyl isocyanides dichloride (method A3a then; 125g, 0.5mol, 1.0 equivalents), add Virahol (500mL) subsequently.At room temperature, the mixture that stirring generates 1 hour adds 3.6M K then 2CO 3Solution (305mL, 2.0 equivalents, 1.1mol) and at room temperature stir the mixture and spend the night.Decompression concentrates the organic layer that generates down and also handles resistates with EtOAc (2L).Water (2 * 500mL) washing organic layers, dry (MgSO 4) also decompression is concentrated down, obtains dark oil (160g).Oil is dissolved in CH 2Cl 2Pass through silica gel plug (3g SiO (150mL) and by the 5%EtOAc/ hexane solution 2/ 1g crude product product), obtain containing the oil (134g) that requires product and some residual isocyanides dichloride to some extent.This oil is dissolved among the EtOAc (500mL) and (1N is at Et with HCl 2Among the O, 500mL) handle.Leach (the 4S)-2-(4-cyano group-2-ethylphenyl imino-)-3 of generation, 4-diisobutyl-1,3-thiazoles alkane HCl salt (147g, 70%): 1H NMR (CDCl 3) δ 0.96 (d, J=5.9Hz, 3H), 1.02 (d, J=6.3Hz, 3H), 1.12 (m, 6H), 1.23 (t, J=7.7Hz, 3H), 1.46-1.76 (m, 3H), 2.10-2.20 (m, 1H), 2.82 (q, J=7.7Hz, 2H), 3.06-3.14 (m, 2H), 3.55 (dd, J=11.4,7.7Hz, 1H), 4.18-4.25 (m, 1H), 5.02 (dd, J=14.3,8.1Hz, 1H), 7.32 (d, J=8.1Hz, 1H), 7.51 (dd, 1H, J=8.1,1.8Hz, 1H), 7.58 (d, J=1.8Hz, 1H).C6b. be converted into 2-thio-ethyl amine is used for Synthetic 2-imino--1,3-thiazoles alkane subsequently with the reaction of isocyanides dichloride logical method by the chloro ethylamine.Synthesizing of 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane HCl salt.
Figure A9981646400971
In the solution of sodium sulfhydrate (31g, 0.55mol, 2.2 equivalents) in water (250mL), add 1-(chloromethyl)-1-(cyclopentyl amino) pentamethylene HCl salt (method B7d; 60g, 0.25mol, 1.0 equivalents).At room temperature, stirred reaction mixture 8 hours adds 2-methyl-4-nitrophenyl isocyanides dichloride (method A3b then; 125g, 0.25mol, 1.0 equivalents), add Virahol (300mL) subsequently.At room temperature, stirred reaction mixture 1 hour adds 3.6MK then 2CO 3Solution (305mL, 2.0 equivalents, 0.5mol).At room temperature reaction stirred is spent the night.To concentrate under moisture organic layer separation in the top that generate and the decompression and handle resistates with EtOAc (1L).Water (organic layer that 2 * 200mL) washings generate, dry (MgSO 4) and reduce pressure concentrated down.(86g) is dissolved in CH irreducible oil 2Cl 2Pass through silica gel plug (3g SiO (50mL) and by the 5%EtOAc/ hexane solution 2/ 1g crude product product) filters, obtain containing the oil (34g) that requires product and some residual isocyanides dichloride to some extent.This oil is dissolved among the EtOAc (300mL) and (1N is at Et with HCl 2Among the O, 1.5L) handle.Leach the solid of generation, obtain 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane HCl salt (36.8g) into white powder: 1H NMR (CD 3OD) δ 1.40-1.55 (m, 2H), 1.55-1.68 (m, 2H), 1.68-1.80 (m, 8H), 1.80-2.00 (m, 4H), 2.16 (s, 3H), 3.16 (s, 2H), 3.60-3.70 (m, 1H), 6.70 (brs, 1H), 6.93 (d, J=8.4Hz, 1H), 7.96-8.04 (m, 1H), 8.03 (d, J=3Hz, 1H).C6c. be converted into 2 thio-ethyl amine are used for Synthetic 2-imino--1,3-thiazoles alkane subsequently with the reaction of isocyanides dichloride logical method by hydroxyethyl amine.Synthesizing of 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.
Figure A9981646400981
Step 1
Ph under 0 ℃ 3Add azoformic acid diisopropyl ester (21.5g, 0.107mol, 1.3 equivalents) and 1-cyclopentyl amino-1-(hydroxymethyl) pentamethylene (method B4d in the solution of P (27.9g, 0.107mol, 1.3 equivalents) in anhydrous THF (400mL) continuously; 15.0g, 0.082mol).The soup compound that generates was stirred 30 minutes, use thiol-acetic acid (7.6mL, 0.107mol, 1.3 equivalents) to handle then.The yellow solution that generates was stirred 15 minutes, and be concentrated into about 100mL under the decompression.Resistates is dissolved among the EtOAc (200mL) also with the 1N HCl solution (solution that 5 * 125mL) extractions generate.(water layer that 2 * 200mL) washings merge is used K with EtOAc 2CO 3Be neutralized to pH7.0-7.5, (5 * 200mL) extract to use EtOAc then.Merge organic layer, dry (Na 2SO 4) and reduce pressure concentrated down.The vacuum-drying resistates obtains 1-cyclopentyl amino-1-(thioacetyl ylmethyl) pentamethylene (19.1g) into yellow oil: TLC (10%EtOAc/ hexane) R f0.16; 1H NMR (CDCl 3) δ 1.20-1.87 (m, 16H), 2.34 (s, 3H), 2.92-3.02 (m, 1H), 3.15 (s, 2H); 13C NMR (CDCl 3) δ 23.9,25.2,29.3,36.4,40.1,55.8,73.0,169.8; CI-LRMS m/z (relative abundance) 242 ((M+H) +, 100%). Step 2
1-cyclopentyl amino-1-(thioacetyl ylmethyl) pentamethylene (19.1g) is 9: 1MeOH: H 2Solution stirring in the 0.33M KOH solution among the O (273mL, 0.090mol, 1.1 equivalents) 30 minutes.Decompression is concentrated reaction mixture and vacuum-drying resistates down, obtains crude product 1-cyclopentyl amino-1-(sulphomethyl) pentamethylene: TLC (10%EtOAc/ hexane) R into yellow oil f(0.18 striped); 1H NMR (CD 3OD) δ 1.32-1.71 (m, 14H), 1.87-1.94 (m, 2H), 2.67 (s, 2H), 3.07-3.14 (m, 1H); FAB-LRMS m/z (relative abundance) 200 ((M+H) +, 19%).This material is not further purified and is used for next step immediately. Step 3
Under 0 ℃, with the anhydrous CH of crude product 1-cyclopentyl amino-1-(sulphomethyl) pentamethylene 2Cl 2(100mL) solution crude product 2-methyl-4-nitrophenyl isocyanides dichloride (method A3b; 19.1g, 0.082mol, 1.0 equivalents are based on 1-cyclopentyl amino-1-(thioacetyl ylmethyl) pentamethylene) at CH 2Cl 2Soup compound (200mL) is handled, and uses Et subsequently 3N (30mL, 0.215mol, 2.6 equivalents) handles and makes reaction mixture be warmed to room temperature and stirred 2 days.Add N, N-dimethyl-ethylenediamine (92g, 0.023mol, 0.3 equivalent) and stirred reaction mixture 1 hour.Add silica gel (50g) and decompression and concentrate the mixture that generates down.The vacuum-drying resistates spends the night and through flash chromatography method (11 * 10cm SiO 2, the 5%EtOAc/ hexane) and purifying, obtain 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane (17.8g, 60% amounts to): mp 120-121 ℃ into yellow granular solids; TLC (10%EtOAc/ hexane) R f0.45; 1HNMR (CDCl 3) δ 1.47-1.91 (m, 14H), 2.22 (s, 3H), 2.46-2.55 (m, 2H), 3.03 (s, 2H), 3.66 (quintet, J=8.8Hz, 1H), 6.89 (d, J=8.5Hz, 1H), 7.95-8.03 (m, 2H); 13C NMR (CDCl 3) δ 18.3,24.3,25.6,28.5,36.0,40.6,56.7,75.3,120.6,122.3,125.3,132.0,142.3,155.1,157.4; LC-LRMS m/z (relative abundance) 360 ((M+H) +, 100%).C 19H 25N 3O 2The analytical calculation value of S: C, 63.48; H, 7.01; N, 11.69.Measured value: C, 63.48; H, 6.89; N, 11.76.C7a. be used for Synthetic 2-imino--1, the logical method of 3-oxazolidine by hydroxyethyl amine and the reaction of aromatic isocyanate dichloride.2-(4-cyano group-2-ethylphenyl imino-)-3-cyclopentyl-4,4-dimethyl-1,3-oxazolidine synthetic.
At room temperature, by syringe, with N-cyclopentyl-(1,1-dimethyl-2-hydroxyethyl) amine (method B4b; 0.12g 0.69mmol) drips of solution in THF (2.5mL) is added to NaH (95%, 0.05g is 1.2mmol) in the soup compound in THF (5mL).Reaction mixture was stirred 15 minutes, drip 4-cyano group-2-ethylphenyl isocyanic ester dichloride (method A3a by syringe then; 0.15g, the 0.63mmol) solution in THF (2.5mL).The mixture stirring that generates is spent the night, use 5% citric acid soln (10mL) to handle then, use EtOAc (25mL) to handle subsequently.With 5% citric acid soln (20mL), H 2O (20mL) and saturated NaCl solution (20mL) order are washed organic phase, dry (Na 2SO 4) and reduce pressure concentrated down.Through chromatography (SiO 2, the 5%EtOAc/ hexane) and the purifying resistates, obtain 2-(4-cyano group-2-ethylphenyl imino-)-3-cyclopentyl-4,4-dimethyl-1,3-oxazolidine (0.09g, 43%): mp112-114 ℃ into yellow solid; TLC (15%EtOAc/ hexane) R f0.60; 1H NMR (CDCl 3) δ 1.16 (t, J=7.5Hz, 3H), 1.32 (s, 6H), 1.49-1.61 (m, 2H), 1.71-1.81 (m, 2H), 1.82-1.92 (m, 2H), and 2.38-2.50 (m, 2H), 2.61 (q, J=7.6Hz, 2H), 3.52-3.58 (m, 1H), 3.97 (s, 2H), 7.04 (d, J=8.3Hz, 1H), 7.35 (dd, J=8.1,1.8Hz, 1H), 7.40 (d, J=1.8Hz, 1H); CI-MS m/z (relative abundance) 3 12 ((M+H) +, 100%).C 17H 23N 3O 3The HRMS calculated value: 311.1998.Measured value: 311.1991.C7b. be used for Synthetic 2-imino--1, the logical method of 3-oxazolidine by hydroxyethyl amine and the reaction of aromatic isocyanate dichloride.(4S)-and 2-(4-cyano group-2-ethylphenyl imino-)-3,4-diisobutyl-1,3-oxazolidine synthetic.
To 4-cyano group-2-ethylphenyl isocyanides dichloride (method A3a; 0.42g, 1.83mmol, 1.2 equivalents) and (2S)-4-methyl-2-(isobutylamino) penta-1-alcohol (method B4c; 0.26g, 1.52mmol) add Et in the solution in THF (5mL) 3N (0.5mL).At room temperature, the mixture that generates was stirred 1 hour, use 2-(dimethylamino) ethylamine (0.5mL) to handle then.At room temperature, stirred this mixture 1 hour, decompression concentrates down then.Through column chromatography (gradient from the 5%EtOAc/ hexane to the 10%EtOAc/ hexane) purifying resistates, obtain (4S)-2-(4-cyano group-2-ethylphenyl imino-)-3 for yellow oil, 4-diisobutyl-1,3-oxazolidine (0.15g): TLC (10%EtOAc/ hexane) R f0.35; 1H NMR (CDCl 3) δ 0.81-1.00 (m, 12H), 1.14 (t, J=4.8Hz, 3H), 1.25-1.43 (m, 2H), 1.53-1.70 (m, 2H), 2.57 (septet, J=7.5Hz, 1H), 2.58 (q, J=7.5Hz, 2H), 3.01 (dd, J=14.0,6.3Hz, 1H), 3.33 (dd, J=13.6,8.8Hz, 1H), and 3.73-3.83 (m, 1H), 3.94 (apparent t, J=7.5Hz, 1H), 4.37 (apparent t, J=7.9Hz, 1H), 7.01 (d, J=8.1Hz, 1H), 7.33 (dd, J=8.1,1.8Hz, 1H), 7.38 (d, J=1.8Hz, 1H); 13C NMR (CDCl 3) δ 13.8,19.9,20.3,21.8,23.6,24.7,24.9,26.7,40.6,50.1,55.3,70.1,104.1,120.2,123.4,129.9,131.8,138 4,151.4,152.9; HPLC ES-MS m/z328 ((M+H) +, 100%).C8a. be used for the logical method of Synthetic 2-imino--4-oxo heterocycle synthetic with the halogen acyl halide reaction subsequently by lsothiocyanates and amine reaction.Synthesizing of 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--1,3-thiazoles alkane-4-ketone.
Figure A9981646401021
To 2-methyl-4-nitrophenyl lsothiocyanates (0.190g, 1.0mmol) (0.4M is solution in DMF to add isobutylamine in the solution in DMF (5.3mL), 5.3mL) and with this reaction mixture stirring 4 hours, at this moment, TLC analysis (hexane: EtOAc 3: 1) shows lsothiocyanates consumption.In the mixture that generates, add chloracetic acid (0.8M is solution in DMF, 4.0mL), add subsequently N-methylmorpholine (0.7mL, 6.4mmol).Under 80 ℃, stirred reaction mixture 18 hours distributes between water (10mL) and EtOAc (25mL) then.With EtOAc (2 * 10mL) the anti-waters that extract.With the organic layer that saturated NaCl solution (25mL) washing merges, dry (Na 2SO 4) and reduce pressure concentrated down.Through MPLC (Biotage 40S silicagel column, gradient from the 5%EtOAc/ hexane to the 33%EtOAc/ hexane) resistates that generates of purifying, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--1,3-thiazoles alkane-4-ketone (0.52g, 85%) for light yellow oil.C9a. the logical method that is used for Synthetic 2-imino--1,3-thiazoles alkane by hydroxyethyl amine and lsothiocyanates reaction subsequently by the acid catalysis cyclization.2-(2,6-dichlorophenyl imino-)-3-cyclohexyl-4,4-dimethyl-1,3-thiazoles alkane synthetic.
Figure A9981646401022
With with the similar method of method B4a, preparation N-cyclohexyl-1,1-dimethyl-2 hydroxy ethylamine.At room temperature, with 2, (1.2g, 6.0mmol) with N-cyclohexyl-1, (1.0g is 6.0mmol) at CH for 1-dimethyl-2 hydroxy ethylamine for 6-dichlorophenyl lsothiocyanates 2Cl 2Solution stirring (10mL) 20 hours.Decompression concentrates the mixture that generates down, uses 33%HCl solution (15mL) to handle then.Under reflux temperature, the mixture that heating generates 1 hour is cooled to room temperature, and neutralizes with 45%NaOH solution.Filter the soup compound that generates, and the solid of water (20mL) washing generation, recrystallization (EtOH) obtains 2-(2,6-dichlorophenyl imino-)-3-cyclohexyl-4,4-dimethyl-1,3-thiazoles alkane (0.70g, 33%): 134 ℃ of mp then.In the time of suitably, by free alkali (5mmol) is dissolved in Et 2Up to can not precipitating more solid, product is converted into HCl salt among the O (5mL) and with this solution of HCl solution-treated of 2N ether.Filter the soup compound that generates and successively use Et 2The solid that O (25mL) and EtOAc (25mL) washing generate.C10a. the logical method that is used for 2-chloro thiazoline salt and aniline reaction.2-(2-(N-phenyl amino formyl radical) phenylimino)-3,4-diisobutyl-1,3-thiazoles alkane synthetic.
Figure A9981646401031
With 2-(N-phenyl amino formyl radical) aniline (0.097g, 0.36mmol, 1.0 equivalents) and Et 3The solution of N (0.5mL, 3.6mmol, 10 equivalents) in P-diox (5mL) joins (4S)-2-chloro-3,4-diisobutyl-4, (method B10a in the 5-dihydro-solution of 1,3-thiazoles quinoline muriate in ethylene dichloride; 0.12M, 0.5mL, 0.36mmol).Under 70 ℃, the mixture overnight that heating generates is cooled to room temperature then, and dilutes with EtOAc (25mL).Water (2 * 25mL) and saturated NaCl solution (25mL) order wash the EtOAc mixture, dry (Na 2SO 4), and decompression concentrates down.Resistates is adsorbed onto SiO 2On, and, obtain 2-(2-(N-phenyl amino formyl radical) phenylimino)-3,4-diisobutyl-1,3-thiazoles alkane (0.090g, 61%) through MPLC (Biotage40S silicagel column, gradient is from the 5%EtOAc/ hexane) purifying.C11a. react the logical method that is used for Synthetic 2-imino--1,3-thiazoles alkane-5-ketone by amino acid ester and lsothiocyanates.Synthesizing of 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--1,3-thiazoles alkane-5-ketone.
Figure A9981646401041
Use Et 3(0.71mL, (0.41g, the 2.57mmol) solution in water (5mL) are used 2-methyl-4-nitrophenyl lsothiocyanates (0.50g, 2.57mmol) solution-treated in acetone (5mL) to N subsequently 5.15mmol) to handle N-isobutyl glycine ethyl ester.Under 40 ℃, the mixture that heating generates 2 hours is cooled to room temperature and decompression then and concentrates down.Between water (25mL) and ethyl acetate (25mL), separate resistates.Dry (MgSO 4) also decompression is concentrated down for organic phase, obtains 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--1,3-thiazoles alkane-5-ketone (0.16g, 88%): 152 ℃ of mp.D. be used for the logical method that the imino-heterocyclic transforms mutually.D1a. be used for logical method with the imino-heteroaryl salt.(4S)-and 2-(4-cyano group-2-ethylphenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane synthetic.
Figure A9981646401042
To (4S)-2-(4-cyano group-2-ethylphenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane HCl salt (method C6a; 304g, 0.8mol), add NaHCO in the mixture of water (1L) and EtOAc (1.4L) 3(150g, 1.78mol, 2.2 equivalents).The mixture that generates was stirred 1 hour.Dry (MgSO 4) also decompression is concentrated down for organic layer.Handle the viscous oil and the decompression that generate with EtOH and concentrate twice down, obtain being low melting point solid (4S)-2-(4-cyano group-2-ethylphenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane (264g, 96%): mp50 ℃; [a] D=+2.4, (c1.0, CH 3OH); 1H NMR (CDCl 3) δ 0.92-0.99 (m, 12H), 1.13 (t, J=7.4Hz, 3H), 1.47-1.52 (m, 1H), and 1.58-1.67 (m, 2H), 2.07-2.11 (m, 1H), 2.54 (q, J=7.4Hz, 2H), 2.84-2.90 (m, 2H), 3.28 (dd, J=10.6,6.6Hz, 1H), 3.68 (dd, J=13.6,8.1Hz, 1H), 3.81-3.87 (m, 1H), 6.85 (d, J=7.9Hz, 1H), 7.36-7.42 (m, 2H); CI-MS m/z 344 ((M+H) +).D1b. be used for logical method with the imino-heteroaryl salt.Synthesizing of 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.
1-cyclopentyl-2-in the mixture of water-soluble (300mL) and EtOAc (500mL) (2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane HCl salt (method C6b; 52.4g, 0.132mol) the middle NaHCO that adds 3(15g, 0.178mol, 1.3 equivalents).Mixture was stirred 1 hour and dry (MgSO 4) organic layer that generates and following the concentrating of reducing pressure.The pale yellow colored solid body and function EtOH (100mL) that generates is handled, and concentrate twice under the decompression, obtain 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane (46g, 97%): mp 111-112 ℃; 1H NMR (CDCl 3) δ 1.49-1.53 (m, 2H), 1.63-1.80 (m, 8H), 1.81-1.91 (m, 4H), 2.21 (s, 3H), 3.02 (s, 2H), 3.60-3.70 (m, 1H), 6.87 (d, J=8.5Hz, 1H), 8.02 (m, 2H); CI-MS m/z 360 ((M+H) +).D2a. the logical method that is used for 2-imino-heterocyclic ring azanylization.(4S)-and 2-(2-methyl-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane HCl salt synthetic.
Figure A9981646401061
Under 90 ℃, with (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane (method C1a; 0.10g, 0.34mmol), isobutyl bromide (0.11mL, 1.03mmol) and Cs 2CO 3(0.12g, 0.38mmol) heating of the soup compound in DMF (2mL) is 18 hours, is cooled to 20 ℃ then, with EtOAc (50mL) dilution and water (2 * 200mL) washings.Dry (MgSO 4) organic phase, decompression concentrates down, and through chromatography (SiO 2, gradient from 100% hexane to the 10%EtOAc/ hexane) the purifying resistates.The material that generates is dissolved in CH 2Cl 2(10mL), (1M is at Et with HCl solution 2Among the O, 2mL) handle, decompression concentrates down then, obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane HCl salt (0.088g, 68%): TLC (free alkali, 20%EtOAc/ hexane) R f0.74.D2b. the logical method that is used for 2-imino-heterocyclic ring azanylization.Synthesizing of 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.
Figure A9981646401062
With 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane (method C2a; 33.2g, 114mmol) solution in DMF (1L) with NaOH (690g, 17.3mol) and cyclopentyl bromide (865mL 6.3mol) handles and under 20-40 ℃ the mixture that generates was stirred 18 hours, is cooled to 4 ℃ then, and water (1.5L) processing.Add dense HCl solution with adjusting pH to 0, and extract mixture with EtOAc (80mL).With 1N HCl solution (1L) washing organic phase, dry (MgSO 4) and reduce pressure concentrated down.Resistates is dissolved in CH 2Cl 2(9 * 4cm) filter (500mL) and by silicagel pad.In the solution that generates, add hexane and slowly remove volatile matter up to forming crystallization through partial vacuum.Collect solid, obtain 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane (10.9g, 26%): mp118-9 ℃ into yellow crystal; TLC (5%EtOAc/ hexane) R f0.34.D2c. the logical method that is used for 2-imino-heterocyclic ring azanylization.(4R)-and 3-isobutyl--4-sec.-propyl-2-(2-methyl-4-nitrophenyl imino-) tetrahydrochysene-2H-1,3-thiazine synthetic.
Figure A9981646401071
With with the similar method of method D2a, make (R)-4-sec.-propyl-2-(2-methyl-4-nitrophenyl imino-)-2,3,4,5-tetrahydrochysene-1, the reaction of 3-thiazine (method C3a) and isobutyl bromide.Obtain (4R)-3-isobutyl--4-sec.-propyl-2-(2-methyl-4-nitrophenyl imino-) tetrahydrochysene-2H-1,3-thiazine (0.081g, 32%).TLC (33%EtOAc/ hexane) R f0.76.D2d. the logical method that is used for 2-imino-heterocyclic ring azanylization.Synthesizing of 2-(2-methyl-4-nitrophenyl imino-)-3-propionyl-1,3-thiazoles alkane.
Figure A9981646401072
To 2-(2-methyl-4-nitrophenyl imino-)-1,3-thiazoles alkane (with the similar method preparation of in method C1a, describing; 0.084g, 0.35mmol) at CH 2Cl 2Add in the solution (5mL) propionyl chloride (0.033g, 0.35mmol) and Et 3N (0.049mL, 0.35mmol).At room temperature, mixture was stirred 1 hour, use CH then 2Cl 2(40mL) dilution.The solution that water (10mL) and saturated NaCl solution (10mL) order washing generate, dry (Na 2SO 4), and decompression concentrates down.Through preparation type TLC (40%EtOAc/ hexane) purifying resistates, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-propionyl-1,3-thiazoles alkane (0.036g, 35%): FAB-MS m/z 294 ((M+H) +).D2e. the logical method that is used for 2-imino-heterocyclic ring azanylization.Synthesizing of 1-(cyclohexyl methyl)-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.
To 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane (method C2a; 0.10g, 0.3432mmol) with in the solution of bromomethyl hexanaphthene (1.00mL) in DMF (1.00mL) add NaOH (approximately 0.13g).Under 45 ℃, the mixture that stir to generate 2 days, during it becomes bright orange from scarlet.Then, reaction mixture is cooled to room temperature, filtration and decompression concentrate down.Through chromatography (SiO 2The 5%EtOAc/ hexane) oil of purifying remnants obtains mp85-7 ℃ of 1-(cyclohexyl methyl)-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane (0.042g, 32%).
D2f. the logical method that is used for 2-imino-heterocyclic ring azanylization.(4S)-and 2-(2-chloro-4-cyano group-6-aminomethyl phenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane trifluoroacetate synthetic.
To (4S)-2-(2-chloro-4-cyano group-6-aminomethyl phenyl imino-)-4-isobutyl--1,3-thiazoles alkane (method C1c; 0.050g, 0.16mmol) add NaH (0.0045g, 1.1 equivalents) in the solution in DMF (1.0mL), and at room temperature the mixture that generates stirred 5 minutes.Add isobutyl bromide (0.053mL, 3 equivalents) then and stirred 4 hours at 98 ℃ following mixture that generates.Filter reaction mixture, decompression concentrates down then.(the C-18 post, gradient is from 0.1%TFA/20%CH through preparation type reversed-phase HPLC 3CN/79.9% water is to 0.1%TFA/99.9%CH 3CN) purifying resistates obtains (4S)-2-(2-chloro-4-cyano group-6-aminomethyl phenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane trifluoroacetate (0.030g, 52% yield).D2g. the logical method that is used for 2-imino-heterocyclic ring azanylization.2-(2-methyl-4-nitrophenyl imino-)-3-(2-methyl-third-2-thiazolinyl)-4,4-dimethyl-1,3-thiazoles alkane HBr salt synthetic.
To prepare 2-(2-methyl-4-nitrophenyl imino-)-4,4-dimethyl-1,3-thiazoles alkane with the similar method of in method C1a, describing.To 2-(2-methyl-4-nitrophenyl imino-)-4,4-dimethyl-1, adding 2-methyl-prop in the suspension of 3-thiazolidine (1.5mmol) in toluene (10mL)-basic bromide (4.5mmol) of 2-alkene-1-also heats reaction mixture 3 hours under reflux temperature, at this moment, finish through TLC judgement reaction.Under 50 ℃, filter the precipitation that generates.With toluene (20mL) and CH 2Cl 2(20mL) solid of washing collection obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(2-methyl-third-2-thiazolinyl)-4,4-dimethyl-1,3-thiazoles alkane HBr salt (1.14g, 77%): mp229 ℃.D2h. the logical method that is used for 2-imino-heterocyclic ring azanylization.Synthesizing of 2-(2,4-dimethyl-3-cyano group-6-pyridyl imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane.
Figure A9981646401101
To 2-(2,4-dimethyl-3-cyano group-6-pyridyl imino-)-3-thia-1-azaspiro [4.4] nonane (method C1e; 0.192g, 0.669mmol) and in the solution of isobutyl bromide (0.5mL) in dry DMF (0.5mL) add NaH (95% in batches; 0.62g, 6.69mmol).Under 50 ℃,, use MeOH (approximately 0.5mL) to handle then and decompression concentrates down the mixture heating up that generates 3 hours.Through chromatography (SiO 2Gradient from the 20%EtOAc/ hexane to 100%CH 2Cl 2) the purifying resistates, obtain 2-(2,4-dimethyl-3-cyano group-6-pyridyl imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane (0.04g, 17%): CI-MS m/z 343 ((M+H)+).D3a. the logical method that removes protection that is used for the alcohol of tert.-butoxy formamyl protection.(4S)-4-(1 (R)-hydroxyethyl)-3-isobutyl--2-(2-methyl-4-nitrophenyl imino-)-1,3-thiazoles alkane synthetic.
Figure A9981646401111
The solution of TFA (8mL) is cooled to 4 ℃ and join solid (4S)-4-(1 (R)-tert.-butoxy ethyl)-3-isobutyl--2-(2-methyl-4-nitrophenyl imino-)-1,3-thiazoles alkane (method C5b by sleeve pipe; 0.16g, 0.42mmol) in.The solution that generates is warmed to 20 ℃ and stirred 1.5 hours under this temperature.Decompression is concentrated reaction mixture and at Et down 2O (100mL) and saturated NaHCO 3Distribute resistates between the solution (100mL).Dry (MgSO 4) also decompression is concentrated down for the ether layer.Through chromatography (SiO 2Gradient from hexane to the 10%EtOAc/ hexane) the purifying resistates, obtain (4S)-4-(1 (R)-hydroxyethyl)-3-isobutyl--2-(2-methyl-4-nitrophenyl imino-)-1,3-thiazoles alkane (0.13g, 90%): TLC (25%EtOAc/ hexane) R f0.13.D4a. be used for Synthetic 2-imino--1,3-thiazoles alkane 3-oxide compound and 2-imino--1,3-thiazoles alkane 3, the logical method of 3-dioxide by 2-imino--1,3-thiazoles alkoxide.1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane 3-oxide compound and 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane 3,3-dioxide synthetic.
Figure A9981646401112
With 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane (method D2b; 0.041g, 0.11mmol) and metachloroperbenzoic acid (about 80%, 0.040g is 0.19mmol) at CH 2Cl 2Solution stirring (5mL) 30 minutes is used saturated NaHCO then 3Washing, dry (MgSO 4) and reduce pressure concentrated down.Through chromatography (SiO 2Gradient from hexane to the 30%EtOAc/ hexane) the purifying resistates, obtain 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane 3,3-dioxide (0.030g, 67%), obtain 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane 3-oxide compound (0.011g, 26%) subsequently.1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane 3,3-dioxide: TLC (25%EtOAc/ hexane) R f0.27.1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane 3-oxide compound: TLC (25%EtOAc/ hexane) R f0.10.D5a. the heterocyclic that contains ketone or aldehyde that is used to reduce leads to method.Synthesizing of 2-(2-methyl-4-nitrophenyl imino-)-3-(3,3-dimethyl-2-hydroxybutyl)-1,3-thiazoles alkane.
With with the similar method of in method C2a, describing, preparation 2-(2-methyl-4-nitrophenyl imino-)-1, the 3-thiazolidine, and with the similar method of in method D2a, describing, with 1-bromo-3,3-dimethyl-2-butanone alkylation obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(3,3-dimethyl-2-oxo butyl)-1,3-thiazoles alkane.(3,3-dimethyl-2-oxo butyl)-(0.022g 0.065mmol) adds NaBH in the solution in MeOH (2mL) to 1,3-thiazoles alkane in batches to 2-(2-methyl-4-nitrophenyl imino-)-3- 4(0.0096g, 0.26mmol).At room temperature, the mixture that generates was stirred 4 hours, then at EtOAc (10mL) and H 2Separate between the O (5mL) and with EtOAc (3 * 10mL) extraction water layers.Use H 2The organic layer that O (15mL), the washing of saturated NaCl solution (15mL) order merge, dry (Na 2SO 4), and decompression concentrates down.Through preparation type TLC (20%EtOAc/ hexane) purifying resistates, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(3,3-dimethyl-2-hydroxybutyl)-1,3-thiazoles alkane (0.024g, 92%): FAB-MS m/z 338 ((M+H) +).D6a. be used for the logical method that carboxylic acid derivative transforms mutually.(4S)-and 2-(4-formamyl-2-aminomethyl phenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane synthetic.
Figure A9981646401131
Step 1
To (4S)-2-(4-methoxycarbonyl-2-aminomethyl phenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane is (to prepare with the similar method of describing in method D2a; 0.035g, 0.097mmol) at MeOH (1.5mL) and H 2Add in the solution in the mixture of O (1.5mL) LiOH (0.016g, 0.39mmol).At room temperature, the mixture that generates was stirred 2 days, decompression concentrates down then.With 1%HCl solution resistates is adjusted to pH1, (4 * 10mL) extract to use EtOAc then.Use H 2The organic layer that O (15mL), saturated NaCl solution (15mL) order washing merge, and dry (Na 2SO 4).Decompression concentrates down, obtains (4S)-2-(4-carboxyl-2-aminomethyl phenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane (0.034g, 100%): TLC (40%EtOAc/ hexane) R f0.08.This material is not further purified and promptly is used for next step. Step 2
To (4S)-2-(4-carboxyl-2-aminomethyl phenyl imino-)-3, (0.035g is 0.10mmol) at CH for 4-diisobutyl-1,3-thiazoles alkane 2Cl 2Add in the solution (5mL) carbonyl dimidazoles (0.047g, 0.29mmol).At room temperature, mixture was stirred 2 hours, then under-78 ℃ with anhydrous NH 3(about 30) condensation enters solution.Make the mixture of generation be warmed to ambient temperature overnight, use H then 2O (20mL) handles.Use CH 2Cl 2(3 * 20mL) extract water layer, use H 2O (20mL) and saturated NaCl solution (20mL) order washing, dry (Na 2SO 4), and decompression concentrates down.Through flash chromatography method (40%EtOAc/ hexane) purifying resistates, obtain (4S)-2-(4-formamyl-2-aminomethyl phenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane (0.027g, 73%): mp130-131 ℃ into white solid.D6b. be used for the logical method that carboxylic acid derivative transforms mutually.Synthesizing of 2-(2-ethyl-4-(N-methylamino formyl radical) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.
To 2-(4-carboxyl-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (method D9a; 0.58g, 0.167mmol) at CHCl 3Add SOCl in the solution (5mL) 2(0.06mL, 0.83mmol).Under reflux temperature, reaction mixture heating 3 hours, decompression concentrated down then.Resistates is dissolved in CH 2Cl 2(2.0M 4mL) handles in THF (3mL) and with methylamine.At room temperature, reaction mixture was stirred 2 hours, use 1N NaOH solution (10mL) to handle then.Use CH 2Cl 2(3 * 20mL) extract the mixture that generates, and wash the organic layer that merges with saturated NaCl solution (20mL), dry (Na 2SO 4) and reduce pressure concentrated down.Through preparation type TLC (50%EtOAc/ hexane) purifying resistates, obtain 2-(2-ethyl-4-(N-methylamino formyl radical) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (36g, 56%): TLC (30%EtOAc/ hexane) R f0.44.D7a. be used for from the logical method of the synthetic cyano-aryl imines of iodo aryl imine.Synthesizing of 2-(4-cyano group-2-propyl group phenylimino)-3-thia-1-azaspiro [4.4] nonane.
Figure A9981646401151
With with the similar method of method A2b, 4-iodo-2-n-propyl aniline is converted into 4-iodo-2-n-propyl phenyl lsothiocyanates.Simultaneously, 1-amino-1-(hydroxymethyl) pentamethylene is converted into the chloro methyl analogue, to react, obtains 2-(4-iodo-2-propyl group phenylimino)-3-thia-1-azaspiro [4.4] nonane then with similar method of method C2a and lsothiocyanates.Under 140 ℃, with 2-(4-iodo-2-propyl group phenylimino)-3-thia-1-azaspiro [4.4] nonane (0.54g, 1.35mmol) and CuCN (0.24g, 2.70mmol) the soup compound heated overnight in DMF (4mL).The mixture that generates is cooled to room temperature, decompression concentrates down and through flash chromatography method (10%EtOAc/ hexane) purifying, obtain 2-(4-cyano group-2-propyl group phenylimino)-3-thia-1-azaspiro [4.4] nonane (0.26g, 65%): TLC (30%EtOAc/ hexane) R for white solid f0.37.D8a. the logical method that is used for synthesis of phenyl acetylene.Synthesizing of 2-(2,3-dimethyl-4-ethynyl phenyl imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane. Step 1
With with the similar method of method A2b, 4-iodo-23 dimethyl aniline is converted into 4-iodo-2,3-3,5-dimethylphenyl lsothiocyanates.With with the similar method of in method C2a, describing, the preparation 2-(2,3-dimethyl-4-iodine substituted phenyl imino-)-3-thia-1-azaspiro [4.4] nonane, then with the similar method of in method D2a, describing, use the isobutyl bromide alkylation.At room temperature, with the iodine substituted phenyl compound (0.009g, 0.021mmol), (trimethyl silyl) acetylene (30mL, 0.21mmol), Pd (PPh 3) 2Cl 2(0.005g) and CuI (0.012g is 0.063mmol) at Et 3Mixture among the N (2mL) stirred 18 hours.Filter the soup compound that generates, and concentrated filtrate under the decompression.Through preparation type TLC (2%EtOAc/ hexane) purifying resistates, obtain 2-(2,3-dimethyl-4-(2-trimethyl silyl-1-ethynyl) phenylimino)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane (0.005g, 59%).
Figure A9981646401161
Step 2
At room temperature, with 2-(2,3-dimethyl-4-(2-trimethyl silyl-1-ethynyl) phenylimino)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane (0.005g, 0.0125mmol) and NaOH (0.006g, 0.15mmol) mixture in MeOH (2mL) stirs and to spend the night.Use CH 2Cl 2(20mL) diluted reaction mixture filters, and concentrated filtrate under the decompression.Through preparation type TLC (2%EtOAc/ hexane) purifying resistates, obtain 2-(2,3-dimethyl-4-ethynyl phenyl imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane (0.003.2g, 78%): TLC (20%EtOAc/ hexane) R f0.70.D9a. hydrolysis is used for the logical method of synthesizing benzoic acids by benzonitrile.Synthesizing of 2-(4-carboxyl-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.
With with the similar method of method C2a, the preparation 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane and with the similar method of method D2b, with the thiazolidine alkylation, obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Under 100 ℃, with 2-(4-cyano group-2-ethylphenyl imino-)-(0.32g, 9.42mmol) the solution heated overnight in dense HCl (15mL) is cooled to room temperature to 1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane then, obtains white precipitate.With 1N NaOH solution the mixture that generates is adjusted to pH6.5, uses CH then 2Cl 2(4 * 40mL) extract.The organic layer that water (30mL) and saturated NaCl solution (30mL) order washing merge, dry (Na 2SO 4) also decompression is concentrated down, obtains 2-(4-carboxyl-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.34g, 100%) into white solid: mp208-209 ℃.D10a. be used for carboxylic acid is converted into the logical method of ketone.Synthesizing of 2-(4-ethanoyl-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.
Figure A9981646401172
Under-78 ℃, to 2-(4-carboxyl-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (method D9a; 0.046g (1.4M is at Et 0.128mmol) to add lithium methide in the solution in THF (10mL) 2Among the O, 0.91mL, 1.28mmol).Make reaction mixture be warmed to room temperature gradually, stir then and spend the night.Add trimethylsilyl chloride (0.5mL) and, add 1N HCl solution (2mL) then at room temperature mixture stirring 2 hours.Mixture was stirred 0.5 hour, use saturated NaHCO then 3Solution (10mL) is handled.(4 * 20mL) extract the mixture that generates, and wash the organic layer that merges with saturated NaCl solution (30mL), dry (Na with EtOAc 2SO 4) and reduce pressure concentrated down.Through preparation type TLC (10%EtOAc/ hexane) purifying resistates, obtain 2-(4-ethanoyl-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.032g, 73%): mp114-115 ℃ into white solid.D11a. be used for nitrile is converted into the logical method of aldehyde.Synthesizing of 2-(2-ethyl-4-formyl radical phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.
Figure A9981646401181
With with the similar method of method C2a, the preparation 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane and with the similar method of method D2b with the thiazolidine alkylation, obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Under-78 ℃, to 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.21g, 0.60mmol) add in the solution in dry toluene (20mL) DIBAL (1.0M in toluene, 1.20mL, 1.20mmol).Under-78 ℃, reaction mixture stirring 3 hours, add EtOAc (3mL) down at-78 ℃ then, continue to stir 0.5 hour, the wet silica gel of adding (5% water, 2g).Reaction mixture is warmed to room temperature, stirred 3 hours, pass through Celite then Pad filters.Decompression is concentrated filtrate down; and through preparation type TLC (30%EtOAc/ hexane) purifying resistates; obtain 2-(2-ethyl-4-formyl radical phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.16g, 75%): mp104-105 ℃ for white solid.D12a. the logical method that is used for the chain homologization of aldehydes or ketones.Synthesizing of 2-(2-ethyl-4-((1E)-2-ethoxy carbonyl vinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.
To 2-(2-ethyl-4-formyl radical phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (method D11a; 0.053g, 0.149mmol) at CH 3Add in the solution among the CN LiCl (0.0076g, 0.182mmol), add subsequently DBU (0.025g, 0.167mmol) and phosphonic acids acetate triethyl ester (0.041g, 0.182mmol).At room temperature, reaction mixture was stirred 18 hours, decompression concentrates down then.Through flash chromatography method (3%EtOAc/ hexane) purifying resistates, obtain 2-(2-ethyl-4-((1E)-2-ethoxy carbonyl vinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.029g, 48%): TLC (30%EtOAc/ hexane) R for water white oil f0.68.D12b. the logical method that is used for the chain homologization of aldehydes or ketones.Synthesizing of 2-(2-ethyl-4-((1E)-2-nitroethylene base) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.
Figure A9981646401192
To 2-(2-ethyl-4-formyl radical phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (method D11a; 0.041g, 0.115mmol) at CH 2Cl 2Add MeNO in the solution (10mL) 2(2) and piperidines (4).Under reflux temperature,, be cooled to room temperature and decompression then and concentrate down the reaction mixture heated overnight.Through flash chromatography method (3%EtOAc/ hexane) purifying resistates, obtain 2-(2-ethyl-4-((1E)-2-nitroethylene base) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.022g, 48%): mp141-142 ℃ for red solid.D12c. the logical method that is used for the chain homologization of aldehydes or ketones.Synthesizing of 2-(2-ethyl-4-(2,2-dicyano vinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.
To 2-(2-ethyl-4-formyl radical phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (method D11a; 0.037g, 0.104mmol) add in the solution in EtOH (10mL) propane dinitrile (0.007g, 0.104mmol) and piperidines (4).At room temperature, reaction mixture was stirred 2 hours, decompression concentrates down then.Through preparation type TLC (20%EtOAc/ hexane) purifying resistates, obtain 2-(2-ethyl-4-(2 for yellow solid, 2-dicyano vinyl) phenylimino)-and 1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.012g, 28%): mp135-136 ℃.D12d. the logical method that is used for the chain homologization of aldehydes or ketones.Synthesizing of 2-(2-ethyl-4-(2-cyano group vinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.
Under reflux temperature, (0.024g is 0.36mmol) at CH to KOH 3Add 2-(2-ethyl-4-formyl radical phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (method D11a in the solution among the CN (20ml); 0.127g, 0.36mmol).Under reflux temperature, reaction mixture heating 4 hours, be cooled to room temperature, and decompression concentrates down.Water (15mL) dilutes and uses CH 2Cl 2(3 * 15mL) extract resistates.Organic layer and dry (Na with saturated NaCl solution washing merging 2SO 4).Through the material that preparation type TLC (30%EtOAc/ hexane) purifying generates, obtaining is 2-(2-ethyl-4-(2-cyano group vinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.050g): TLC (30%EtOAc/ hexane) R of 1: 3 suitable/trans isomer mixture f0.56.D13a. be used for the alkylating logical method of chloro methyl chains.Synthesizing of 2-(2-methyl-4-nitrophenyl imino-)-4-(N-methylamino methyl)-1,3-thiazoles alkane.
To the solution of methylamine in methyl alcohol (2.0M, add in 5mL) 2-(2-methyl-4-nitrophenyl imino-)-4-(chloromethyl)-1,3-thiazoles alkane (with the similar method preparation of in method C2a, describing; 0.040g, 0.140mmol) and at room temperature the mixture that generates was stirred 72 hours.Decompression is enriched mixture and through flash chromatography method (5%MeOH/CH down 2Cl 2) resistates that purifying generates, obtain being solid 2-(2-methyl-4-nitrophenyl imino-)-4-(N-methylamino methyl)-1,3-thiazoles alkane (0.014g, 35%).The rearrangement of D14a. acid catalyzed carbon carbon-two keys.Synthesizing of 2-(4-nitrophenyl imino-)-3-(2-methyl-prop-1-alkene-1-yl)-1,3-thiazoles alkane.
Figure A9981646401221
According to method C1a, make chlorination 2-chloro ethyl ammonium (entry 1) and the reaction of 4-nitrophenyl lsothiocyanates, obtain 2-(4-nitrophenyl)-1,3-thiazoles alkane.According to method D2a, make thiazolidine and 1-bromo-2-methyl-2-propylene reaction, obtain 2-(4-nitrophenyl imino-)-3-(2-methyl-prop-2-alkene-1-yl)-1,3-thiazoles alkane.Under 80 ℃, with 2-(4-nitrophenyl imino-)-3-(2-methyl-prop-2-alkene-1-yl)-mixture heating up of 1,3-thiazoles alkane (0.20g) in polyphosphoric acid (0.4mL) 5 hours.Then by ultrasonic, reaction mixture is dissolved in 0 ℃ the water (20mL).With 1N NaOH solution aqueous mixture is adjusted to pH12, (3 * 25mL) extract to use EtOAc then.Dry (K 2CO 3) organic phase and the decompression that merge concentrate down.Through preparation HPLC purifying resistates (0.21g), obtain 2-(4-nitrophenyl imino-)-3-(2-methyl-prop-1-alkene-1-yl)-1,3-thiazoles alkane.The preparation of particular compound
The following description that is provided for the detailed preparation process of the particular compound listed among the preparation table 1-4.According to several different methods, can synthesize the chemical compound lot of in described table, listing.Therefore, only by illustrating, following specific embodiment is provided and should constitute limitation of the scope of the invention by any way.Entry 1
According to method C1a, 2-chloro ethylamine HCl salt and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-1,3-thiazoles alkane.Entry 2
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and the reaction of 4-nitrophenyl lsothiocyanates obtain 2-(4-nitrophenyl imino-)-1, the 3-thiazolidine, according to method D2a, it and isobutyl bromide react, obtain 2-(4-nitrophenyl imino-)-3-isobutyl--1,3-thiazoles alkane.Entry 3
Figure A9981646401233
Chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction according to method D2a, with the isobutyl bromide reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--1,3-thiazoles alkane again.Entry 4
Figure A9981646401234
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2, the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-1, the 3-thiazolidine, according to method D2a, it and isobutyl bromide react, and obtain 2-(2,3-dichlorophenyl imino-)-3-isobutyl--1,3-thiazoles alkane.Entry 5
According to method C1d, chlorination N-chloroethyl-N '-isobutyl-ammonium (as preparing among the method B7c) and 2-methoxyl group-4-nitrophenyl lsothiocyanates reaction obtain 2-(2-methoxyl group-4-nitrophenyl imino-)-3-isobutyl--1,3-thiazoles alkane.Entry 6
According to method C1d, chlorination N-chloroethyl-N '-isobutyl-ammonium (as preparing among the method B7c) and the reaction of 4-cyano-phenyl lsothiocyanates obtain 2-(4-cyano-phenyl-imino)-3-isobutyl--1,3-thiazoles alkane.Entry 7
Figure A9981646401243
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and the reaction of 2-methyl-5-nitro phenyl lsothiocyanates obtain thiazolidine, according to method D2a, it and isobutyl bromide react, and obtain 2-(2-methyl-5-nitro phenylimino)-3-isobutyl--1,3-thiazoles alkane HCl salt.Entry 8
Figure A9981646401251
According to method C1d, chlorination N-chloroethyl-N '-isobutyl-ammonium (as preparing among the method B7c) and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtain 2-(4-cyano group-2-ethylphenyl imino-)-3-isobutyl--1,3-thiazoles alkane.Entry 9
Figure A9981646401252
According to method C1d, chlorination N-chloroethyl-N '-isobutyl-ammonium (as preparing among the method B7c) and the reaction of 4-chloro-2-(trifluoromethyl) phenyl lsothiocyanates obtain 2-(4-chloro-2-(trifluoromethyl) phenylimino)-3-isobutyl--1,3-thiazoles alkane.Entry 10
Figure A9981646401253
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and the reaction of 4-nitrophenyl lsothiocyanates obtain thiazolidine, according to method D2a, it and 1-bromo-2-methyl-2-propylene react, and obtain 2-(4-nitrophenyl imino-)-3-(2-methyl-prop-2-alkene-1-yl)-1,3-thiazoles alkane.According to method D14a, 3-allyl group-1,3-thiazoles alkane is reset, and obtains 2-(4-nitrophenyl imino-)-3-(2-methyl-prop-1-alkene-1-yl)-1,3-thiazoles alkane.Entry 11
Figure A9981646401261
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain thiazolidine, according to method D2a, it and 1-bromo-2-methyl-2-propylene react, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(2-methyl-prop-2-alkene-1-yl)-1,3-thiazoles alkane.Entry 12
Figure A9981646401262
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and the reaction of 4-nitrophenyl lsothiocyanates obtain thiazolidine, according to method D2a, it and 1-bromo-2-methyl-2-propylene react, and obtain 2-(4-nitrophenyl imino-)-3-(2-methyl-prop-2-alkene-1-yl)-1,3-thiazoles alkane.Entry 13
Figure A9981646401263
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 3, the reaction of 4-dichlorophenyl lsothiocyanates, obtain thiazolidine, according to method D2a, it and 1-bromo-2-methyl-2-propylene react, obtain 2-(3,4-dichlorophenyl imino-)-3-(2-methyl-prop-2-alkene-1-yl)-1,3-thiazoles alkane.Entry 14
Figure A9981646401271
According to method B7a, N-(2-hydroxyethyl)-N-(2-methyl butyl) amine and SOCl 2Reaction obtains chlorination N-(2-chloroethyl)-N-(2-methyl butyl) ammonium.According to method C1a, described chloroethyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(2-methyl-1-butene base)-1,3-thiazoles alkane.Entry 15
Figure A9981646401272
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtain thiazolidine, according to method D2a, it and 4-bromine but-1-ene react, and obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(but-1-ene-4-yl)-1,3-thiazoles alkane.Entry 16
Figure A9981646401273
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtain thiazolidine, according to method D2a, it and 1-bromine fourth-2-alkyne reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(fourth-2-alkynes-1-yl)-1,3-thiazoles alkane.Entry 17
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtain thiazolidine, according to method D2a, it and 2-ethyl-butyl bromine reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(2-ethyl-1-butyl)-1,3-thiazoles alkane.Entry 18
Figure A9981646401282
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtain thiazolidine, according to method D2a, it and 2-methyl butyl bromine reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(2-methyl-1-butene base)-1,3-thiazoles alkane.Entry 19
Figure A9981646401283
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtain thiazolidine, according to method D2a, it and 1-nonyl bromine reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(1-nonyl)-1,3-thiazoles alkane.Entry 20
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain thiazolidine, according to method D2a, it and 2,2-dimethyl propyl bromine reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(2, the 2-dimethyl propyl)-1,3-thiazoles alkane.Entry 21
Figure A9981646401292
According to method B5a, the 2-butylamine is converted into N-(2-hydroxyethyl)-N-(2-butyl) amine.According to method B7a, make this amine and SOCl 2Reaction obtains chlorination N-(2-chloroethyl)-N-(2-butyl) ammonium.According to method C1a, this chloroethyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(2-butyl)-1,3-thiazoles alkane.Entry 22
Figure A9981646401293
According to method B5a, the 3-amylamine is converted into N-(2-hydroxyethyl)-M-(3-amyl group) amine.According to method B7a, make amine and SOCl 2Reaction obtains chlorination N-(2-chloroethyl)-N-(2-amyl group) ammonium.According to method C1a, this chloroethyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(3-amyl group)-1,3-thiazoles alkane.Entry 23
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtain thiazolidine, according to method D2a, it and 1-heptyl bromine reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(1-heptyl)-1,3-thiazoles alkane.Entry 24
Figure A9981646401302
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtain thiazolidine, according to method D2a, it and 8-bromo-1-octene react, and obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(suffering-1-alkene-8-yl)-1,3-thiazoles alkane.Entry 25
According to method B2b step 2,2-propyl group-1-hydroxyl pentane is converted into 1-bromo-2-propyl group pentane.According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain thiazolidine, according to method D2a, it and 1-bromo-2-propyl group pentane react, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(2-propyl group-1-amyl group)-1,3-thiazoles alkane.Entry 26
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain thiazolidine, according to method D2a, it and 1,1-two cyclopropyl but-1-ene-4-base bromine reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(1,1-two cyclopropyl but-1-ene-4-yl)-1,3-thiazoles alkane.Entry 27
Figure A9981646401312
According to method C8a, 2, the reaction of 6-two chloro-4-nitrophenyl lsothiocyanates and 2-butylamine subsequently with chloroacetate reaction, obtain 2-(2,6-two chloro-4-nitrophenyl imino-s)-3-(2-butyl)-1,3-thiazoles alkane-4-ketone.Entry 28
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain thiazolidine, according to method D2a, it with (E/Z)-1, the reaction of 3-propylene bromide obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(bromo third-1-alkene-3-the yl)-1,3-thiazoles alkane as the E-/Z-mixture.Use preparation type TLC separating mixture, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-((Z-) bromo third-1-alkene-3-yl)-1,3-thiazoles alkane.Entry 29
Figure A9981646401321
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain thiazolidine, according to method D2a, it with (E)-1, the reaction of 3-dichloropropylene obtains 2-(2-methyl-4-nitrophenyl imino-)-3-((E-)-chloro third-1-alkene-3-yl)-1,3-thiazoles alkane.Entry 30
Figure A9981646401322
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtain thiazolidine, according to method D2a, it and 3-chloro-1-propyne react, and obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(third-1-alkynes-3-yl)-1,3-thiazoles alkane.Entry 31
Figure A9981646401323
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain thiazolidine, according to method D2a, it with (E/Z)-1, the reaction of 3-propylene bromide obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(bromo third-1-alkene-3-the yl)-1,3-thiazoles alkane as the E-/Z-mixture.Use preparation type TLC separating mixture, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-((E-) bromo third-1-alkene-3-yl)-1,3-thiazoles alkane.Entry 32
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain thiazolidine, according to method D2a, it with (Z)-4-chloro-3-oxyethyl group but-2-ene acetoacetic ester reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(1-ethoxy carbonyl-2-ethoxy-c-1-alkene-3-yl)-1,3-thiazoles alkane.Entry 33
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain thiazolidine, according to method D2a, it and 4-bromo-butyric acid methyl esters react, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(1-methoxycarbonyl-3-propyl group)-1,3-thiazoles alkane.Entry 34
Figure A9981646401333
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtain thiazolidine, according to method D2a, it and methyl chloroacetate react, and obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(1-methoxycarbonyl methyl)-1,3-thiazoles alkane.Entry 35
Figure A9981646401341
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain thiazolidine, according to method D2a, it and alpha-chloro acetophenone react, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(1-oxo-1-phenyl-2-ethyl)-1,3-thiazoles alkane.According to method D5a, this ketone reduction is obtained 2-(2-methyl-4-nitrophenyl imino-)-3-(1-hydroxyl-1-phenyl-2-ethyl)-1,3-thiazoles alkane.Entry 36
Figure A9981646401342
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain thiazolidine, according to method D2a, it and 1-chloro-3,3-dimethyl-2-butanone reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(2-oxo-3,3-dimethyl-1-butyl)-1,3-thiazoles alkane.Method 37
Figure A9981646401343
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtain thiazolidine, according to method D2a, it and 1-chloro-2-butanone react, and obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(2-oxo-1-butyl)-1,3-thiazoles alkane.Method 38
Figure A9981646401351
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtain thiazolidine, according to method D2a, it and 1-chloro-2-butanone react, and obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(2-oxo-1-butyl)-1,3-thiazoles alkane.According to method D5a, this ketone reduction is obtained 2-(2-methyl-4-nitrophenyl imino-)-3-(2-hydroxyl-1-butyl)-1,3-thiazoles alkane.Method 39
Figure A9981646401352
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain thiazolidine, according to method D2a, it and 1-chloro-3,3-dimethyl-2-butanone reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(2-oxo-3,3-dimethyl-1-butyl)-1,3-thiazoles alkane.According to method D5a, this ketone reduction is obtained 2-(2-methyl-4-nitrophenyl imino-)-3-(2-hydroxyl-3,3-dimethyl-1-butyl)-1,3-thiazoles alkane.Entry 40
Figure A9981646401353
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtain thiazolidine, according to method D2a, it and 5-bromo-2 pentanone react, and obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(2-oxo-5-amyl group)-1,3-thiazoles alkane.Entry 41
Figure A9981646401361
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain thiazolidine, according to method D2a, it and 1,1, the reaction of 3-three chloro-1-propylene, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(1,1-dichloro third-1-alkene-3-yl)-1,3-thiazoles alkane.Entry 42
Figure A9981646401362
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtain thiazolidine, according to method D2a, it and propionyl chloride react, and obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(1-oxo-1-propyl group)-1,3-thiazoles alkane.Entry 43
Figure A9981646401363
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl isocyanate reaction, obtain thiazolidine, according to method D2a, it with (E)-reaction of 1-chloro-5-methoxyl group-2-amylene, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-((E)-5-methoxyl group penta-2-alkene-1-yl)-1,3-thiazoles alkane.Entry 44
According to method B4b step 1,2 hydroxy ethylamine and cyclopentanone reaction obtain 4-azepine-1-oxaspiro [4.4] nonane.According to method B4b step 2, Hai Yuan oxazolidine obtains N-cyclopentyl-N-(2-hydroxyethyl) amine.According to method B7c, make this alcohol and SOCl 2Reaction obtains N-cyclopentyl-N-(2-chloroethyl) amine.According to method C1d, this amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(cyclopentyl)-1,3-thiazoles alkane.Entry 45
According to method B4b step 1,2 hydroxy ethylamine and cyclopentanone reaction obtain 4-azepine-1-oxaspiro [4.4] nonane.According to method B4b step 2, reduce Gai oxazolidine, obtain N-cyclopentyl-N-(2-hydroxyethyl) amine.According to method B7c, make this alcohol and SOCl 2Reaction obtains N-cyclopentyl-N-2-chloroethyl) amine.According to method C1d, this amine and 2-methoxyl group-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methoxyl group-4-nitrophenyl imino-)-3-(cyclopentyl)-1,3-thiazoles alkane.Entry 46
Figure A9981646401381
According to method B4b step 1,2 hydroxy ethylamine and cyclopentanone reaction obtain 4-azepine-1-oxaspiro [4.4] nonane.According to method B4b step 2, reduce Gai oxazolidine, obtain N-cyclopentyl-N-(2-hydroxyethyl) amine.According to method B7c, make this alcohol and SOCl 2Reaction obtains N-cyclopentyl-N-(2-chloroethyl) amine.According to method C1d, this amine and 2, the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-3-cyclopentyl-1,3-thiazoles alkane.Entry 47
Figure A9981646401382
According to method B2b step 1, hexamethylene-2-alkene-1-ketone reduction is obtained hexamethylene-2-alkene-1-alcohol.According to method B2b step 2, this alcohol is converted into 3-bromo-1-tetrahydrobenzene.According to method B2b step 3, this halogenide is converted into N-(hexamethylene-2-alkene-1-yl)-N (2-hydroxyethyl) amine.According to method B7a, make this alcohol and SOCl 2Reaction obtains chlorination N-(hexamethylene-2-alkene-1-yl)-N-(2-chloroethyl) ammonium.According to method C1a, this chlorethamin and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(hexamethylene-2-alkene-1-yl)-1,3-thiazoles alkane.Entry 48
Figure A9981646401391
According to method B4a step 1,2 hydroxy ethylamine and pimelinketone reaction obtain 4-azepine-1-oxaspiro [4.5] decane.According to method B4a step 2, reduce Gai oxazolidine, obtain N-cyclohexyl-N-(2-hydroxyethyl) amine.According to method B7c, make this alcohol and SOCl 2Reaction obtains N-cyclohexyl-N-(2-chloroethyl) amine.According to method C1d, this amine and 2-methoxyl group-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-cyclohexyl-1,3-thiazoles alkane.Entry 49
Figure A9981646401392
According to method B7a, N-(2-hydroxyethyl) aniline and SOCl 2Reaction obtains chlorination N-2-chloroethyl) puratized agricultural spray.According to method C1a, this chloroethyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-phenyl-1,3-thiazoles alkane.Entry 50
According to method B2a, 2 hydroxy ethylamine and suberyl bromine reaction obtain N-suberyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-suberyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-suberyl-1,3-thiazoles alkane.Entry 51
Figure A9981646401401
According to method B2a, 2 hydroxy ethylamine and the reaction of ring n-octyl bromide obtain N-ring octyl group-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-ring octyl group-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-and encircles octyl group-1,3-thiazoles alkane.Entry 52
Figure A9981646401402
According to method B2a, 2 hydroxy ethylamine and the reaction of ring n-octyl bromide obtain N-ring octyl group-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-ring octyl group-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2-methoxyl group-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methoxyl group-4-nitrophenyl imino-)-3-and encircles octyl group-1,3-thiazoles alkane.Entry 53
According to method B2a, 2 hydroxy ethylamine and the reaction of ring n-octyl bromide obtain N-ring octyl group-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-ring octyl group-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2, the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-3-and encircles octyl group-1,3-thiazoles alkane.Entry 54
Figure A9981646401412
According to method B2a, 2 hydroxy ethylamine and the reaction of cyclopropyl monobromomethane obtain N-cyclopropyl methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclopropyl methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2, the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-3-(cyclopropyl methyl)-1,3-thiazoles alkane.Entry 55
Figure A9981646401413
According to method B2a, 2 hydroxy ethylamine and the reaction of cyclopropyl monobromomethane obtain N-cyclopropyl methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclopropyl methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(cyclopropyl methyl)-1,3-thiazoles alkane.Entry 56
Figure A9981646401421
According to method B2a, 2 hydroxy ethylamine and the reaction of cyclopropyl monobromomethane obtain N-cyclopropyl methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclopropyl methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and the reaction of 2,4 dichloro benzene base lsothiocyanates obtain 2-(2,4 dichloro benzene base imino-)-3-(cyclopropyl methyl)-1,3-thiazoles alkane.Entry 57
Figure A9981646401422
According to method B2a, 2 hydroxy ethylamine and the reaction of cyclopropyl monobromomethane obtain N-cyclopropyl methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclopropyl methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 3, the reaction of 4-dichlorophenyl lsothiocyanates obtains 2-(3,4-dichlorophenyl imino-)-3-(cyclopropyl methyl)-1,3-thiazoles alkane.Entry 58
According to method B2a, 2 hydroxy ethylamine and cyclobutylmethyl bromine reaction obtain N-cyclobutylmethyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclobutylmethyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2, the reaction of 2-dichlorophenyl lsothiocyanates obtains 2-(2,2-dichlorophenyl imino-)-3-(cyclobutylmethyl)-1,3-thiazoles alkane.Entry 59
Figure A9981646401432
According to method B2a, 2 hydroxy ethylamine and cyclobutylmethyl bromine reaction obtain N-cyclobutylmethyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclobutylmethyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and the reaction of 2,4 dichloro benzene base lsothiocyanates obtain 2-(2,4 dichloro benzene base imino-)-3-(cyclobutylmethyl)-1,3-thiazoles alkane.Entry 60
Figure A9981646401433
According to method B2a, 2 hydroxy ethylamine and cyclobutylmethyl bromine reaction obtain N-cyclobutylmethyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclobutylmethyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 3, the reaction of 4-dichlorophenyl lsothiocyanates obtains 2-(3,4-dichlorophenyl imino-)-3-(cyclobutylmethyl)-1,3-thiazoles alkane.Entry 61
Figure A9981646401441
According to method B2a, 2 hydroxy ethylamine and cyclobutylmethyl bromine reaction obtain N-cyclobutylmethyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclobutylmethyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2, the reaction of 3-3,5-dimethylphenyl lsothiocyanates obtains 2-(2,3-3,5-dimethylphenyl imino-)-3-(cyclobutylmethyl)-1,3-thiazoles alkane.Entry 62
According to method B2a, 2 hydroxy ethylamine and cyclobutylmethyl bromine reaction obtain N-cyclobutylmethyl-N-(2-hydroxyethyl) amine.According to method B7c, make this alcohol and SOCl 2Reaction obtains chlorination N-cyclobutylmethyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and the reaction of 3-chloro-2-aminomethyl phenyl lsothiocyanates obtain 2-(3-chloro-2-aminomethyl phenyl imino-)-3-(cyclobutylmethyl)-1,3-thiazoles alkane.Entry 63
Figure A9981646401451
According to method B2a, 2 hydroxy ethylamine and cyclopentyl-methyl bromine reaction obtain N-cyclopentyl-methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclopentyl-methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2, the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-3-(cyclopentyl-methyl)-1,3-thiazoles alkane.Entry 64
According to method B2a, 2 hydroxy ethylamine and cyclopentyl-methyl bromine reaction obtain N-cyclopentyl-methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclopentyl-methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 3, the reaction of 4-dichlorophenyl lsothiocyanates obtains 2-(3,4-dichlorophenyl imino-)-3-(cyclopentyl-methyl)-1,3-thiazoles alkane.Entry 65
According to method B2a, 2 hydroxy ethylamine and cyclopentyl-methyl bromine reaction obtain N-cyclopentyl-methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclopentyl-methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(cyclopentyl-methyl)-1,3-thiazoles alkane.Entry 66
Figure A9981646401461
According to method B2a, 2 hydroxy ethylamine and cyclopentyl-methyl bromine reaction obtain N-cyclopentyl-methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclopentyl-methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and the reaction of 2,4 dichloro benzene base lsothiocyanates obtain 2-(2,4 dichloro benzene base imino-)-3-(cyclopentyl-methyl)-1,3-thiazoles alkane.Entry 67
Figure A9981646401462
According to method B2a, 2 hydroxy ethylamine and cyclopentyl-methyl bromine reaction obtain N-cyclopentyl-methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclopentyl-methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2, the reaction of 3-3,5-dimethylphenyl lsothiocyanates obtains 2-(2,3-3,5-dimethylphenyl imino-)-3-(cyclopentyl-methyl)-1,3-thiazoles alkane.Entry 68
According to method B2a, 2 hydroxy ethylamine and cyclopentyl-methyl bromine reaction obtain N-cyclopentyl-methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclopentyl-methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and the reaction of 3-chloro-2-aminomethyl phenyl lsothiocyanates obtain 2-(3-chloro-2-aminomethyl phenyl imino-)-3-(cyclopentyl-methyl)-1,3-thiazoles alkane.Entry 69
According to method B2a, 2 hydroxy ethylamine and cyclohexyl methyl bromine reaction obtain N-cyclohexyl methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclohexyl methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2, the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-3-(cyclohexyl methyl)-1,3-thiazoles alkane.Entry 70
According to method B2a, 2 hydroxy ethylamine and cyclohexyl methyl bromine reaction obtain M-cyclohexyl methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclohexyl methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(cyclohexyl methyl)-1,3-thiazoles alkane.Entry 71
According to method B2a, 2 hydroxy ethylamine and cyclohexyl methyl bromine reaction obtain N-cyclohexyl methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-cyclohexyl methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2-methoxyl group-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methoxyl group-4-nitrophenyl imino-)-3-(cyclohexyl methyl)-1,3-thiazoles alkane.Entry 72
Figure A9981646401482
According to method B5a, 1-cyclohexyl-1-ethylamine is converted into N-(2-hydroxyethyl)-N-(1-cyclohexyl-1-ethyl) amine.According to method B7a, this alcohol and SOCl 2Reaction obtains chlorination N-(2-chloroethyl)-N-(1-cyclohexyl-1-ethyl) ammonium.According to method C1a, this chloroethyl amine and 2-methyl-4-nitrophenyl isocyanate reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(1-cyclohexyl-1-ethyl)-1,3-thiazoles alkane.Entry 73
Figure A9981646401491
According to method B2a, 2 hydroxy ethylamine and bromotoluene reaction obtain N-benzyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-benzyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and the reaction of 3-chloro-2-aminomethyl phenyl lsothiocyanates obtain 2-(3-chloro-2-aminomethyl phenyl imino-)-3-benzyl-1,3-thiazoles alkane.Entry 74
According to method B2a, 2 hydroxy ethylamine and bromotoluene reaction obtain N-benzyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-benzyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 3, the reaction of 4-dichlorophenyl lsothiocyanates obtains 2-(3,4-dichlorophenyl imino-)-3-benzyl-1,3-thiazoles alkane.Entry 75
Figure A9981646401493
According to method B2a, 2 hydroxy ethylamine and bromotoluene reaction obtain N-benzyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-benzyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and the reaction of 2,4 dichloro benzene base lsothiocyanates obtain 2-(2,4 dichloro benzene base imino-)-3-benzyl-1,3-thiazoles alkane.Entry 76
Figure A9981646401501
According to method B2a, 2 hydroxy ethylamine and bromotoluene reaction obtain N-benzyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-benzyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-benzyl-1,3-thiazoles alkane.Entry 77
Figure A9981646401502
According to method B2a, 2 hydroxy ethylamine and bromotoluene reaction obtain N-benzyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-benzyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2, the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-3-benzyl-1,3-thiazoles alkane.Entry 78
According to method B2a, 2 hydroxy ethylamine and 4-benzyl chloride base bromine reaction obtain N-(4-benzyl chloride base)-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-(4-benzyl chloride base)-N-(2-chloroethyl) ammonium.This chloroethyl amine and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-(4-benzyl chloride base)-1,3-thiazoles alkane.Entry 79
Figure A9981646401511
According to method B2a, 2 hydroxy ethylamine and 4-benzyl chloride base bromine reaction obtain N-(4-benzyl chloride base)-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-(4-benzyl chloride base)-N-(2-chloroethyl) ammonium.This chloroethyl amine and the reaction of 2-chloro-4-cyano-phenyl lsothiocyanates obtain 2-(2-chloro-4-cyano-phenyl-imino)-3-(4-benzyl chloride base)-1,3-thiazoles alkane.Entry 80
According to method B2a, 2 hydroxy ethylamine and the reaction of suberyl monobromomethane obtain N-suberyl methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-suberyl methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(suberyl methyl)-1,3-thiazoles alkane.Entry 81
According to method B2a, 2 hydroxy ethylamine and the reaction of suberyl monobromomethane obtain N-suberyl methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-suberyl methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2-methoxyl group-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methoxyl group-4-nitrophenyl imino-)-3-(suberyl methyl)-1,3-thiazoles alkane.Entry 82
Figure A9981646401522
According to method B2a, 2 hydroxy ethylamine and the reaction of suberyl monobromomethane obtain N-suberyl methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-suberyl methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and 2, the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-3-(suberyl methyl)-1,3-thiazoles alkane.Entry 83
According to method B2a, 2 hydroxy ethylamine and the reaction of suberyl monobromomethane obtain N-suberyl methyl-N-(2-hydroxyethyl) amine.According to method B7c, this alcohol and SOCl 2Reaction obtains chlorination N-suberyl methyl-N-(2-chloroethyl) ammonium.This chloroethyl amine and the reaction of 4-cyano-phenyl lsothiocyanates obtain 2-(4-cyano-phenyl-imino)-3-(suberyl methyl)-1,3-thiazoles alkane.Entry 84
Figure A9981646401531
According to method B2b step 1, the cyclo-dodecyl carboxylate methyl ester is reduced to cyclo-dodecyl methyl alcohol.According to method B2b step 2, alcohol is converted into the cyclo-dodecyl monobromomethane.According to method B2b step 3, this halogenide and 2 hydroxy ethylamine reaction obtain N-(2-hydroxyethyl)-N-(cyclododecane ylmethyl) amine.According to method B7a, this alcohol and SOCl 2Reaction obtains chlorination N-(2-chloroethyl)-N-(cyclododecane ylmethyl) ammonium.According to method C1a, this chloroethyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(cyclododecane ylmethyl)-1,3-thiazoles alkane.Entry 85
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-1, the 3-thiazolidine, according to method D2a, it and 3-(chloromethyl)-6, the reaction of 6-dimethyl dicyclo [3.1.1] hept-2-ene", obtain 2-(4-nitrophenyl imino-)-3-((6,6-dimethyl dicyclo [3.1.1] hept-2-ene"-3-yl) methyl)-1,3-thiazoles alkane.Entry 86
According to method C1a, chlorination 2-chloroethyl ammonium (entry 1) and 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-1, the 3-thiazolidine, according to method D2a, it and 5-(brooethyl) dicyclo [2.2.1] hept-2-ene" react, and obtain 2-(4-nitrophenyl imino-)-3-((dicyclo [2.2.1] hept-2-ene"-5-yl) methyl)-1,3-thiazoles alkane.Entry 87
Figure A9981646401542
According to method A2c, the 3-quinolylamine is converted into 3-quinoline lsothiocyanates.As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B4c step 1-2,2 hydroxy ethylamine is converted into (2S)-4-methyl-2-(isobutylamino) amylalcohol.As described at method B7c, this alcohol is converted into chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-N-(isobutyl-) ammonium.According to method C1f, 3-quinoline lsothiocyanates and chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-reaction of N-(isobutyl-) ammonium, obtain 2-(3-quinolyl imino-)-3,5-diisobutyl-1,3-thiazoles alkane.Entry 88
Figure A9981646401543
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B4c step 1-2,2 hydroxy ethylamine is converted into (2S)-4-methyl-2-(isobutylamino) amylalcohol.As described at method B7c, alcohol is converted into chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-N-(isobutyl-) ammonium.According to method C1f, 4-nitrophenyl lsothiocyanates and chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-reaction of N-(isobutyl-) ammonium, obtain 2-(4-nitrophenyl imino-)-3,5-diisobutyl-1,3-thiazoles alkane.Entry 89
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B4c step 1-2,2 hydroxy ethylamine is converted into (2S)-4-methyl-2-(isobutylamino) amylalcohol.As described at method B7c, this alcohol is converted into chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-N-(isobutyl-) ammonium.According to method C1f, 4-cyano-phenyl lsothiocyanates and chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-reaction of N-(isobutyl-) ammonium, obtain 2-(4-cyano-phenyl-imino)-3,5-diisobutyl-1,3-thiazoles alkane.Entry 90
Figure A9981646401552
As described at method B7a, (1S)-1-(hydroxymethyl)-3-methylbutylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane HCl salt.Entry 91
Figure A9981646401561
As described at method B7a, (1S)-1-(hydroxymethyl)-3-methylbutylamine is converted into chlorination (1R)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1R)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane HCl salt.Entry 92
Figure A9981646401562
As described at method B7a, (1S)-1-(hydroxymethyl)-3-methylbutylamine is converted into chlorination (1R)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-5-nitro phenyl lsothiocyanates and chlorination (1R)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4R)-2-(2-methyl-5-nitro phenylimino)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4R)-2-(2-methyl-5-nitro phenylimino)-3,4-diisobutyl-1,3-thiazoles alkane HCl salt.Entry 93
Figure A9981646401571
As described at method B7a, (1S)-1-(hydroxymethyl)-3-methylbutylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-5-nitro phenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-5-nitro phenylimino)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2-methyl-5-nitro phenylimino)-3,4-diisobutyl-1,3-thiazoles alkane HCl salt.Entry 94
Figure A9981646401572
As described at method B7a, (1S)-1-(hydroxymethyl)-3-methylbutylamine is converted into chlorination (1R)-1-(chloromethyl)-3-methyl fourth ammonium according to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1R)-1-(chloromethyl)-3-methyl fourth ammonium reaction, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and iodomethane reaction obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--3-methyl isophthalic acid, 3-thiazolidine HCl salt.Entry 95
Figure A9981646401573
As described at method B7a, (1S)-1-(hydroxymethyl)-3-methylbutylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and iodomethane reaction obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--3-methyl isophthalic acid, 3-thiazolidine HCl salt.Entry 96
Figure A9981646401581
As described at method B7a, (1S)-1-(hydroxymethyl)-3-methylbutylamine is converted into chlorination (1R)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-5-nitro phenyl lsothiocyanates and chlorination (1R)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4R)-2-(2-methyl-5-nitro phenylimino)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and iodomethane reaction obtain (4R)-2-(2-methyl-5-nitro phenylimino)-4-isobutyl--3-methyl isophthalic acid, 3-thiazolidine HCl salt.Entry 97
As described at method B7a, (1S)-1-(hydroxymethyl)-3-methylbutylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and the reaction of 1-bromo-2-ethyl butane obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--3-(2-ethyl-1-butyl)-1,3-thiazoles alkane HCl salt.Entry 98
Figure A9981646401591
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and 1-chloro-3,3-dimethyl-2-butanone reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--3-(2-oxo-3,3-dimethyl-1-butyl)-1,3-thiazoles alkane.Entry 99
Figure A9981646401592
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-ethyl-4-cyano-phenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2f, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2-ethyl-4-cyano-phenyl-imino)-4-isobutyl--3-(2-oxo-3,3-dimethyl-1-butyl)-1,3-thiazoles alkane.Entry 100
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and the reaction of cyclopropyl monobromomethane obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--3-(cyclopropyl methyl)-1,3-thiazoles alkane.Entry 101
Figure A9981646401602
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and cyclobutylmethyl bromine reaction obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--3-(cyclobutylmethyl)-1,3-thiazoles alkane.Entry 102
Figure A9981646401611
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and 2-chloro-3,3-dimethyl-2-butanone reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--3-(2-oxo-3,3-dimethyl-1-butyl)-1,3-thiazoles alkane.According to method D5a, this ketone is reduced to (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--3-(3,3-dimethyl-2-hydroxyl-1-butyl)-1,3-thiazoles alkane.Entry 103
Figure A9981646401612
As described at method B7a, (1S)-1-(methylol)-3-methylbutylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method A2b, with 2,6-dimethyl-4-N-methyl-p-nitroaniline is converted into 2,6-dimethyl-4-nitrophenyl lsothiocyanates.According to method C1a, 2,6-dimethyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2,6-dimethyl-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane HCl salt.Entry 104
Figure A9981646401621
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2,3-dichlorophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and the reaction of 3-bromo pentane silane obtain (4S)-2-(2,3-dichlorophenyl imino-)-4-isobutyl--3-(3-amyl group)-1,3-thiazoles alkane.Entry 105
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and the reaction of 5-iodo heptane obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--3-(5-heptyl)-1,3-thiazoles alkane.Entry 106
Figure A9981646401631
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2,3-dichlorophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2,3-dichlorophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane.Entry 107
Figure A9981646401632
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1c, 2-(trifluoromethyl)-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction, obtain (4S)-2-(2-(trifluoromethyl)-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane trifluoroacetate.Entry 108
Figure A9981646401633
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1c, 2-(trifluoromethyl)-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-(trifluoromethyl)-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2f, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2-(trifluoromethyl)-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane trifluoroacetate.Entry 109
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1c, 4-cyano group-2-(trifluoromethyl) phenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(4-cyano group-2-(trifluoromethyl) phenylimino)-4-isobutyl--1,3-thiazoles alkane.According to method D2f, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-cyano group-2-(trifluoromethyl) phenylimino)-3,4-diisobutyl-1,3-thiazoles alkane trifluoroacetate.Entry 110
Figure A9981646401642
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1c, 2-chloro-4-cyano group-6-aminomethyl phenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-chloro-4-cyano group-6-aminomethyl phenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2f, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2-chloro-4-cyano group-6-aminomethyl phenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane trifluoroacetate.Entry 111
Figure A9981646401651
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 4-(methoxycarbonyl)-2-aminomethyl phenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(4-(methoxycarbonyl)-2-aminomethyl phenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-(methoxycarbonyl)-2-aminomethyl phenyl imino-)-3,4 diisobutyls-1,3-thiazoles alkane.Entry 112
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method A2a step 3,3,5-dimethyl-4-N-methyl-p-nitroaniline is converted into 3,5-dimethyl-4-nitrophenyl lsothiocyanates.According to method C1a, 3,5-dimethyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(3,5-dimethyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(3,5-dimethyl-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane.Entry 113
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 4-(methoxycarbonyl)-2-aminomethyl phenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(4-(methoxycarbonyl)-2-aminomethyl phenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-(methoxycarbonyl)-2-aminomethyl phenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane.According to method D6a step 1,, obtain (4S)-2-(4-carboxyl-2-aminomethyl phenyl imino-)-3 the thiazolidine saponification, 4-diisobutyl-1,3-thiazoles alkane.As described in method D6a step 2, should acid and ammonia coupling, obtain (4S)-2-(4-formamyl-2-aminomethyl phenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane.Entry 114
Figure A9981646401662
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 4-fluoro-2-aminomethyl phenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(4-fluoro-2-aminomethyl phenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-fluoro-2-aminomethyl phenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane.Entry 115
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 4-chloro-2-aminomethyl phenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(4-chloro-2-aminomethyl phenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-chloro-2-aminomethyl phenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane.Entry 116
Figure A9981646401672
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 4-bromo-2-aminomethyl phenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(4-bromo-2-aminomethyl phenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-bromo-2-aminomethyl phenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane.Entry 117
According to method C2a, (1S)-1-(hydroxymethyl)-3-methyl butyl amine and SOCl 2Reaction is reacted with 4-cyano group-2-ethylphenyl lsothiocyanates subsequently, obtains (4S)-2-(4-cyano group-2-ethylphenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-cyano group-2-ethylphenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane.Entry 118
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B4c, 2 hydroxy ethylamine is converted into (2S)-4-methyl-2-(isobutylamino) penta-1-alcohol.According to method B7c, the 2 hydroxy ethylamine that generates is converted into chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-N-(isobutyl-) ammonium.According to method C1b, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-reaction of N-(isobutyl-) ammonium, obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane.Entry 119
Figure A9981646401683
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B4c, 2 hydroxy ethylamine is converted into (2S)-4-methyl-2-(isobutylamino) penta-1-alcohol.According to method B7c, the 2 hydroxy ethylamine that generates is converted into chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-N-(isobutyl-) ammonium.According to method A2b, 4-amino-3-picoline is converted into 3-methyl-4-pyridyl isocyanic ester.According to method C1b, 3-methyl-4-pyridyl lsothiocyanates and chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-reaction of N-(isobutyl-) ammonium, obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane.Entry 120
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.According to method A2b, 4-nitro-naphthalidine is converted into 4-nitro-1-naphthyl lsothiocyanates.According to method C2a, 4-nitro-1-naphthyl lsothiocyanates with (1S)-1-(hydroxymethyl)-3-methylbutylamine reaction, obtain (4S)-2-(4-nitro-1-naphthyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-nitro-1-naphthyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane.Entry 121
Figure A9981646401692
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B4c, 2 hydroxy ethylamine is converted into (2S)-4-methyl-2-(isobutylamino) penta-1-alcohol.According to method B7c, the 2 hydroxy ethylamine that generates is converted into chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-N-(isobutyl-) ammonium.According to method C1f, 4-nitrophenyl isocyanic ester and chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-reaction of N-(isobutyl-) ammonium, obtain (4S)-2-(4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane.Entry 122
Figure A9981646401701
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B4c, 2 hydroxy ethylamine is converted into (2S)-4-methyl-2-(isobutylamino) penta-1-alcohol.According to method B7c, the 2 hydroxy ethylamine that generates is converted into chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-N-(isobutyl-) ammonium.According to method C1f, 4-cyano-phenyl isocyanic ester and chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-reaction of N-(isobutyl-) ammonium, obtain (4S)-2-(4-cyano-phenyl-imino)-3,4-diisobutyl-1,3-thiazoles alkane.Entry 123
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B4c, 2 hydroxy ethylamine is converted into (2S)-4-methyl-2-(isobutylamino) penta-1-alcohol.According to method B7c, the 2 hydroxy ethylamine that generates is converted into chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-N-(isobutyl-) ammonium.According to method A2b, 4-amino-3-picoline is converted into 3-methyl-4-pyridyl isocyanic ester.According to method C1b, 3-methyl-4-pyridyl lsothiocyanates and chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-reaction of N-(isobutyl-) ammonium, obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane.According to method D4a,, obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane 1-oxide compound with this thiazolidine oxidation.Entry 124
Figure A9981646401711
As described at method B7a, (1S, 2S)-1-(hydroxymethyl)-2-methyl butyl amine be converted into chlorination (1S, 2S)-1-(chloromethyl)-2-methyl fourth ammonium.According to method C1a, and 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S, 2S)-1-(chloromethyl)-2-methyl fourth ammonium reaction, obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-((2S)-2-butyl)-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-((2S)-2-butyl)-3-isobutyl--1,3-thiazoles alkane HCl salt.Entry 125
As described in method B1a step 2, from N-(tert.-butoxy formamyl)-(L)-other-Isoleucines prepare N-(tert.-butoxy formamyl)-(1S, 2R)-1-(hydroxymethyl)-2-methyl butyl amine.As described at method B7b, this carbamate be converted into chlorination (1S, 2R)-1-(chloromethyl)-2-methyl fourth ammonium.According to method C1e, and 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S, 2R)-1-(chloromethyl)-2-methyl fourth ammonium reaction, obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-((2R)-2-butyl)-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-((2R)-2-butyl)-3-isobutyl--1,3-thiazoles alkane HCl salt.Entry 126
Figure A9981646401721
According to method B1a step 2, from N-(tert.-butoxy formamyl)-(L)--Cyclohexylglycine prepares N-(tert.-butoxy formamyl)-(1S)-1-cyclohexyl-2-hydroxyethyl butylamine.According to method B1b, this carbamate and SOCl 2Reaction, and according to method C1a, the material of generation and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-cyclohexyl-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-cyclohexyl-3-isobutyl--1,3-thiazoles alkane HCl salt.Entry 127
As described at method B1b, from (L)-Isoleucine methyl esters preparation (1S)-1-(hydroxymethyl)-2-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium.According to method C1a, 4-methoxycarbonyl-2-aminomethyl phenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium reaction obtains (4S)-2-(4-methoxycarbonyl-2-aminomethyl phenyl imino-)-4-(2-butyl)-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-methoxycarbonyl-2-aminomethyl phenyl imino-)-4-(2-butyl)-3-isobutyl--1,3-thiazoles alkane.Entry 128
According to method B7a, (1S)-1-sec.-propyl-2 hydroxy ethylamine is converted into chlorination (1S)-2-chloro-1-sec.-propyl second ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-2-chloro-1-sec.-propyl second ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-sec.-propyl-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-sec.-propyl-3-isobutyl--1,3-thiazoles alkane HCl salt.Entry 129
As described at method B1b, from (L)-Isoleucine methyl esters preparation (1S)-1-(hydroxymethyl)-2-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium.According to method A2a, 5-amino-2,3-dihydro 1-Indanone is converted into 1-oxo-5-(2, the 3-indanyl) lsothiocyanates.According to method C1a, this lsothiocyanates and chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium reaction obtains (4S)-2-(1-oxo-5-(2, the 3-indanyl) imino-)-4-(2-butyl)-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(1-oxo-5-(2, the 3-indanyl) imino-)-4-(2-butyl)-3-isobutyl--1,3-thiazoles alkane.Entry 130
Figure A9981646401732
As described at method B1b, from (L)-Isoleucine methyl esters preparation (1S)-1-(hydroxymethyl)-2-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium.According to method A2a step 3,4-chloro-3-(trifluoromethyl) aniline is converted into 4-chloro-3-(trifluoromethyl) phenyl lsothiocyanates.According to method C1a, 4-chloro-3-(trifluoromethyl) phenyl lsothiocyanates and chlorination (1S)-(chloromethyl)-2-methyl fourth ammonium reaction obtains (4S)-2-(4-chloro-3-(trifluoromethyl) phenylimino)-4-(2-butyl)-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-chloro-3-(trifluoromethyl) phenylimino)-4-(2-butyl)-3-isobutyl--1,3-thiazoles alkane.Entry 131
Figure A9981646401741
As described at method B1b, from (L)-Isoleucine methyl esters preparation (1S)-1-(hydroxymethyl)-2-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium.According to method A2a step 3,4-cyano group-3-(trifluoromethyl) aniline is converted into 4-cyano group-3-(trifluoromethyl) phenyl lsothiocyanates.According to method C1a, this lsothiocyanates and chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium reaction obtains (4S)-2-(4-cyano group-3-(trifluoromethyl) phenylimino)-4-(2-butyl)-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-cyano group-3-(trifluoromethyl) phenylimino)-4-(2-butyl)-3-isobutyl--1,3-thiazoles alkane.Entry 132
As described at method B1b, from (L)-Isoleucine methyl esters preparation (1S)-1-(hydroxymethyl)-2-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium.According to method A2b, 4-nitro-naphthalidine is converted into 4-nitro-1-naphthyl lsothiocyanates.According to method C1a, 4-nitro-1-naphthyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium reaction obtains (4S)-2-(4-nitro-1-naphthyl imino-)-4-(2-butyl)-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-nitro-1-naphthyl imino-)-4-butyl-3-isobutyl--1,3-thiazoles alkane.Entry 133
As described at method B1b, from (L)-Isoleucine methyl esters preparation (1S)-1-(hydroxymethyl)-2-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium.According to method C1a, 4-cyano group-2-ethylphenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium reaction obtains (4S)-2-(4-cyano group-2-ethylphenyl imino-)-4-(2-butyl)-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-cyano group-2-ethylphenyl imino-)-4-butyl-3-isobutyl--1,3-thiazoles alkane.Entry 134
Figure A9981646401752
As described at method B1b, from (L)-Isoleucine methyl esters preparation (1S)-1-(hydroxymethyl)-2-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium.As described at method A1a, synthetic 4-cyano group-2-aminotoluene.As described in method A2a step 3, aniline is converted into 4-cyano group-2-aminomethyl phenyl lsothiocyanates.According to method C1a, 4-cyano group-2-aminomethyl phenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium reaction obtains (4S)-2-(4-cyano group-2-aminomethyl phenyl imino-)-4-(2-butyl)-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-cyano group-2-aminomethyl phenyl imino-)-4-butyl-3-isobutyl--1,3-thiazoles alkane.Entry 135
As described at method B1b, from (L)-Isoleucine methyl esters preparation (1S)-1-(hydroxymethyl)-2-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium.As described at method A1a, 2,5-dimethyl-4-nitrobenzonitrile is converted into 4-cyano group-2, the 5-xylidine.As described in method A2a step 3, this aniline is converted into 4-cyano group-2,5-3,5-dimethylphenyl lsothiocyanates.According to method C1a, 4-cyano group-2,5-3,5-dimethylphenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium reaction obtains (4S)-2-(4-cyano group-2,5-3,5-dimethylphenyl imino-)-4-(2-butyl)-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(4-cyano group-2,5-3,5-dimethylphenyl imino-)-4-butyl-3-isobutyl--1,3-thiazoles alkane.Entry 136
Figure A9981646401762
As described at method B1b, from (L)-Isoleucine methyl esters preparation (1S)-1-(hydroxymethyl)-2-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium.According to method A2a, with 2, the 5-xylidine is converted into 2,5-dimethyl-4-nitrophenyl lsothiocyanates.According to method C1a, 2,5-dimethyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-2-methyl fourth ammonium reaction obtains (4S)-2-(2,5-dimethyl-4-nitrophenyl imino-)-4-(2-butyl)-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2,5-dimethyl-4-nitrophenyl imino-)-4-butyl-3-isobutyl--1,3-thiazoles alkane.Entry 137
Figure A9981646401771
According to method C2a, (1R)-1-sec.-propyl-2 hydroxy ethylamine and SOCl 2Reaction is reacted with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtains (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-sec.-propyl-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-sec.-propyl-3-isobutyl--1,3-thiazoles alkane.Entry 138
Figure A9981646401772
According to method C2a, (1S)-1-sec.-propyl-2 hydroxy ethylamine and SOCl 2Reaction with 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-sec.-propyl-1,3-thiazoles alkane subsequently.According to method D2a, this thiazolidine and cyclopentyl bromide reaction obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-sec.-propyl-3-cyclopentyl-1,3-thiazoles alkane.Entry 139
According to method B7b, (1S)-1-benzyl-2 hydroxy ethylamine is converted into chlorination (1S)-2-chloro-1-benzyl ethyl ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-2-chloro-1-benzyl second ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-benzyl-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-benzyl-3-isobutyl--1,3-thiazoles alkane HCl salt.Entry 140
Figure A9981646401782
According to B7b, (1S)-1-phenyl-2 hydroxy ethylamine is converted into chlorination (1S)-2-chloro-1-phenylethyl ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-2-chloro-1-benzyl ethyl ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-phenyl-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-phenyl-3-isobutyl--1,3-thiazoles alkane HCl salt.Entry 141
As described at method B1b, prepare the 2-piperidine carbinols from the pipecolinic acid methyl esters.According to method B7a, 2 hydroxy ethylamine is converted into chlorination 2-chloromethyl piperidines.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and the reaction of chlorination 2-chloromethyl piperidines obtain 9-(2-methyl-4-nitrophenyl imino-)-1-azepine-8-thia dicyclo [4.3.0] nonane.Entry 142
Figure A9981646401791
As described at method B1b, prepare the 2-pyrrolidine carbinol from proline methyl ester.According to method B7a, 2 hydroxy ethylamine is converted into chlorination 2-chloromethyl tetramethyleneimine.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and the reaction of chlorination 2-chloromethyl tetramethyleneimine obtain 3-(2-methyl-4-nitrophenyl imino-)-2,5,6,7,7a-pentahydro--2-thia pyrroles mile piperazine (pyrrolizine).Entry 143
As described at method B1b, from (L)-L-Tyrosine methyl ester preparation (1S)-1-(4-hydroxy phenyl methyl)-2 hydroxy ethylamine.According to method B4c step 1,2 hydroxy ethylamine is converted into (4S)-2-sec.-propyl-4-(4-hydroxy phenyl methyl)-1, the 3-oxazolidine.According to method B4c step 2, Gai oxazolidine is reduced to N-((1S)-1-(4-hydroxy phenyl methyl)-2-hydroxyethyl)-N-isobutylamine.According to method B7c, use SOCl 2Handle the 2-hydroxyethyl amine that generates, obtain N-chlorination ((1S)-1-(4-hydroxy phenyl methyl)-2-chloroethyl)-N-isobutylamine.According to method C1b, 2-ethyl-4-cyano-phenyl lsothiocyanates and chlorination N-((1S)-1-(4-hydroxy phenyl methyl)-2-chloroethyl)-N-isobutyl-ammonium reaction, obtain (4S)-2-(2-ethyl-4-cyano-phenyl-imino)-4-(4-hydroxy phenyl methyl)-3-isobutyl--1,3-thiazoles alkane HCl salt.Entry 144
Figure A9981646401801
As described at method B1b, from (L)-4-chlorophenylalanine methyl esters preparation (1S)-1-(4-Chlorophenylmethyl)-2 hydroxy ethylamine.According to method B4c step 1,2 hydroxy ethylamine is converted into (4S)-2-sec.-propyl-4-(4-Chlorophenylmethyl)-1, the 3-oxazolidine.According to method B4c step 2, Gai oxazolidine is reduced to N-((1S)-1-(4-Chlorophenylmethyl)-2-hydroxyethyl)-N-isobutylamine.According to method B7c, use SOCl 2Handle the 2-hydroxyethyl amine that generates, obtain chlorination N-((1S)-1-(4-Chlorophenylmethyl)-2-chloroethyl)-N-isobutyl-ammonium.According to method C1b, 2-ethyl-4-cyano-phenyl lsothiocyanates and chlorination N-((1S)-1-(4-Chlorophenylmethyl)-2-chloroethyl)-N-isobutyl-ammonium reaction, obtain (4S)-2-(2-ethyl-4-cyano-phenyl-imino)-4-(4-Chlorophenylmethyl)-3-isobutyl--1,3-thiazoles alkane HCl salt.Entry 145
Figure A9981646401802
As described at method B1b, from (L)-S-benzyl acthiol-J preparation (1S)-1-(benzyl sulphomethyl)-2 hydroxy ethylamine.According to method B4c step 1,2 hydroxy ethylamine is converted into (4S)-2-sec.-propyl-4--(4-benzyl sulphomethyl)-1, the 3-oxazolidine.According to method B4c step 2, oxazolidine is reduced to N-((1S)-1-(benzyl sulphomethyl)-2-hydroxyethyl)-N-isobutylamine.According to method B7c, use SOCl 2Handle the 2-hydroxyethyl amine that generates, obtain chlorination N-((1S)-1-(benzyl sulphomethyl)-2-chloroethyl)-N-isobutyl-ammonium.According to method C1b, 2-ethyl-4-cyano-phenyl lsothiocyanates and chlorination N-((1S)-1-(benzyl sulphomethyl)-2-chloroethyl)-N-isobutyl-ammonium reaction, obtain (4S)-2-(2-ethyl-4-cyano-phenyl-imino)-4-(benzyl sulphomethyl)-3-isobutyl--1,3-thiazoles alkane HCl salt.Entry 146
Figure A9981646401811
As described at method B3a, from (D)-serine methylester preparation (R)-N-isobutyl-serine methylester HCl salt.According to method C2a, this ester and SOCl 2Reaction is reacted with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-(methoxycarbonyl)-3-isobutyl--1,3-thiazoles alkane HCl salt.Entry 147
Figure A9981646401812
As described at method B3a, from (L)-serine methylester preparation (S)-N-isobutyl-serine methylester HCl salt.According to method C2a, this ester and SOCl 2Reaction is reacted with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtains (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-(methoxycarbonyl)-3-isobutyl--1,3-thiazoles alkane HCl salt.Entry 148
Figure A9981646401821
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2-methyl-4-nitrophenyl lsothiocyanates reaction reacts with isobutyl bromide subsequently, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-isobutyl--1,3-thiazoles alkane.Entry 149
Figure A9981646401822
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2-methyl-4-nitrophenyl lsothiocyanates reaction reacts with cyclopentyl bromide subsequently, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 150
Figure A9981646401831
As described at method B8a, from (L)-(1S, 2S)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2S)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method C5b, chlorination (1R, 2S)-1-mesyloxy methyl)-reaction of 2-(tert.-butoxy) third ammonium and 2-methyl 4-nitrophenyl lsothiocyanates reacts with cyclopentyl bromide subsequently, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-((1S)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 151
Figure A9981646401832
As described at method B8a, from (L)-(1S, 2S)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2S)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method C5b, chlorination (1R, 2S)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2-methyl-4-nitrophenyl lsothiocyanates reaction reacts with isobutyl bromide subsequently, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-((1S)-1-tert.-butoxy ethyl)-3-isobutyl--1,3-thiazoles alkane.Entry 152
As described at method B8a, from (L)-(1S, 2S)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2S)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method C5b, chlorination (1R, 2S)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 4-cyano group-2-aminomethyl phenyl lsothiocyanates reaction reacts with cyclopentyl bromide subsequently, obtain (4R)-2-(4-cyano group-2-aminomethyl phenyl imino-)-4-((1S)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 153
Figure A9981646401842
As described at method B8a, from (L)-(1S, 2S)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2S)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, 4-nitro-naphthalidine is converted into 4-nitro-1-naphthyl lsothiocyanates.According to method C5b, chlorination (1R, 2S)-1-mesyloxy methyl)-reaction of 2-(tert.-butoxy) third ammonium and 4-nitro naphthyl lsothiocyanates reacts with isobutyl bromide subsequently, obtain (4R)-2-(4-nitro-1-naphthyl imino-)-4-((1S)-1-tert.-butoxy ethyl)-3-isobutyl--1,3-thiazoles alkane.Entry 154
Figure A9981646401851
As described at method B8a, from (L)-(1S, 2S)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2S)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, 4-nitro-naphthalidine is converted into 4-nitro-1-naphthyl lsothiocyanates.According to method C5b, chlorination (1R, 2S)-1-mesyloxy methyl)-reaction of 2-(tert.-butoxy) third ammonium and 4-nitro naphthyl lsothiocyanates reacts with cyclopentyl bromide subsequently, obtain (4R)-2-(4-nitro-1-naphthyl imino-)-4-((1S)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 155
Figure A9981646401852
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2a, with 1-amino-5,6,7, the 8-naphthane is converted into 4-nitro-5,6,7,8-naphthane-1-base lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 4-nitro-5,6,7,8-naphthane-1-base lsothiocyanates reaction is reacted with cyclopentyl bromide subsequently, obtain (4R)-2-(4-nitro-5,6,7,8-naphthane-1-base imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 156
Figure A9981646401861
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2a, with 1-amino-5,6,7, the 8-naphthane is converted into 4-nitro-5,6,7,8-naphthane-1-base lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 4-nitro-5,6,7,8-naphthane-1-base lsothiocyanates reaction is reacted with isobutyl bromide subsequently, obtain (4R)-2-(4-nitro-5,6,7,8-naphthane-1-base imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-isobutyl--1,3-thiazoles alkane.Entry 157
Figure A9981646401862
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2a, the 2-isopropyl aniline is converted into 2-sec.-propyl-4-nitrophenyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2-sec.-propyl-4-nitrophenyl lsothiocyanates reaction reacts with isobutyl bromide subsequently, obtain (4R)-2-(2-sec.-propyl-4-nitrophenyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-isobutyl--1,3-thiazoles alkane.Entry 158
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2a, the 2-isopropyl aniline is converted into 2-sec.-propyl-4-nitrophenyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2-sec.-propyl-4-nitrophenyl lsothiocyanates reaction reacts with cyclopentyl bromide subsequently, obtain (4R)-2-(2-sec.-propyl-4-nitrophenyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 159
Figure A9981646401872
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, with 2,3-dimethyl-4-N-methyl-p-nitroaniline is converted into 2,3-dimethyl-4-nitrophenyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2,3-dimethyl-4-nitrophenyl lsothiocyanates reaction is reacted with cyclopentyl bromide subsequently, obtain (4R)-2-(2,3-dimethyl-4-nitrophenyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 160
Figure A9981646401881
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, with 2,3-dimethyl-4-N-methyl-p-nitroaniline is converted into 2,3-dimethyl-4-nitrophenyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2,3-dimethyl-4-nitrophenyl lsothiocyanates reaction is reacted with isobutyl bromide subsequently, obtain (4R)-2-(2,3-dimethyl-4-nitrophenyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-isobutyl--1,3-thiazoles alkane.Entry 161
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, with 2,3-dimethyl-4-N-methyl-p-nitroaniline is converted into 2,3-dimethyl-4-nitrophenyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2,3-dimethyl-4-nitrophenyl lsothiocyanates reaction is reacted with 2-ethyl-1-butyl bromide subsequently, obtain (4R)-2-(2,3-dimethyl-4-nitrophenyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-(2-ethyl-1-butyl)-1,3-thiazoles alkane.Entry 162
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, with 1-amino-4-cyano group-5,6,7, the 8-naphthane is converted into 4-cyano group-5,6,7,8-tetralyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 4-cyano group-5,6,7, the reaction of 8-tetralyl lsothiocyanates is reacted with cyclopentyl bromide subsequently, obtain (4R)-2-(4-cyano group-5,6,7,8-tetralyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 163
Figure A9981646401892
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, with 1-amino-4-cyano group-5,6,7, the 8-naphthane is converted into 4-cyano group-5,6,7,8-tetralyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 4-cyano group-5,6,7, the reaction of 8-tetralyl lsothiocyanates is reacted with isobutyl bromide subsequently, obtain (4R)-2-(4-cyano group-5,6,7,8-tetralyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-isobutyl--1,3-thiazoles alkane.Entry 164
Figure A9981646401901
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2-methyl-4-nitrophenyl lsothiocyanates reaction reacts with isobutyl bromide subsequently, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-((1R)-1-tert.-butoxy)-3-isobutyl--1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-((1R)-1-hydroxyethyl)-3-isobutyl--1,3-thiazoles alkane.Entry 165
As described at method B8a, from (L)-(1S, 2S)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2S)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, 4-nitro-naphthalidine is converted into 4-nitro-1-naphthyl lsothiocyanates.According to method C5b, chlorination (1R, 2S)-1-mesyloxy methyl)-reaction of 2-(tert.-butoxy) third ammonium and 4-nitro naphthyl lsothiocyanates reacts with cyclopentyl bromide subsequently, obtain (4R)-2-(4-nitro-1-naphthyl imino-)-4-((1S)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(4-nitro-1-naphthyl imino-)-4-((1S)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 166
Figure A9981646401911
As described at method B8a, from (L)-(1S, 2S)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2S)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method C5b, chlorination (1R, 2S)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2-methyl-4-nitrophenyl lsothiocyanates reaction reacts with cyclopentyl bromide subsequently, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-((1S)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-((1S)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 167
Figure A9981646401912
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2-methyl-4-nitrophenyl lsothiocyanates reaction reacts with cyclopentyl bromide subsequently, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-((1R)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 168
Figure A9981646401921
As described at method B8a, from (L)-(1S, 2S)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2S)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method C5b, chlorination (1R, 2S)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2-methyl-4-nitrophenyl lsothiocyanates reaction reacts with cyclopentyl bromide subsequently, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-((1S)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-((1S)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 169
Figure A9981646401922
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, the 2-tertiary butyl-4-cyano-aniline is converted into the 2-tertiary butyl-4-cyano-phenyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and the 2-tertiary butyl-4-cyano-phenyl lsothiocyanates reaction reacts with cyclopentyl bromide subsequently, obtain (4R)-2-(the 2-tertiary butyl-4-cyano-phenyl-imino)-4-((1R)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(the 2-tertiary butyl-4-cyano-phenyl-imino)-4-((1R)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 170
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method bA2a, the 2-tertiary butyl-4-cyano-aniline is converted into the 2-tertiary butyl-4-cyano-phenyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and the 2-tertiary butyl-4-cyano-phenyl lsothiocyanates reaction reacts with isobutyl bromide subsequently, obtain (4R)-2-(the 2-tertiary butyl-4-cyano-phenyl-imino)-4-((1R)-1-tert.-butoxy ethyl)-3-isobutyl--1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(the 2-tertiary butyl-4-cyano-phenyl-imino)-4-((1R)-1-hydroxyethyl)-3-isobutyl--1,3-thiazoles alkane.Entry 171
Figure A9981646401932
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, 4-nitro-naphthalidine is converted into 4-nitro-1-naphthyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-reaction of 2-(tert.-butoxy) third ammonium and 4-nitro naphthyl lsothiocyanates reacts with cyclopentyl bromide subsequently, obtain (4R)-2-(4-nitro-1-naphthyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(4-nitro-1-naphthyl imino-)-4-((1R)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 172
Figure A9981646401941
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2a, with 1-amino-5,6,7, the 8-naphthane is converted into 4-nitro-5,6,7,8-naphthane-1-base lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 4-nitro-5,6,7,8-naphthane-1-base lsothiocyanates reaction is reacted with cyclopentyl bromide subsequently, obtain (4R)-2-(4-nitro-5,6,7,8-naphthane-1-base imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(4-nitro-5,6,7,8-naphthane-1-base imino-)-4-((1R)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 173
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2a, with 1-amino-5,6,7, the 8-naphthane is converted into 4-nitro-5,6,7,8-naphthane-1-base lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 4-nitro-5,6,7,8-naphthane-1-base lsothiocyanates reaction is reacted with isobutyl bromide subsequently, obtain (4R)-2-(4-nitro-5,6,7,8-naphthane-1-base imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-isobutyl--1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(4-nitro-5,6,7,8-naphthane-1-base imino-)-4-((1R)-1-hydroxyethyl)-3-isobutyl--1,3-thiazoles alkane.Entry 174
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2a, the 2-isopropyl aniline is converted into 2-sec.-propyl-4-nitrophenyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2-sec.-propyl-4-nitrophenyl lsothiocyanates reaction reacts with isobutyl bromide subsequently, obtain (4R)-2-(2-sec.-propyl-4-nitrophenyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-isobutyl--1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(2-sec.-propyl-4-nitrophenyl imino-)-4-((1R)-1-hydroxyethyl)-3-isobutyl--1,3-thiazoles alkane.Entry 175
Figure A9981646401952
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2a, the 2-isopropyl aniline is converted into 2-sec.-propyl-4-nitrophenyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2-sec.-propyl-4-nitrophenyl lsothiocyanates reaction reacts with cyclopentyl bromide subsequently, obtain (4R)-2-(2-sec.-propyl-4-nitrophenyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(2-sec.-propyl-4-nitrophenyl imino-)-4-((1R)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 176
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, with 2,3-dimethyl-4-N-methyl-p-nitroaniline is converted into 2,3-dimethyl-4-nitrophenyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2,3-dimethyl-4-nitrophenyl lsothiocyanates reaction is reacted with 2-ethyl-1-butyl bromide subsequently, obtain (4R)-2-(2,3-dimethyl-4-nitrophenyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-(2-ethyl-1-butyl)-1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(2,3-dimethyl-4-nitrophenyl imino-)-4-((1R)-1-hydroxyethyl)-3-(2-ethyl-1-butyl)-1,3-thiazoles alkane.Entry 177
Figure A9981646401962
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, with 2,3-dimethyl-4-N-methyl-p-nitroaniline is converted into 2,3-dimethyl-4-nitrophenyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2,3-dimethyl-4-nitrophenyl lsothiocyanates reaction is reacted with isobutyl bromide subsequently, obtain (4R)-2-(2,3-dimethyl-4-nitrophenyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-isobutyl--1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(2,3-dimethyl-4-nitrophenyl imino-)-4-((1R)-1-hydroxyethyl)-3-isobutyl--1,3-thiazoles alkane.Entry 178
Figure A9981646401971
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, with 2,3-dimethyl-4-N-methyl-p-nitroaniline is converted into 2,3-dimethyl-4-nitrophenyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 2,3-dimethyl-4-nitrophenyl lsothiocyanates reaction is reacted with cyclopentyl bromide subsequently, obtain (4R)-2-(2,3-dimethyl-4-nitrophenyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(2,3-dimethyl-4-nitrophenyl imino-)-4-((1R)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 179
Figure A9981646401972
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, with 1-amino-4-cyano group-5,6,7, the 8-naphthane is converted into 4-cyano group-5,6,7,8-tetralyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 4-cyano group-5,6,7, the reaction of 8-tetralyl lsothiocyanates is reacted with cyclopentyl bromide subsequently, obtain (4R)-2-(4-cyano group-5,6,7,8-tetralyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-cyclopentyl-1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(4-cyano group-5,6,7,8-tetralyl imino-)-4-((1R)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazoles alkane.Entry 180
As described at method B8a, from (L)-(1S, 2R)-N-(benzyloxycarbonyl)-O-tertiary butyl Threonine dicyclohexyl amine salt prepares chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium.According to method A2b, with 1-amino-4-cyano group-5,6,7, the 8-naphthane is converted into 4-cyano group-5,6,7,8-tetralyl lsothiocyanates.According to method C5b, chlorination (1R, 2R)-1-mesyloxy methyl)-2-(tert.-butoxy) third ammonium and 4-cyano group-5,6,7, the reaction of 8-tetralyl lsothiocyanates is reacted with isobutyl bromide subsequently, obtain (4R)-2-(4-cyano group-5,6,7,8-tetralyl imino-)-4-((1R)-1-tert.-butoxy ethyl)-3-isobutyl--1,3-thiazoles alkane.According to method D3a, tertbutyl ether is removed protection, obtain (4R)-2-(4-cyano group-5,6,7,8-tetralyl imino-)-4-((1R)-1-hydroxyethyl)-3-isobutyl--1,3-thiazoles alkane.Entry 181
Figure A9981646401991
According to method C2a, 2-amino-1, ammediol and excessive SOCl 2Reaction is reacted with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtains 2-(2-methyl-4-nitrophenyl imino-)-4-(chloromethyl)-1,3-thiazoles alkane.According to method D13a, this thiazolidine and the reaction of N-methylamine obtain 2-(2-methyl-4-nitrophenyl imino-)-4-(N-methylamino methyl)-1,3-thiazoles alkane.According to method D2a, it and isobutyl bromide react, and obtain 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-(N-isobutyl--N-methylamino methyl)-1,3-thiazoles alkane.Entry 182
According to method C2a, 2-amino-1, ammediol and excessive SOCl 2Reaction is reacted with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtains 2-(2-methyl-4-nitrophenyl imino-)-4-(chloromethyl)-1,3-thiazoles alkane.According to method D13a, this thiazolidine and dimethylamine reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-4-(N-isobutyl--N-methylamino methyl)-1,3-thiazoles alkane.According to method D2a, it and isobutyl bromide react, and obtain 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-(N, N-dimethylaminomethyl)-1,3-thiazoles alkane.Entry 183
Figure A9981646401993
According to method C2a, (L)-histidinol and SOCl 2Reaction is reacted with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-(1-(isobutyl-imidazolyl) methyl)-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-(1-(isobutyl-imidazolyl) methyl)-1,3-thiazoles alkane.Entry 184
Figure A9981646402001
According to method C2a, (L)-histidinol and SOCl 2Reaction is reacted with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-(1-(isobutyl-imidazolyl) methyl)-1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4S)-2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-(3-(isobutyl-imidazolyl) methyl)-1,3-thiazoles alkane.Entry 185
According to method B7a, 2-hydroxyl propylamine is converted into chlorination 2-chloropropyl ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and the reaction of chlorination 2-chloropropyl ammonium obtain 2-(2-methyl-4-nitrophenyl imino-)-5-methyl isophthalic acid, the 3-thiazolidine.According to method D2g, this thiazolidine and 2-methyl-prop-2-alkene-1-base bromine reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(2-methyl-prop-2-alkene-1-yl)-5-methyl isophthalic acid, 3-thiazolidine HBr salt.Entry 186
Figure A9981646402011
According to method B4c step 1,2-phenyl-2 hydroxy ethylamine and isobutyric aldehyde reaction obtain 2-sec.-propyl-5-phenyl-1, the 3-oxazolidine.According to method B4c step 2,, obtain N-isobutyl--2-phenyl-2 hydroxy ethylamine Jiang Gai oxazolidine reduction.According to method C2f, this thanomin and SOCl 2Reaction is reacted with 2-chloro-4-(trifluoromethyl) phenyl lsothiocyanates subsequently, obtains 2-(2-chloro-4-(trifluoromethyl) phenylimino)-3-isobutyl--5-phenyl-1,3-thiazoles alkane HCl salt.Entry 187
According to method B4c step 1,2-phenyl-2 hydroxy ethylamine and isobutyric aldehyde reaction obtain 2-sec.-propyl-5-phenyl-1, the 3-oxazolidine.According to method B4c step 2,, obtain N-isobutyl--2-phenyl-2 hydroxy ethylamine Jiang Gai oxazolidine reduction.According to method C2f, this thanomin and SOCl 2Reaction is subsequently with 2, and the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-3-isobutyl--5-phenyl-1,3-thiazoles alkane.Entry 188
According to method B4c step 1,3-phenyl-2-hydroxyl propylamine and isobutyric aldehyde reaction obtain 2-sec.-propyl-5-benzyl-1, the 3-oxazolidine.According to method B4c step 2,, obtain N-isobutyl--3-phenyl-2-hydroxyl propylamine Jiang Gai oxazolidine reduction.According to method C2f, this Propanolamine and SOCl 2Reaction is subsequently with 2, and the reaction of 3-chloro-phenyl-lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-3-isobutyl--5-benzyl-1,3-thiazoles alkane HCl salt.Entry 189
According to method B4c step 1,2-methyl-2-hydroxyl propylamine and hexanaphthene formaldehyde reaction obtain 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine.According to method B4c step 2,, obtain N-cyclohexyl-2-methyl-2-hydroxyl propylamine Jiang Gai oxazolidine reduction.According to method C2f, this Propanolamine and SOCl 2Reaction is subsequently with 2, and the reaction of 6-dichlorophenyl lsothiocyanates obtains 2-(2,6-dichlorophenyl imino-)-3-cyclohexyl-5,5-dimethyl-1,3-thiazoles alkane.Entry 190
Figure A9981646402022
According to method B5b, (1R)-1-cyclohexyl-1-ethylamine and 1,2-epoxy-2-methylpropane reaction obtains N-((1R)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl) amine.According to method C2f, N-((1R)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl) amine and SOCl 2Reaction is subsequently with 2, and the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-3-((1R)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazoles alkane HCl salt.Entry 191
Figure A9981646402031
According to method B5b, (1S)-1-cyclohexyl-1-ethylamine and 1,2-epoxy-2-methylpropane reaction obtains N-((1S)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl) amine.According to method C2f, N-((1S)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl) amine and SOCl 2Reaction is reacted with 2,4 dichloro benzene base lsothiocyanates subsequently, obtains 2-(2,4 dichloro benzene base imino-)-3-((1S)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazoles alkane HCl salt.Entry 192
Figure A9981646402032
According to method B5b, (1S)-1-cyclohexyl-1-ethylamine and 1,2-epoxy-2-methylpropane reaction obtains N-((1S)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl) amine.According to method C2f, N-((1S)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl) amine and SOCl 2Reaction is subsequently with 2, and the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-3-((1S)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazoles alkane HCl salt.Entry 193
Figure A9981646402041
According to method C2f, 2-methyl-2-hydroxypropyl amine and SOCl 2Reaction is subsequently with 2, and the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-5,5-dimethyl-1,3-thiazoles alkane.According to method B5b, 2-(2,3-dichlorophenyl imino-)-5,5-dimethyl-1,3-thiazoles alkane and reacting ethylene oxide obtains 2-(2,3-dichlorophenyl imino-)-5,5-dimethyl-1,3-thiazoles alkane HCl salt.Entry 194
Figure A9981646402042
According to method C1a, 2-methyl-2-hydroxypropyl amine and SOCl 2Reaction is reacted with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtains 2-(2-methyl-4-nitrophenyl imino-)-5,5-dimethyl-1,3-thiazoles alkane.Entry 195
Figure A9981646402043
According to method C1a, 2-methyl-2-hydroxypropyl amine and SOCl 2Reaction is reacted with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtains 2-(2-methyl-4-nitrophenyl imino-)-5,5-dimethyl-1,3-thiazoles alkane.According to method D2g, this thiazolidine and 2-methyl-prop-2-alkene-1-base bromine reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(2-methyl-prop-2-alkene-1-yl)-5,5-dimethyl-1,3-thiazoles alkane HBr salt.Entry 196
According to method C1a, 2-methyl-2-hydroxypropyl amine and SOCl 2Reaction is reacted with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtains 2-(2-methyl-4-nitrophenyl imino-)-5,5-dimethyl-1,3-thiazoles alkane.According to method D2g, this thiazolidine and isobutyl bromide reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--5,5-dimethyl-1,3-thiazoles alkane.Entry 197
Figure A9981646402052
According to method C1a, 2-methyl-2-hydroxypropyl amine and SOCl 2Reaction is subsequently with 2, and the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-5,5-dimethyl-1,3-thiazoles alkane.According to method D2g, this thiazolidine and isobutyl bromide reaction obtain 2-(2,3-dichlorophenyl imino-)-3-isobutyl--5,5-dimethyl-1,3-thiazoles alkane.Entry 198
According to method B4c step 1,2-methyl-2-hydroxyl propylamine and hexanaphthene formaldehyde reaction obtain 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine.According to method B4c step 2,, obtain N-cyclohexyl-2-methyl-2-hydroxyl propylamine Jiang Gai oxazolidine reduction.According to method C2f, this Propanolamine and SOCl 2Reaction is reacted with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtains 2-(2-methyl-4-nitrophenyl imino-)-3-cyclohexyl-5,5-dimethyl-1,3-thiazoles alkane.Entry 199
According to method B4c step 1,2-methyl-2-hydroxyl propylamine and hexanaphthene formaldehyde reaction obtain 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine.According to method B4c step 2,, obtain N-cyclohexyl-2-methyl-2-hydroxyl propylamine Jiang Gai oxazolidine reduction.According to method C2f, this Propanolamine and SOCl 2Reaction is subsequently with 2, and the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-3-cyclohexyl-5,5-dimethyl-1,3-thiazoles alkane.Entry 200
Figure A9981646402062
According to method B5b, (1R)-1-cyclohexyl-1-ethylamine and 1,2-epoxy-2-methylpropane reaction obtains N-((1R)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl) amine.According to method C2f, N-((1R)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl) amine and SOCl 2Reaction is reacted with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtains 2-(2-methyl-4-nitrophenyl imino-)-3-((1R)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazoles alkane HCl salt.Entry 201
Figure A9981646402071
According to method B5b, (1S)-1-cyclohexyl-1-ethylamine and 1,2-epoxy-2-methylpropane reaction obtains N-((1S)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl) amine.According to method C2f, N-((1S)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl) amine and SOCl 2Reaction is reacted with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtains 2-(2-methyl-4-nitrophenyl imino-)-3-((1S)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazoles alkane HCl salt.Entry 202
Figure A9981646402072
According to method B5b, isopropylamine and 1,2-epoxy-2-methylpropane reaction obtains N-sec.-propyl-N-(2,2-dimethyl-2-hydroxyethyl) amine.According to method C2f, N-sec.-propyl-N-(2,2-dimethyl-2-hydroxyethyl) amine and SOCl 2Reaction is reacted with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtains 2-(2-methyl-4-nitrophenyl imino-)-3-sec.-propyl-5,5-dimethyl-1,3-thiazoles alkane.Entry 203
Figure A9981646402073
According to method B5b, isopropylamine and 1,2-epoxy-2-methylpropane reaction obtains N-sec.-propyl-N-(2,2-dimethyl-2-hydroxyethyl) amine.According to method C2f, N-sec.-propyl-N-(2,2-dimethyl-2-hydroxyethyl) amine and SOCl 2Reaction is subsequently with 2, and the reaction of 3-dichlorophenyl lsothiocyanates obtains 2-(2,3-dichlorophenyl imino-)-3-sec.-propyl-5,5-dimethyl-1,3-thiazoles alkane.Entry 204
Figure A9981646402081
According to method B5b, isobutylamine and 1,2-epoxy-2-methylpropane reaction obtains N-isobutyl--N-(2,2-dimethyl-2-hydroxyethyl) amine.According to method C2f, N-isobutyl--N-(2,2-dimethyl-2-hydroxyethyl) amine and SOCl 2Reaction is reacted with 2,4 dichloro benzene base lsothiocyanates subsequently, obtains 2-(2,4 dichloro benzene base imino-)-3-isobutyl--5,5-dimethyl-1,3-thiazoles alkane HCl salt.Entry 205
Figure A9981646402082
According to method B7a, with 1,1-dimethyl-2-oxyamine is converted into chlorination 1,1-dimethyl-2-chloroethyl ammonium.According to method Cla, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination 1,1-dimethyl-2-chloroethyl ammonium reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-4,4-dimethyl-1,3-thiazoles alkane.According to method D2g, this thiazolidine and 2-methyl-prop-2-alkene-1-base bromine reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-4,4-dimethyl-3-(2-methyl-prop-2-alkene-1-yl)-1,3-thiazoles alkane HBr salt.Entry 206
Figure A9981646402091
According to method B1c step 1, the aminoisobutyric acid methyl esters is converted into aminoisobutyric acid methyl esters HCl salt.According to method B1c step 2, this ester is reduced to 3-hydroxy-2-methyl-2-propyl group amine.According to method B7b, use SOCl 2Handle this 2-hydroxyethyl amine,, handle, obtain 2-(2-methyl-4-nitrophenyl imino-)-4,4-dimethyl-1,3-thiazoles alkane with 2-methyl-3-nitro phenyl lsothiocyanates subsequently according to method C1a.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-4,4-dimethyl-3-isobutyl--1,3-thiazoles alkane.Entry 207
As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.As described at method B4a, synthetic 1-(cyclohexyl amino)-1-hydroxymethyl pentamethylene.According to method C2a, use SOCl 2Handle 2-hydroxyethyl amine and handle with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtain 3-cyclohexyl-2-(2-methyl-4-nitrophenyl imino-)-1-thia-3-azaspiro [4.4] nonane.Entry 208
Figure A9981646402101
According to method A2a step 1, the 2-ethylaniline is converted into 2-ethyl n-Acetanilide.According to method A2a step 2, this monoacetylaniline is converted into 2-ethyl-4-nitro monoacetylaniline.According to method A2a step 3, this monoacetylaniline is removed protection, obtain 2-ethyl-4-N-methyl-p-nitroaniline.According to method A2a step 3, this aniline is converted into 2-ethyl-4-nitrophenyl lsothiocyanates.As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7a, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1a, 2-chloro ethylamine and 2-ethyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-ethyl-4-nitrophenyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 3-cyclopentyl-2-(2-ethyl-4-nitrophenyl imino-)-1-thia-3-azaspiro [4.4] nonane.Entry 209
According to method A5a, 2-n-propyl aniline is converted into 4-iodo-2-n-propyl aniline.According to method A2b, this aniline is converted into 4-iodo-2-n-propyl phenyl lsothiocyanates.As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7a, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1a, 2-chloro ethylamine and 4-iodo-2-n-propyl phenyl lsothiocyanates reaction obtains 2-(4-iodo-2-n-propyl phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 3-cyclopentyl-2-(4-iodo-2-n-propyl phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D7a, these phenyl iodide and CuCN reaction obtain 3-cyclopentyl-2-(4-cyano group-2-n-propyl phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.Entry 210
According to method A5a, the 2-isopropyl aniline is converted into 4-iodo-2-isopropyl aniline.According to method A2b, this aniline is converted into 4-iodo-2-isopropyl phenyl lsothiocyanates.As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7a, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1a, 2-chloro ethylamine and 4-iodo-2-isopropyl phenyl lsothiocyanates reaction obtains 2-(4-iodo-2-isopropyl phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 3-cyclopentyl-2-(4-iodo-2-isopropyl phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D7a, these phenyl iodide and CuCN reaction obtain 3-cyclopentyl-2-(4-cyano group-2-isopropyl phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.Entry 211
Figure A9981646402121
According to method A5a, 2-tertiary butyl aniline is converted into 4-iodo-2-tertiary butyl aniline.According to method A2b, this aniline is converted into 4-iodo-2-tert-butyl-phenyl lsothiocyanates.As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7a, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1a, 2-chloro ethylamine and 4-iodo-2-tert-butyl-phenyl lsothiocyanates reaction obtains 2-(4-iodo-2-tert-butyl-phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 3-cyclopentyl-2-(4-iodo-2-tert-butyl-phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D7a, these phenyl iodide and CuCN reaction obtain 3-cyclopentyl-2-(4-cyano group-2-tert-butyl-phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.Entry 212
Figure A9981646402122
As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B4a step 1, this amino alcohol and the reaction of 2-methyl-cyclopentanone obtain 13-azepine-1-methyl-6-oxo two spiral shells [4.2.4.1] tridecane, and according to method B4a step 2, it uses NaBH 4Reduction obtains 1-(2-methylcyclopentyl) amino-1-(hydroxymethyl) pentamethylene.According to method C2a, 2-hydroxyethyl amine and SOCl 2Reaction with 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtains 3-(2-methylcyclopentyl)-2-(2-methyl-4-nitrophenyl imino-)-1-thia-3-azaspiro [4.4] nonane subsequently.Entry 213
As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7a, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1e, 2-chloro ethylamine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain 1-isobutyl--2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.Entry 214
Figure A9981646402132
According to method A2a step 1, the 2-ethylaniline is converted into 2-ethyl n-Acetanilide.According to method A2a step 2, this monoacetylaniline is converted into 2-ethyl-4-nitro monoacetylaniline.According to method A2a step 3, this monoacetylaniline is removed protection, obtain 2-ethyl-4-N-methyl-p-nitroaniline.According to method A2a step 3, this aniline is converted into 2-ethyl-4-nitrophenyl lsothiocyanates.As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7a, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1a, 2-chloro ethylamine and 2-ethyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-ethyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2a, thiazolidine and isobutyl bromide reaction obtain 1-isobutyl--2-(2-ethyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.Entry 215
Figure A9981646402141
According to method A2a step 1,2-n-propyl aniline is converted into 2-n-propyl monoacetylaniline.According to method A2a step 2, this monoacetylaniline is converted into 2-n-propyl-4-nitro monoacetylaniline.According to method A2a step 3, this monoacetylaniline is removed protection, obtain 2-n-propyl-4-N-methyl-p-nitroaniline.According to method A2a step 3, this aniline is converted into 2-n-propyl-4-nitrophenyl lsothiocyanates.As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7a, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1a, 2-chloro ethylamine and 2-n-propyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-n-propyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain 1-isobutyl--2-(2-n-propyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.Entry 216
According to method A2a step 1, the 2-isopropyl aniline is converted into 2-sec.-propyl monoacetylaniline.According to method A2a step 2, described monoacetylaniline is converted into 2-sec.-propyl-4-nitro monoacetylaniline.According to method A2a step 3, described monoacetylaniline is removed protection, obtain 2-sec.-propyl-4-N-methyl-p-nitroaniline.According to method A2a step 3, this aniline is converted into 2-sec.-propyl-4-nitrophenyl lsothiocyanates.As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7a, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1a, 2-chloro ethylamine and 2-sec.-propyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-sec.-propyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain 1-isobutyl--2-(2-sec.-propyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.Entry 217
Figure A9981646402151
As described at method A4a, Synthetic 2,3-dimethyl-4-N-methyl-p-nitroaniline.As described at method A2d, this aniline is converted into 2,3-dimethyl-4-nitrophenyl lsothiocyanates.As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.As described at method B7e, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1c, 2-chloro ethylamine and 2,3-dimethyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2,3-dimethyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain 1-isobutyl--2-(2-sec.-propyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.Entry 218
According to method A2a step 3,3-methyl-4-N-methyl-p-nitroaniline is converted into 3-methyl-4-nitrophenyl lsothiocyanates.As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7a, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1a, 2-chloro ethylamine and 3-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(3-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain 1-isobutyl--2-(3-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.Entry 219
Figure A9981646402161
According to method A2a step 1, with 1-amino-5,6,7, the 8-naphthane is converted into 1-acetylaminohydroxyphenylarsonic acid 5,6,7, the 8-naphthane.According to method A2a step 2, this monoacetylaniline is converted into 1-acetylaminohydroxyphenylarsonic acid 4-nitro-5,6,7,8-naphthane.According to method A2a step 3, this monoacetylaniline is removed protection, obtain 1-amino-4-nitro-5,6,7, the 8-naphthane.According to method A2a step 3, aniline is converted into 4-nitro-5,6,7,8-tetrahydrochysene-1-naphthyl lsothiocyanates.As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7a, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1a, 2-chloro ethylamine and 4-nitro-5,6,7,8-tetrahydrochysene-1-naphthyl lsothiocyanates reaction obtains 2-(4-nitro-5,6,7,8-tetrahydrochysene-1-naphthyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain 1-isobutyl--2-(4-nitro-5,6,7,8-tetrahydrochysene-1-naphthyl imino-)-3-thia-1-azaspiro [4.4] nonane.Entry 220
Figure A9981646402162
As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7e, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1a, 2-chloro ethylamine and the reaction of 4-cyano-phenyl lsothiocyanates obtain 2-(4-cyano-phenyl-imino)-3-thia-1-azaspiro [4.4] nonane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain 1-isobutyl--2-(4-cyano-phenyl-imino)-3-thia-1-azaspiro [4.4] nonane.Entry 221
Figure A9981646402171
As described at method A1a, synthetic 4-cyano group-2-aminotoluene.According to method A2a step 3, this aniline is converted into 4-cyano group-2-aminomethyl phenyl lsothiocyanates.As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7a, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1a, 2-chloro ethylamine and 4-cyano group-2-aminomethyl phenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-aminomethyl phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and isobutyl bromide reaction obtain 3-isobutyl--2-(4-iodo-2-aminomethyl phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.Entry 222
Figure A9981646402172
As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7a, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1a, 2-chloro ethylamine and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-aminomethyl phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and isobutyl bromide reaction obtain 3-isobutyl--2-(4-cyano group-2-aminomethyl phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.Entry 223
Figure A9981646402181
As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7a, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method A2a step 3,1-amino-4-cyano group naphthalene is converted into 4-cyano group-1-naphthyl lsothiocyanates.According to method C1a, 2-chloro ethylamine and 4-cyano group-1-naphthyl lsothiocyanates reaction obtains 2-(4-cyano group-1-naphthyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and isobutyl bromide reaction obtain 3-isobutyl--2-(4-cyano group-1-naphthyl imino-)-1-thia-3-azaspiro [4.4] nonane.Entry 224
According to method A5a, 23 dimethyl aniline is converted into 2,3-dimethyl-4-iodo aniline.According to method A2a step 3, this aniline is converted into 2,3-dimethyl-4-iodine substituted phenyl lsothiocyanates.As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7e, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method C1e, 2-chloro ethylamine and 2,3-dimethyl-4-iodine substituted phenyl lsothiocyanates reaction obtains 2-(2,3-dimethyl-4-iodine substituted phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D2h, this thiazolidine and isobutyl bromide reaction obtain 3-isobutyl--2-(4-iodo-2-n-propyl phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D7a, these phenyl iodide and CuCN reaction obtain 3-isobutyl--2-(2,3-dimethyl-4-cyano-phenyl-imino)-1-thia-3-azaspiro [4-4] nonane.Entry 225
Figure A9981646402191
According to method A5a, 23 dimethyl aniline is converted into 2,3-dimethyl-4-iodo aniline.According to method A2a step 3, this aniline is converted into 2,3-dimethyl-4-iodine substituted phenyl lsothiocyanates.As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method C2a, 2-hydroxyethyl amine and SOCl 2Reaction is subsequently with 2, and 3-dimethyl-4-iodine substituted phenyl lsothiocyanates reaction obtains 2-(2,3-dimethyl-4-iodine substituted phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain 3-isobutyl--2-(4-iodo-2-n-propyl phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D8a step 1, these phenyl iodide and trimethyl silyl acetylene reaction obtain 3-isobutyl--2-(2,3-dimethyl-4-(2-trimethyl silyl ethynyl) phenylimino)-1-thia-3-azaspiro [4.4] nonane.According to method D8a step 2, this silyl acetylene is removed protection, obtain 3-isobutyl--2-(2,3-dimethyl-4-ethynyl phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.Entry 226
According to method A5a, 23 dimethyl aniline is converted into 2,3-dimethyl-4-iodo aniline.According to method A2a step 3, this aniline is converted into 2,3-dimethyl-4-iodine substituted phenyl lsothiocyanates.As described at method B1c, synthetic 1-amino-1-(hydroxymethyl) pentamethylene.According to method B7e, 2-hydroxyethyl amine and SOCl 2Reaction obtains 1-amino-1-(chloromethyl) pentamethylene HCl salt.According to method Cle, 2-chloro ethylamine and 2,3-dimethyl-4-iodine substituted phenyl lsothiocyanates reaction obtains 2-(2,3-dimethyl-4-iodine substituted phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.According to method D2h, this thiazolidine and isobutyl bromide reaction obtain 3-isobutyl--2-(4-iodo-2-n-propyl phenyl imino-)-1-thia-3-azaspiro [4.4] nonane.Entry 227
Figure A9981646402201
According to method A4a, 23 dimethyl aniline is converted into 2,3-dimethyl-6-N-methyl-p-nitroaniline.According to method A2d, this aniline is converted into 2,3-dimethyl-6-nitrophenyl lsothiocyanates.According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 2,3-dimethyl-6-nitrophenyl lsothiocyanates reaction obtains 2-(2,3-dimethyl-6-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and isobutyl bromide reaction obtain 2-(2,3-dimethyl-6-nitrophenyl imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane.Entry 228
According to method A1a, 2-cyano group-5-nitrothiophene is reduced to 2-amino-5-cyano thiophene.According to method A2b, this aminothiophene is converted into 5-cyano group-1-thiophene lsothiocyanates.According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 5-cyano group-1-thiophene lsothiocyanates reaction obtains 2-(5-cyano thiophene base imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain 2-(5-cyano thiophene base imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane.Entry 229
Figure A9981646402211
According to method A2c, 6-amino-3-cyano group-2,3 dimethyl pyridine is converted into 3-cyano group-2,3-dimethyl-6-pyridyl lsothiocyanates.According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 3-cyano group-2,3-dimethyl-6-pyridyl lsothiocyanates reaction obtains 2-(3-cyano group-2,3-dimethyl-6-pyridyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2h, this thiazolidine and isobutyl bromide reaction obtain 2-(5-bromothiophene base imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane.Entry 230
Figure A9981646402212
According to method B1c, preparation 1-(hydroxymethyl) cyclopentamine.According to method C2a, the continuous and SOCl of 2-hydroxyethyl amine 2With 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2a, this thiazolidine and the reaction of 1-bromo-2-ethyl butane obtain 2-(2-methyl-4-nitrophenyl imino-)-1-(2-ethyl-1-butyl)-3-thia-1-azaspiro [4.4] nonane.Entry 231
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and the reaction of 3-bromo pentane silane obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-(3-amyl group)-3-thia-1-azaspiro [4.4] nonane.Entry 232
Figure A9981646402222
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2e, this thiazolidine and isopropyl bromide reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-1-(2-propyl group)-3-thia-1-azaspiro [4.4] nonane.Entry 233
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2e, this thiazolidine and the reaction of 3-bromo-2-methacrylic obtain 2-(2-methyl-4-nitrophenyl imino-)-1-(2-methyl-prop-1-alkene-3-yl)-3-thia-1-azaspiro [4.4] nonane.Entry 234
Figure A9981646402232
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2e, this thiazolidine and allyl bromide 98 reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-1-(third-1-alkene-3-yl)-3-thia-1-azaspiro [4.4] nonane.Entry 235
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2e, this thiazolidine and the reaction of cyclopropyl monobromomethane obtain 2-(2-methyl-4-nitrophenyl imino-)-1-(cyclopropyl methyl)-3-thia-1-azaspiro [4.4] nonane.Entry 236
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2e, this thiazolidine and cyclohexyl methyl bromine reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-1-(cyclohexyl methyl)-3-thia-1-azaspiro [4.4] nonane.Entry 237
Figure A9981646402251
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2e, this thiazolidine and 2-(brooethyl) tetrahydrochysene-2H-pyrans reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-1-(tetrahydrochysene-2H-pyrans-2-ylmethyl)-3-thia-1-azaspiro [4.4] nonane.Entry 238
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2e, this thiazolidine and 2-(2-bromotrifluoromethane)-1, the reaction of 3-diox obtains 2-(2-methyl-4-nitrophenyl imino-)-1-(2-(1,3-diox-2-yl) ethyl)-3-thia-1-azaspiro [4.4] nonane.Entry 239
Figure A9981646402261
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl phenylimino)-3-thia-1-azaspiro [4.4] nonane.According to method D2e, this thiazolidine and cyclobutyl bromine reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-1-cyclobutyl-3-thia-1-azaspiro [4.4] nonane.Entry 240
Figure A9981646402262
According to method B1c, preparation 1-(hydroxymethyl) cyclopentamine.According to method C2a, use SOCl 2Handle 2-hydroxyethyl amine and handle with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtain 2-(2-methyl-4-nitrophenyl phenylimino)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 241
Figure A9981646402263
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method C2a, use SOCl 2Handle 2-hydroxyethyl amine and handle with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtain 2-(2-methyl-4-nitrophenyl phenylimino)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-1-2-cyclopentyl-3-thia-1-azaspiro [4-4] nonane.According to method D4a,, obtain 2-(2-methyl-4-nitrophenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane-3-oxide compound with this thiazolidine of m-CPBA oxidation.Entry 242
Figure A9981646402271
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method C2a, use SOCl 2Handle 2-hydroxyethyl amine and handle with 2-methyl-4-nitrophenyl lsothiocyanates subsequently, obtain 2-(2-methyl-4-nitrophenyl phenylimino)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D4a,, obtain 2-(2-methyl-4-nitrophenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane-3, the 3-dioxide with this thiazolidine of m-CPBA oxidation.Entry 243
Figure A9981646402272
According to method A2a step 1, the protection of 2-ethylaniline is 2-ethyl n-Acetanilide.This ethanamide is converted into 2-ethyl-4-N-methyl-p-nitroaniline, removes protection according to method A2a step 2 subsequently.According to method A2a step 3, this aniline is converted into 2-ethyl-4-nitrophenyl lsothiocyanates.According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method Cle, 1-chloromethyl cyclopentamine HCl salt and 2-ethyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-ethyl-4-nitrophenyl phenylimino)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(2-ethyl-4-nitrophenyl phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 244
Figure A9981646402281
According to method A2a step 3,3-methyl-4-N-methyl-p-nitroaniline is converted into 3-methyl-4-nitrophenyl lsothiocyanates.According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 3-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(3-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(3-methyl-4-nitrophenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 245
Figure A9981646402282
According to method A2a step 1, be 2 with the 23 dimethyl aniline protection, 3-dimethyl monoacetylaniline.This ethanamide is converted into 2,3-dimethyl-4-N-methyl-p-nitroaniline, then, according to method A2a step 2 deprotection.According to method A2a step 3, this aniline is converted into 2 ,-dimethyl-4-nitrophenyl lsothiocyanates.According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 2,3-dimethyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2,3-dimethyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(2,3-dimethyl-4-nitrophenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 246
Figure A9981646402291
According to method A2a step 1, be 2 with the 23 dimethyl aniline protection, 3-dimethyl monoacetylaniline.This ethanamide is converted into 2, and 3-dimethyl-6-N-methyl-p-nitroaniline removes protection according to method A2a step 2 then.According to method A2a step 3, this aniline is converted into 2 ,-dimethyl-6-nitrophenyl lsothiocyanates.According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 2,3-dimethyl-6-nitrophenyl lsothiocyanates reaction obtains 2-(2,3-dimethyl-6-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(2,3-dimethyl-6-nitrophenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 247
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and the reaction of 4-iodine substituted phenyl lsothiocyanates obtain 2-(4-iodine substituted phenyl phenylimino)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-iodine substituted phenyl imino-)-1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D2h, these phenyl iodide and CuCN reaction obtain 2-(4-cyano-phenyl-imino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 248
Figure A9981646402301
According to method A1a, preparation 4-cyano group-2-aminotoluene.According to method A2b, this aniline is converted into 4-cyano group-2-aminomethyl phenyl lsothiocyanates.According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-aminomethyl phenyl lsothiocyanates reaction obtains 2-(4-cyano-phenyl phenylimino)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-cyano group-2-aminomethyl phenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 249
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 250
Figure A9981646402311
According to method A2b, 4-iodo-2-n-propyl aniline is converted into 4-iodo-2-n-propyl phenyl lsothiocyanates.According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method C2a, the continuous and SOCl of 2-hydroxyethyl amine 2With 4-iodo-2-n-propyl phenyl lsothiocyanates reaction, obtain 2-(4-iodo-2-n-propyl phenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-iodo-2-n-propyl phenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D7a, these phenyl iodide and CuCN reaction obtain 2-(4-cyano group-2-n-propyl phenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 251
Figure A9981646402312
According to method A2b, 4-iodo-2-isopropyl aniline is converted into 4-iodo-2-isopropyl phenyl lsothiocyanates.According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method C2a, the continuous and SOCl of 2-hydroxyethyl amine 2With 4-iodo-2-isopropyl phenyl lsothiocyanates reaction, obtain 2-(4-iodo-2-isopropyl phenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-iodo-2-isopropyl phenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D7a, these phenyl iodide and CuCN reaction obtain 2-(4-cyano group-2-isopropyl phenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 252
Figure A9981646402321
According to method A2b, 4-iodo-2 3 dimethyl aniline is converted into 4-iodo-2,3-3,5-dimethylphenyl lsothiocyanates.According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method C2a, the continuous and SOCl of 2-hydroxyethyl amine 2With 4-iodo-2, the reaction of 3-3,5-dimethylphenyl lsothiocyanates obtains 2-(4-iodo-2,3-3,5-dimethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-iodo-2,3-3,5-dimethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D7a, these phenyl iodide and CuCN reaction obtain 2-(4-cyano group-2,3-3,5-dimethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 253
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D9a,, obtain 2-(4-carboxyl-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane with this nitrile hydrolysis.Entry 254
Figure A9981646402331
According to method A1a, preparation 4-cyano group-2-aminotoluene.According to method A2b, this aniline is converted into 4-cyano group-2-aminomethyl phenyl lsothiocyanates.According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-aminomethyl phenyl lsothiocyanates reaction obtains 2-(4-cyano-phenyl phenylimino)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-cyano group-2-aminomethyl phenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D9a,, obtain 2-(4-carboxyl-2-aminomethyl phenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane with this nitrile hydrolysis.Entry 255
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D9a,, obtain 2-(4-carboxyl-2-ethylphenyl imino-)-1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane with this nitrile hydrolysis.According to method D10a, this phenylformic acid is converted into 2-(4-ethanoyl-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 256
Figure A9981646402341
According to method A2b, 4-amino-3-methyl-toluate is converted into 4-methoxycarbonyl-2-aminomethyl phenyl lsothiocyanates.According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method C2a, the continuous and SOCl of 2-hydroxyethyl amine 2With 4-methoxycarbonyl-2-aminomethyl phenyl lsothiocyanates reaction, obtain 2-(4-methoxycarbonyl-2-aminomethyl phenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2h, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-methoxycarbonyl-2-aminomethyl phenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 257
Figure A9981646402342
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D9a,, obtain 2-(4-carboxyl-2-ethylphenyl imino-)-1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane with this nitrile hydrolysis.According to method D6b, this phenylformic acid and methylamine reaction obtain 2-(4-(N-methylamino formyl radical)-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 258
Figure A9981646402351
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D9a,, obtain 2-(4-carboxyl-2-ethylphenyl imino-)-1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane with this nitrile hydrolysis.According to method D6b, this phenylformic acid and dimethylamine reaction obtain 2-(4-(N, N-formyl-dimethylamino)-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 259
Figure A9981646402352
According to method A3a step 1, with 2, the 3-dichlorphenamide bulk powder is converted into 2,3-dichloro formanilide.According to method A3a step 2, this formanilide is converted into 2,3-dichlorophenyl isocyanides dichloride.According to method B1c, synthetic 1-hydroxymethyl cyclopentamine HCl salt.According to method B4d step 1,2-hydroxyethyl amine is converted into 13-azepine-6-oxa-two spiral shells [4.2.4.1] tridecane.According to method B4d step 2,, obtain 1-(cyclopentyl amino)-1-(hydroxymethyl) pentamethylene Jiang Gai oxazolidine reductive ring open.According to method C6c step 1, the 2-hydroxyethyl amine of this replacement is converted into 1-(cyclopentyl amino)-1-(ethanoyl sulphomethyl) pentamethylene.According to method C6c step 2,, obtain 1-(cyclopentyl amino)-1-(sulphomethyl) pentamethylene with this thioacetate hydrolysis.According to method C6c, 2-thio-ethyl amine and 2, the reaction of 3-dichlorophenyl isocyanides dichloride obtains 2-(2,3-dichlorophenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 260
Figure A9981646402361
According to method A3a step 1,2-(trifluoromethyl) aniline is converted into 2-(trifluoromethyl) formanilide.According to method A3a step 2, this formanilide is converted into 2-(trifluoromethyl) phenyl isocyanides dichloride.According to method B1c, synthetic 1-hydroxymethyl cyclopentamine HCl salt.According to method B4d step 1,2-hydroxyethyl amine is converted into 13-azepine-6-oxa-two spiral shells [4.2.4.1] tridecane.According to method B4d step 2,, obtain 1-(cyclopentyl amino)-1-(hydroxymethyl) pentamethylene Jiang Gai oxazolidine reductive ring open.According to method C6c step 1, the 2-hydroxyethyl amine that replaces is converted into 1-(cyclopentyl amino)-1-(thioacetyl ylmethyl) pentamethylene.According to method C6c step 2,, obtain 1-(cyclopentyl amino)-1-(sulphomethyl) pentamethylene with this thioacetate hydrolysis.According to method C6c, the reaction of 2-thio-ethyl amine and 2-(trifluoromethyl) phenyl isocyanides dichloride obtains 2-(2-(trifluoromethyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 261
Figure A9981646402371
According to method A3a step 1,4-(trifluoromethyl) aniline is converted into 4-(trifluoromethyl) formanilide.According to method A3a step 2, this formanilide is converted into 4-(trifluoromethyl) phenyl isocyanides dichloride.According to method B1c, synthetic 1-hydroxymethyl cyclopentamine HCl salt.According to method B4d step 1,2-hydroxyethyl amine is converted into 13-azepine-6-oxa-two spiral shells [4.2.4.1] tridecane.According to method B4d step 2,, obtain 1-(cyclopentyl amino)-1-(hydroxymethyl) pentamethylene Jiang Gai oxazolidine reductive ring open.According to method C6c step 1, the 2-hydroxyethyl amine that replaces is converted into 1-(cyclopentyl amino)-1-(thioacetyl ylmethyl) pentamethylene.According to method C6c step 2,, obtain 1-(cyclopentyl amino)-1-(sulphomethyl) pentamethylene with this thioacetate hydrolysis.According to method C6c, the reaction of 2-thio-ethyl amine and 4-(trifluoromethyl) phenyl isocyanides dichloride obtains 2-(4-(trifluoromethyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 262
Figure A9981646402372
According to method A3a step 1,2-chloro-3-monomethylaniline is converted into 2-chloro-3-methyl N-formylaniline.According to method A3a step 2, this formanilide is converted into 2-chloro-3-aminomethyl phenyl isocyanides dichloride.According to method B1c, synthetic 1-hydroxymethyl cyclopentamine HCl salt.According to method B4d step 1,2-hydroxyethyl amine is converted into 13-azepine-6-oxa-two spiral shells [4.2.4.1] tridecane.According to method B4d step 2,, obtain 1-(cyclopentyl amino)-1-(hydroxymethyl) pentamethylene Jiang Gai oxazolidine reductive ring open.According to method C6c step 1, the 2-hydroxyethyl amine that replaces is converted into 1-(cyclopentyl amino)-1-(thioacetyl ylmethyl) pentamethylene.According to method C6c step 2,, obtain 1-(cyclopentyl amino)-1-(sulphomethyl) pentamethylene with this thioacetate hydrolysis.According to method C6c, 2-thio-ethyl amine and the reaction of 2-chloro-3-aminomethyl phenyl isocyanides dichloride obtain 2-(2-chloro-3-aminomethyl phenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 263
Figure A9981646402381
According to method A3a step 1,3-(trifluoromethyl) aniline is converted into 3-(trifluoromethyl) formanilide.According to method A3a step 2, this formanilide is converted into 3-(trifluoromethyl) phenyl isocyanides dichloride.According to method B1c, synthetic 1-hydroxymethyl cyclopentamine HCl salt.According to method B4d step 1,2-hydroxyethyl amine is converted into 13-azepine-6-oxa-two spiral shells [4.2.4.1] tridecane.According to method B4d step 2,, obtain 1-(cyclopentyl amino)-1-(hydroxymethyl) pentamethylene Jiang Gai oxazolidine reductive ring open.According to method C6c step 1, the 2-hydroxyethyl amine that replaces is converted into 1-(cyclopentyl amino)-1-(thioacetyl ylmethyl) pentamethylene.According to method C6c step 2,, obtain 1-(cyclopentyl amino)-1-(sulphomethyl) pentamethylene with the thioacetate hydrolysis.According to method C6c, the reaction of 2-thio-ethyl amine and 3-(trifluoromethyl) phenyl isocyanides dichloride obtains 2-(3-(trifluoromethyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 265
According to method A3a step 1,3-chloro-2-aminotoluene is converted into 3-chloro-2-methyl N-formylaniline.According to method A3a step 2, this formanilide is converted into 3-chloro-2-aminomethyl phenyl isocyanides dichloride.According to method B1c, synthetic 1-hydroxymethyl cyclopentamine HCl salt.According to method B4d step 1,2-hydroxyethyl amine is converted into 1 3-azepine-6-oxa-two spiral shells [4.2.4.1] tridecane.According to method B4d step 2,, obtain 1-(cyclopentyl amino)-1-(hydroxymethyl) pentamethylene Jiang Gai oxazolidine reductive ring open.According to method C6c step 1, the 2-hydroxyethyl amine that replaces is converted into 1-(cyclopentyl amino)-1-(thioacetyl ylmethyl) pentamethylene.According to method C6c step 2,, obtain 1-(cyclopentyl amino)-1-(sulphomethyl) pentamethylene with this thioacetate hydrolysis.According to method C6c, 2-thio-ethyl amine and the reaction of 3-chloro-2-aminomethyl phenyl isocyanides dichloride obtain 2-(3-chloro-2-aminomethyl phenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 265
According to method A3a step 1, with 2,3-two chloro-4-monomethylanilines are converted into 2,3-two chloro-4-methyl N-formylanilines.According to method A3a step 2, this formanilide is converted into 2,3-two chloro-4-aminomethyl phenyl isocyanides dichloride.According to method B1c, synthetic 1-hydroxymethyl cyclopentamine HCl salt.According to method B4d step 1,2-hydroxyethyl amine is converted into 13-azepine-6-oxa-two spiral shells [4.2.4.1] tridecane.According to method B4d step 2,, obtain 1-(cyclopentyl amino)-1-(hydroxymethyl) pentamethylene Jiang Gai oxazolidine reductive ring open.According to method C6c step 1, the 2-hydroxyethyl amine that replaces is converted into 1-(cyclopentyl amino)-1-(thioacetyl ylmethyl) pentamethylene.According to method C6c step 2,, obtain 1-(cyclopentyl amino)-1-(sulphomethyl) pentamethylene with this thioacetate hydrolysis.According to method C6c, 2-thio-ethyl amine and 2, the reaction of 3-two chloro-4-aminomethyl phenyl isocyanides dichloride obtains 2-(2,3-two chloro-4-aminomethyl phenyl imino-s)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 266
Figure A9981646402401
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method C2a, the continuous and SOCl of 2-hydroxyethyl amine 2With the reaction of 4-bromo-2-aminomethyl phenyl lsothiocyanates, obtain 2-(4-bromo-2-aminomethyl phenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-bromo-2-aminomethyl phenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 267
Figure A9981646402402
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D11a,, obtain 2-(4-formyl radical-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane with this nitrile reduction.Entry 268
Figure A9981646402403
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D11a,, obtain 2-(4-formyl radical-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane with this nitrile reduction.According to method D12a, this aldehyde and the reaction of phosphonic acids acetate triethyl ester obtain 2-(2-ethyl-4-((1E)-2-ethoxy carbonyl vinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 269
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D11a,, obtain 2-(4-formyl radical-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane with this nitrile reduction.According to method D12b, this aldehyde and Nitromethane 99Min. reaction obtain 2-(2-ethyl-4-((1E)-2-nitroethylene base) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 270
Figure A9981646402421
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D11a,, obtain 2-(4-formyl radical-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane with this nitrile reduction.According to method D12a, this aldehyde and the reaction of phosphonic acids acetate triethyl ester obtain 2-(2-ethyl-4-((1E)-2-ethoxy carbonyl vinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D6a,, obtain 2-(2-ethyl-4-((1E)-2-carboxy vinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane with this ester saponification.Entry 271
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D11a,, obtain 2-(4-formyl radical-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane with this nitrile reduction.According to method D12c, this aldehyde and propane dinitrile reaction obtain 2-(2-ethyl-4-(2,2-dicyano vinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 272
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D11a,, obtain 2-(4-formyl radical-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane with this nitrile reduction.According to method D12a, this aldehyde and diethyl (2-oxopropyl) phosphonate reaction obtains 2-(2-ethyl-4-((1E)-2-ethanoyl vinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 273
Figure A9981646402432
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method B7e, 2-hydroxyethyl amine is converted into 1-chloromethyl cyclopentamine HCl salt.According to method C1e, 1-chloromethyl cyclopentamine HCl salt and 4-cyano group-2-ethylphenyl lsothiocyanates reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2b, this thiazolidine and cyclopentyl bromide reaction obtain 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.According to method D11a,, obtain 2-(4-formyl radical-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane with this nitrile reduction.According to method D12d, this aldehyde and acetonitrile reaction obtain 2-(2-ethyl-4-((1E)-2-cyano group vinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.Entry 274
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method C2a, the continuous and SOCl of 2-hydroxyethyl amine 2With 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2e, this thiazolidine and cyclohexyl bromide reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-1-cyclohexyl-3-thia-1-azaspiro [4.4] nonane.Entry 275
According to method B1c, preparation 1-hydroxymethyl cyclopentamine.According to method C2a, the continuous and SOCl of 2-hydroxyethyl amine 2With 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.4] nonane.According to method D2e, this thiazolidine and suberyl bromine reaction obtain 2-(2-methyl-4-nitrophenyl imino-)-1-suberyl-3-thia-1-azaspiro [4.4] nonane.Entry 276
Figure A9981646402451
According to method B1a step 1,1-aminocyclohexane-1-carboxylic acid protection is benzyloxycarbonyl amine.According to method B1a step 2,1-(benzyloxycarbonyl amino) hexanaphthene-1-carboxylic acid is reduced to 1-(benzyloxycarbonyl amino)-1-(hydroxymethyl) hexanaphthene.According to method B1a step 3, this carbamate is removed protection, obtain 1-amino-1-(hydroxymethyl) hexanaphthene.According to method C2a, the continuous and SOCl of 2-hydroxyethyl amine 2With 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-thia-1-azaspiro [4.5] decane.According to method D2b, with this thiazolidine alkylation, obtain 2-(2-methyl-4-nitrophenyl imino-)-1-isobutyl--3-thia-1-azaspiro [4.5] decane with isobutyl bromide.Entry 277
Figure A9981646402452
According to method A3a step 1,2-methyl-4-N-methyl-p-nitroaniline is converted into 2-methyl-4-nitro formanilide.According to method A3a step 2, this formanilide is converted into 2-methyl-4-nitrophenyl isocyanides dichloride.According to method B1b step 1, the amino tetrahydrochysene of 3--2H-pyrans-3-carboxylic acid is converted into methyl esters.According to method B1b step 2, the amino tetrahydrochysene of 3--2H-pyrans-3-carboxylate methyl ester is reduced to 3-amino-3-(hydroxymethyl) tetrahydrochysene-2H-pyrans.According to method B4c step 1,2-hydroxyethyl amine and isobutyric aldehyde reaction obtain 2-sec.-propyl-1-azepine-3,7-dioxo spiro [4.51 decane.Gai oxazolidine is reduced to 3-isobutylamino-3-(hydroxymethyl) tetrahydrochysene-2H-pyrans.According to method C6c step 1, the 2-hydroxyethyl amine that replaces is converted into 3-isobutylamino-3-(ethanoyl sulphomethyl) tetrahydrochysene-2H-pyrans.According to method C6c step 2,, obtain 3-isobutylamino-3-(sulphomethyl) tetrahydrochysene-2H-pyrans with this thioacetate saponification.2-thio-ethyl amine and 2-methyl-4-nitrophenyl isocyanides dichloride reaction obtains 2-(2-methyl-4-nitrophenyl imino--1-isobutyl--1-azepine-7-oxa--3-thia spiral shell [4.5] decane.Entry 278
According to method A3a step 1,2-methyl-4-N-methyl-p-nitroaniline is converted into 2-methyl-4-nitro formanilide.According to method A3a step 2, this formanilide is converted into 2-methyl-4-nitrophenyl isocyanides dichloride.According to method B1b step 1, the amino tetrahydrochysene of 4--2H-pyrans-4-carboxylic acid is converted into methyl esters.According to method B1b step 2, the amino tetrahydrochysene of 4--2H-pyrans-4-carboxylate methyl ester is reduced to 4-amino-4-(hydroxymethyl) tetrahydrochysene-2H-pyrans.According to method B4c step 1,2-hydroxyethyl amine and isobutyric aldehyde reaction obtain 2-sec.-propyl-1-azepine-3,8-dioxo spiro [4.5] decane.Gai oxazolidine is reduced to 4-isobutylamino-4-(hydroxymethyl) tetrahydrochysene-2H-pyrans.According to method C6c step 1, the 2-hydroxyethyl amine that replaces is converted into 4-isobutylamino-4-(ethanoyl sulphomethyl) tetrahydrochysene-2H-pyrans.According to method C6c step 2,, obtain 4-isobutylamino-4-(sulphomethyl) tetrahydrochysene-2H-pyrans with the thioacetate saponification.2-thio-ethyl amine and 2-methyl-4-nitrophenyl isocyanides dichloride reaction obtains 2-(2-methyl-4-nitrophenyl imino--1-isobutyl--1-azepine-8-oxa--3-thia spiral shell [4.5] decane.Entry 279
According to method B1a step 1, will be converted into N-benzyloxycarbonyl analogue as the 2-amino-2-norbornane-1-carboxylic acid of isomer mixture.According to method B1a step 2,1-(benzyloxycarbonyl amino)-2-norbornane-1-carboxylic acid is reduced to 1-(benzyloxycarbonyl amino)-1-(hydroxymethyl)-2-norbornane.According to method B1a step 3, this carbamate is removed protection, obtain 1-amino-1-(hydroxymethyl)-2-norbornane.According to method B2a, with 2-hydroxyethyl amino-alkylation, obtain N-isobutyl--1-amino-1-(hydroxymethyl)-2-norbornane with isobutyl bromide.According to method B7a, use SOCl 2Handle alkylating 2-hydroxyethyl amine, obtain N-isobutyl--2-chloro ethylamine HCl salt.According to method C1a, handle chloroethyl amine with 2-methyl-4-nitrophenyl lsothiocyanates, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl-spiral shell [1,3-thiazoles alkane-4,3 '-dicyclo [3.2.1] octane].Entry 280
Figure A9981646402471
According to method B6a step 1, N-(tert-butoxycarbonyl)-(L)-Xie Ansuan is converted into (S)-3-(tert-butoxycarbonyl amino)-1-diazo-4-methylpenta-2-one.According to method B6a step 2, this diazonium compound is converted into (R)-3-(tert-butoxycarbonyl amino)-4-methylvaleric acid methyl esters.According to method B6a step 3,, obtain (R)-3-(tert-butoxycarbonyl amino)-4-methyl amyl alcohol with this ester reduction.According to method B7e, this carbamate is removed protection and is converted into (R)-3-amino-1-chlorine 4-methylpentane.According to method C2a, handle 3-chloropropyl amine with 2-methyl-4-nitrophenyl lsothiocyanates, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-4-sec.-propyl-1, the 3-thiazine.According to method D2a, with this thiazine alkylation, obtain (4R)-2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-sec.-propyl-1,3-thiazine HCl salt with isobutyl bromide.Entry 281
Figure A9981646402472
According to method B9a step 1,3-aminopropanol and butyraldehyde reaction obtain 2-sec.-propyl tetrahydrochysene 1, the 3-oxazine.According to method B9a step 2,, obtain N-isobutyl--3-hydroxypropyl amine Jiang Gai oxazine reduction.According to method B9a step 3, make 3-hydroxypropyl amine and SOCl 2Reaction obtains N-isobutyl--3-chloropropyl amine HCl salt.According to method C1a, 3-chloropropyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl-tetrahydrochysene-1, the 3-thiazine.Entry 282
According to method B9a step 1,4-amino butanol and butyraldehyde reaction obtain 2-sec.-propyl tetrahydrochysene 1,3-oxygen azatropylidene (oxazepine).According to method B9a step 2, with 1, the reduction of 3-oxygen azatropylidene obtains N-isobutyl--3-hydroxybutyl amine.According to method B9a step 3, make 3-hydroxybutyl amine and SOCl 2Reaction obtains N-isobutyl--3-chlorobutyl amine HCl salt.According to method C1a, 3-chlorobutyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl-tetrahydrochysene-1,3-sulphur azatropylidene (thiazepine).Entry 283
Figure A9981646402482
According to method C8a, the reaction of 3-methyl-4-nitrophenyl lsothiocyanates and isobutylamine subsequently with chloroacetate reaction, obtain 2-(3-methyl-4-nitrophenyl imino-)-3-isobutyl--1,3-thiazoles alkane-4-ketone.Entry 284
According to method C8a, the reaction of 3-methyl-4-nitrophenyl lsothiocyanates and benzyl amine subsequently with chloroacetate reaction, obtain 2-(3-methyl-4-nitrophenyl imino-)-3-(phenyl methyl)-1,3-thiazoles alkane-4-ketone.Entry 285
Figure A9981646402492
According to method C8a, the reaction of 3-methyl-4-nitrophenyl lsothiocyanates and 2-methyl-1-butene base amine subsequently with chloroacetate reaction, obtain 2-(3-methyl-4-nitrophenyl imino-)-3-(2-methyl butyl)-1,3-thiazoles alkane-4-ketone.Entry 286
According to method C8a, the reaction of 3-methyl-4-nitrophenyl lsothiocyanates and 1-amino-1-cyclohexyl ethane subsequently with chloroacetate reaction, obtain 2-(3-methyl-4-nitrophenyl imino-)-3-(1-cyclohexyl ethyl)-1,3-thiazoles alkane-4-ketone.Entry 287
According to method C8a, the reaction of 2-methyl-4-nitrophenyl lsothiocyanates and isobutylamine subsequently with chloroacetate reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--1,3-thiazoles alkane-4-ketone.Entry 288
Figure A9981646402502
According to method C8a, the reaction of 2-methyl-4-nitrophenyl lsothiocyanates and 2-methyl-1-butene base amine subsequently with chloroacetate reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(2-methyl butyl)-1,3-thiazoles alkane-4-ketone.Entry 289
Figure A9981646402503
According to method C8a, the reaction of 2-methyl-4-nitrophenyl lsothiocyanates and benzyl amine subsequently with chloroacetate reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(phenyl methyl)-1,3-thiazoles alkane-4-ketone.Entry 290
Figure A9981646402511
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates and isobutylamine reaction are reacted with α-Lv Bingsuan subsequently, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--5-methyl isophthalic acid, the 3-thiazolidin-4-one.Entry 291
Figure A9981646402512
According to method C8a, the reaction of 2-methyl-4-nitrophenyl lsothiocyanates and 1-amino-1-cyclohexyl ethane subsequently with chloroacetate reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(1-cyclohexyl ethyl)-1,3-thiazoles alkane-4-ketone.Entry 292
Figure A9981646402513
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates with (1S)-reaction of 1-amino-1-cyclohexyl ethane subsequently with chloroacetate reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-((1S)-1-cyclohexyl ethyl)-1,3-thiazoles alkane-4-ketone.Entry 293
Figure A9981646402521
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates with (1R)-reaction of 1-amino-1-cyclohexyl ethane subsequently with chloroacetate reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-((1R)-1-cyclohexyl ethyl)-1,3-thiazoles alkane-4-ketone.Entry 294
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates and isobutylamine reaction are reacted with α-chloro-α-phenylacetic acid subsequently, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--5-phenyl-1,3-thiazoles alkane-4-ketone.Entry 295
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates with (1R)-reaction of 1-amino-1-cyclohexyl ethane reacts with α-Lv Bingsuan subsequently, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-((1R)-1-cyclohexyl ethyl)-5-methyl isophthalic acid, the 3-thiazolidin-4-one.Entry 296
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates with (1R)-reaction of 1-amino-1-cyclohexyl ethane subsequently with α-chloro-α-phenylacetic acid reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-((1R)-1-cyclohexyl ethyl)-5-phenyl-1,3-thiazoles alkane-4-ketone.Entry 297
Figure A9981646402532
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates with (1S)-reaction of 1-amino-1-cyclohexyl ethane reacts with α-Lv Bingsuan subsequently, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-((1S)-1-cyclohexyl ethyl)-5-methyl isophthalic acid, the 3-thiazolidin-4-one.Entry 298
Figure A9981646402533
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates with (1S)-reaction of 1-amino-1-cyclohexyl ethane subsequently with α-chloro-α-phenylacetic acid reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-((1S)-1-cyclohexyl ethyl)-5-phenyl-1,3-thiazoles alkane-4-ketone.Entry 299
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates and 2-ethyl-1-butylamine reaction is reacted with α-Lv Bingsuan subsequently, obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(2-ethyl-1-butyl)-5-methyl isophthalic acid, the 3-thiazolidin-4-one.Entry 300
Figure A9981646402542
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates and isobutylamine reaction are reacted with 2-chloro-4-methylvaleric acid subsequently, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--5-isobutyl--1,3-thiazoles alkane-4-ketone.Entry 301
Figure A9981646402543
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates and 2-ethyl-1-butylamine reaction is reacted with 2-chloro-4-methylvaleric acid subsequently, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--5-(2-ethyl-1-butyl)-1,3-thiazoles alkane-4-ketone.Entry 302
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates and the reaction of 2-methyl butyl amine are reacted with 2-chloro-4-methylvaleric acid subsequently, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(2-butyl)-5-isobutyl--1,3-thiazoles alkane-4-ketone.Entry 303
Figure A9981646402552
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates and the reaction of 2-methyl butyl amine are reacted with 2-chloro-3 Methylbutanoic acid subsequently, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(2-butyl)-5-sec.-propyl-1,3-thiazoles alkane-4-ketone.Entry 304
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates and isobutylamine reaction are reacted with 2-chloro-3 Methylbutanoic acid subsequently, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--5-sec.-propyl-1,3-thiazoles alkane-4-ketone.Entry 305
Figure A9981646402561
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates with (2S)-2-methyl-1-butene base amine reaction subsequently with chloroacetate reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-((2S)-2-methyl-1-butene base)-1,3-thiazoles alkane-4-ketone.Entry 306
Figure A9981646402562
According to method C8a, 2-methyl-4-nitrophenyl lsothiocyanates and 2-ethyl-1-butylamine reaction is reacted with 2-chloro-3 Methylbutanoic acid subsequently, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(2-ethyl-1-butyl)-5-sec.-propyl-1,3-thiazoles alkane-4-ketone.Entry 307
Figure A9981646402563
As described at method B3a, from (D)-serine methylester preparation (R)-N-isobutyl-serine methylester HCl salt.According to method B7b, this alcohol and SOCl 2Reaction subsequently according to method C1a, with 2-methyl-4-nitrophenyl lsothiocyanates reaction, obtains 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-methylene radical-1,3-thiazoles alkane-5-ketone.Entry 308
Figure A9981646402571
According to method C8a, 2,4, the reaction of 6-trichlorophenyl lsothiocyanates and 2-butylamine subsequently with chloroacetate reaction, obtain 2-(2,4,6-trichlorophenyl imino-)-3-(2-butyl)-1,3-thiazoles alkane-4-ketone.Entry 309
Figure A9981646402572
According to method C8a, 3, the reaction of 4-dichlorophenyl lsothiocyanates and 2-methyl butyl amine subsequently with chloroacetate reaction, obtain 2-(3,4-dichlorophenyl imino-)-3-(2-butyl)-1,3-thiazoles alkane-4-ketone.Entry 310
Figure A9981646402573
According to method C11a, N-isobutyl glycine ethyl ester and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--1,3-thiazoles alkane-5-ketone.Entry 311
According to method C8a, the reaction of 2-methyl-4-nitrophenyl lsothiocyanates and 2-ethyl-1-butylamine subsequently with chloroacetate reaction, obtain 2-(2-methyl-4-nitrophenyl imino-)-3-(2-ethyl-1-butyl)-1,3-thiazoles alkane-4-ketone.Entry 312
Figure A9981646402582
According to method C11a, N-isobutyl-leucinethylester and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane-5-ketone.Entry 313
According to method C11a, N-isobutyl-ethyl prolinate and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 4-(2-methyl-4-nitrophenyl imino-)-1-oxo perhydro-2-thia pyrroles mile piperazine.Entry 314
According to method B8b step 1, N-(tert-butoxycarbonyl) glycine tertiary butyl ester and the reaction of 3-bromo-2-methacrylic obtain N-(tert-butoxycarbonyl)-N-(2-methyl-prop-2-thiazolinyl) glycine tertiary butyl ester.According to method B8b step 2,, obtain N-(tert-butoxycarbonyl)-N-(2-hydroxyethyl)-1-amino-2-methyl third-2-alkene with this ester reduction.According to method B8b step 3, handle this alcohol with Tosyl chloride, obtain N-(tert-butoxycarbonyl)-N-(2-tosyloxy ethyl)-1-amino-2-methyl third-2-alkene.According to method B8b step 4, this carbamate is removed protection, obtain trifluoroacetic acid N-(2-tosyloxy ethyl)-2-methyl-prop-2-alkene-1-ammonium.According to method C5a, this tosylate and 2-methyl-4-nitrophenyl isocyanate reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-(2-methyl-prop-2-thiazolinyl)-1, the 3-oxazolidine.Entry 315
Figure A9981646402592
According to method B1b step 2, (L)-valine methyl ester is reduced to (1S)-1-(hydroxymethyl)-2-methyl-propyl amine.According to method B4c step 1,2-hydroxyethyl amine and isobutyric aldehyde reaction obtain (4S)-2,4-di-isopropyl-1,3-oxazolidine.According to method B4c step 2,, obtain (1S)-1-(hydroxymethyl)-N-isobutyl--2-methyl-propyl amine Jiang Gai oxazolidine reduction.According to method B7b, the 2-hydroxyethyl amine and the SOCl of replacement 2Reaction obtains (1S)-1-(chloromethyl)-N-isobutyl--2-methyl-propyl amine.According to method C4a, chloroethyl amine and 2-methyl-4-nitrophenyl isocyanate reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-sec.-propyl-1, the 3-oxazolidine.Entry 316
Figure A9981646402601
According to method B1b step 2, (L)-leucine methyl esters is reduced to (1S)-1-(hydroxymethyl)-3-methyl butyl amine.According to method B4c step 1,2-hydroxyethyl amine and isobutyric aldehyde reaction obtain (4S)-2-sec.-propyl-4-isobutyl--1, the 3-oxazolidine.According to method B4c step 2,, obtain (1S)-1-(hydroxymethyl)-N-isobutyl--3-methyl butyl amine Jiang Gai oxazolidine reduction.According to method B7b, the 2-hydroxyethyl amine and the SOCl of replacement 2Reaction obtains (1S)-1-(chloromethyl)-N-isobutyl--3-methyl butyl amine.According to method C4a, this chloroethyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-oxazolidine.Entry 317
According to method B1b step 2, (L)-leucine methyl esters is reduced to (1S)-1-(hydroxymethyl)-3-methyl butyl amine.According to method B4c step 1,2-hydroxyethyl amine and isobutyric aldehyde reaction obtain (4S)-2-sec.-propyl-4-isobutyl--1, the 3-oxazolidine.According to method B4c step 2,, obtain (1S)-1-(hydroxymethyl)-N-isobutyl--3-methyl butyl amine Jiang Gai oxazolidine reduction.According to method A3a step 1,4-amino-3-ethyl benzonitrile is converted into 4-cyano group-2-ethyl n-formylaniline.According to method A3a step 2, this formanilide and SOCl 2And SO 2Cl 2Reaction obtains 4-cyano group-2-ethylphenyl isocyanides dichloride.According to method C7b, the 2-hydroxyethyl amine of replacement and 4-cyano group-2-ethylphenyl isocyanides dichloride reaction obtains (4S)-2-(4-cyano group-2-ethylphenyl imino-)-3,4-diisobutyl-1,3-oxazolidine.Entry 318
Figure A9981646402611
According to method B4b step 1,2-amino-2-methyl-1-propanol and cyclopentanone reaction obtain 4-azepine-3,3-dimethyl-1-oxaspiro [4.4] nonane.According to method B4b step 2,, obtain N-cyclopentyl-(1,1-dimethyl-2-hydroxyethyl) amine Jiang Gai oxazolidine reduction.According to method A3a step 1,2-methyl-4-N-methyl-p-nitroaniline is converted into 2-methyl-4-nitro formanilide.According to method A3a step 2, this formanilide and SOCl 2And SO 2Cl 2Reaction obtains 2-methyl-4-nitrophenyl isocyanides dichloride.According to method C7a, the 2-hydroxyethyl amine of replacement and 2-methyl-4-nitrophenyl isocyanides dichloride reaction obtains 2-(2-methyl-4-nitrophenyl imino-)-3-cyclopentyl-4,4-dimethyl-1,3-oxazolidine.Entry 319
According to method B4b step 1,2-amino-2-methyl-1-propanol and cyclopentanone reaction obtain 4-azepine-3,3-dimethyl-1-oxaspiro [4.4] nonane.According to method B4b step 2,, obtain N-cyclopentyl-(1,1-dimethyl-2-hydroxyethyl) amine Jiang Gai oxazolidine reduction.According to method A3a step 1,4-amino-3-ethyl benzonitrile is converted into 4-cyano group-2-ethyl n-formylaniline.According to method A3a step 2, this formanilide and SOCl 2And SO 2Cl 2Reaction obtains 4-cyano group-2-ethylphenyl isocyanides dichloride.According to method C7a, the 2-hydroxyethyl amine of replacement and 4-cyano group-2-ethylphenyl isocyanides dichloride reaction obtains 2-(4-cyano group-2-ethylphenyl imino-)-3-cyclopentyl-4,4-dimethyl-1,3-oxazolidine.Entry 320
According to method B1c step 1,1-aminocyclopentanecarboxylic acid is converted into methyl ester.According to method B1c step 2, this ester is reduced to 1-hydroxymethyl cyclopentamine.According to method B4d step 1, this hydroxyethyl amine and cyclopentanone reaction obtain 6-azepine-12-oxa-two spiral shells [4.1.4.2] tridecane.According to method B4d step 2,, obtain 1-(cyclopentyl amino)-1-(hydroxymethyl) pentamethylene Jiang Gai oxazolidine reduction.According to method B7b, the 2-hydroxyethyl amine and the SOCl of replacement 2Reaction obtains 1-(cyclopentyl amino)-1-(chloromethyl) pentamethylene.According to method C4a, 2-chloroethyl amine and 2-methyl-4-nitrophenyl lsothiocyanates reaction obtains 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-oxa--1-azaspiro [4.4] nonane.Entry 321
Figure A9981646402622
According to method B1c step 1,1-aminocyclopentanecarboxylic acid is converted into methyl ester.According to method B1c step 2, this ester is reduced to 1-hydroxymethyl cyclopentamine.According to method B4a step 1, this 2-hydroxyethyl amine and cyclobutanone reaction obtain 5-azepine-12-oxa-two spiral shells [3.1.4.2] dodecane.According to method B4a step 2,, obtain 1-(cyclobutyl amino)-1-(hydroxymethyl) pentamethylene Jiang Gai oxazolidine reduction.According to method B7b, the 2-hydroxyethyl amine and the SOCl of replacement 2Reaction obtains 1-(cyclobutyl amino)-1-(chloromethyl) pentamethylene.According to method C4a, 2-chloro ethylamine and 2-methyl-4-nitrophenyl isocyanate reaction obtains 1-cyclobutyl-2-(2-methyl-4-nitrophenyl imino-)-3-oxa--1-azaspiro [4.4] nonane.Entry 322
According to method B1c step 1,1-aminocyclopentanecarboxylic acid is converted into methyl ester.According to method B1c step 2, this ester is reduced to 1-hydroxymethyl cyclopentamine.According to method B4a step 1, this hydroxyethyl amine and pimelinketone reaction obtain 6-azepine-13-oxa-two spiral shells [4.1.5.2] tetradecane.According to method B4a step 2,, obtain 1-(cyclohexyl amino)-1-(hydroxymethyl) pentamethylene Jiang Gai oxazolidine reduction.According to method B7b, the 2-hydroxyethyl amine and the SOCl of replacement 2Reaction obtains 1-(cyclohexyl amino)-1-(chloromethyl) pentamethylene.According to method C4a, 2-chloroethyl amine and 2-methyl-4-nitrophenyl isocyanate reaction obtains 1-cyclohexyl-2-(2-methyl-4-nitrophenyl imino-)-3-oxa--1-azaspiro [4-4] nonane.Entry 323
Figure A9981646402632
According to method B1c step 1,1-aminocyclopentanecarboxylic acid is converted into methyl ester.According to method B1c step 2, this ester is reduced to 1-hydroxymethyl cyclopentamine.According to method B4d step 1, this hydroxyethyl amine and cyclopentanone reaction obtain 6-azepine-12-oxa-two spiral shells [4.1.4.2] tridecane.According to method B4d step 2,, obtain 1-(cyclopentyl amino)-1-(hydroxymethyl) pentamethylene Jiang Gai oxazolidine reduction.According to method A3a step 1,4-amino-3-ethyl benzonitrile is converted into 4-cyano group-2-ethyl n-formylaniline.According to method A3a step 2, this formanilide and SOCl 2And SO 2Cl 2Reaction obtains 4-cyano group-2-ethylphenyl isocyanides dichloride.According to method C7a, the 2-hydroxyethyl amine of replacement and 2-methyl-4-nitrophenyl isocyanides dichloride reaction obtains 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-oxa--1-azaspiro [4.4] nonane.Entry 324
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B4c step 1-2, this 2 hydroxy ethylamine is converted into (2S)-4-methyl-2-(isobutylamino) amylalcohol.As described at method B7c, this alcohol is converted into chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-N-(isobutyl-) ammonium.According to method C1f, 4-nitrophenyl lsothiocyanates and chlorination N-(1S)-1-(chloromethyl)-3-methyl butyl)-reaction of N-(isobutyl-) ammonium, obtain 2-(4-nitrophenyl sulfo-)-1,5-diisobutyl tetrahydroglyoxaline.Entry 325
Figure A9981646402642
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, this 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and the reaction of 5-iodo heptane obtain (4S)-2-(N-(4-heptyl)-N-(2-methyl-5-nitro phenyl) amino)-4-isobutyl--1,3-thiazoles alkane.Entry 326
Figure A9981646402651
According to method B1b, from (D)-leucine methyl esters preparation (1R)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1R)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-5-nitro phenyl lsothiocyanates and chlorination (1R)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4R)-2-(2-methyl-5-nitro phenylimino)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and isobutyl bromide reaction obtain (4R)-2-(N-isobutyl--N-(2-methyl-5-nitro phenyl) amino)-4-isobutyl--1,3-thiazoles alkane HCl salt.Entry 327
Figure A9981646402652
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2-methyl-4-nitrophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2-methyl-4-nitrophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and neo-pentyl bromine reaction obtain (4S)-2-(N-(2, the 2-dimethyl propyl)-2-methyl-4-nitrophenyl amino)-4-isobutyl--1,3-thiazoles alkane.Entry 328
Figure A9981646402661
As described at method B1b, from (L)-leucine methyl esters preparation (1S)-1-(hydroxymethyl)-3-methyl butyl amine.As described at method B7a, 2 hydroxy ethylamine is converted into chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium.According to method C1a, 2,3-dichlorophenyl lsothiocyanates and chlorination (1S)-1-(chloromethyl)-3-methyl fourth ammonium reaction obtains (4S)-2-(2,3-dichlorophenyl imino-)-4-isobutyl--1,3-thiazoles alkane.According to method D2a, this thiazolidine and the reaction of 3-bromo pentane silane obtain (4S)-2-(N-(3-amyl group)-2-methyl-4-nitrophenyl amino)-4-isobutyl--1,3-thiazoles alkane.
Table
The method of as described above, synthetic compound of listing among the following table 1-4.Table 1.2-imino--1,3-thiazoles alkane and ring expansion homologue
Figure A9981646402671
Figure A9981646402701
Figure A9981646402711
Figure A9981646402741
Figure A9981646402761
Figure A9981646402771
Figure A9981646402801
Figure A9981646402811
Figure A9981646402821
Figure A9981646402831
Figure A9981646402841
Figure A9981646402851
Figure A9981646402861
Figure A9981646402871
Figure A9981646402891
Figure A9981646402911
Figure A9981646402931
Figure A9981646402971
Figure A9981646402991
Figure A9981646403001
(a) Hewlett Packard 1100 HPLC of Finnigan LCQ MS detector and 2 * 300mm Phenomenex 3uM C-18 post are equipped with; Flow velocity 1.0mL/min; Buffer A: 0.02%TFA/2%CH 3CN/ water, buffer B: 0.018%TFA/98%CH 3CN/ water; Under 100% buffer A, kept 1 minute, inside gradient was from 100% buffer A to 100% buffer B in 3 minutes, kept 1 minute under 100% buffer B, 0.5 minute inside gradient kept 1.5 minutes under 100% buffer A from 100% buffer B to 100% buffer A.
(b) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 4 * 100mmDynamax, 3 uM C-18 posts is equipped with; Flow velocity 1.5mL/min; Buffer A: 0.5%TFA/ water, buffer B: 0.5%TFA/CH 3CN; 10 minutes inside gradients kept 5 minutes under 100% buffer B from 100% buffer A to 100% buffer B.
(c) Hewlett Packard 1090 HPLC of UV detector (210nM) and 4 * 125mm Nucleosil 3uM C-18 post are equipped with; Flow velocity 2.0mL/min; Buffer A: 0.01mol%H 3PO 4/ water, buffer B: 0.01mol%H 3PO 4/ CH 3CN; Under 10% buffer B 1 minute, 8 minutes inside gradients were from 10% buffer B to 90% buffer B, and inside gradient was from 90% buffer B to 10% buffer B in 4 minutes.
(d) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 2500mmDynamax 8uM C-18 post is equipped with; Flow velocity 18mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients kept 30 minutes under 100% buffer B from 30% buffer B to 100% buffer B.
(e) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 2500mm Dynamax 8uM C-18 post is equipped with; Flow velocity 18mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients are from 50% buffer B to 60% buffer B, and inside gradient from 60% to 100% in 32 minutes.
(f) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mm Microsorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients kept 30 minutes for 100% time at 100%B from 30% buffer B to 100% buffer B.
(g) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mm Microsorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients kept 7 minutes for 100% time at 100%B from 50% buffer B to 100% buffer B.
(h) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mmMicrosorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 30 minutes inside gradients kept 7 minutes for 100% time at 100%B from 10% buffer B to 100% buffer B.
(i) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 4.6 * 100mmMicrosorb 5uM C-8 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 5 minutes inside gradients kept 1.5 minutes for 100% time at 100%B from 10% buffer B to 100% buffer B.
(j) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mmMicrosorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 30 minutes inside gradients kept 7 minutes for 100% time at 100%B from 20% buffer B to 100% buffer B.Table 2.2-imino--1,3-thiazoles alkane-4-ketone and 2-imino--1,3-thiazoles alkane-5-ketone
Figure A9981646403031
Figure A9981646403041
Figure A9981646403061
(a) Hewlett Packard 1100 HPLC of Finnigan LCQ MS detector and 2 * 300mm Phenomenex 3uM C-18 post are equipped with; Flow velocity 1.0mL/min; Buffer A: 0.02%TFA/2%CH 3CN/ water, buffer B: 0.018%TFA/98%CH 3CN/ water; Under 100% buffer A, kept 1 minute, inside gradient was from 100% buffer A to 100% buffer B in 3 minutes, kept 1 minute under 100% buffer B, 0.5 minute inside gradient kept 1.5 minutes under 100% buffer A from 100% buffer B to 100% buffer A.
(b) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 4 * 100mmDynamax, 3 uM C-18 posts is equipped with; Flow velocity 1.5mL/min; Buffer A: 0.5%TFA/ water, buffer B: 0.5%TFA/CH 3CN; 10 minutes inside gradients kept 5 minutes under 100% buffer B from 100% buffer A to 100% buffer B.
(c) Hewlett Packard 1090 HPLC of UV detector (210nM) and 4 * 125mm Nucleosil 3uM C-18 post are equipped with; Flow velocity 2.0mL/min; Buffer A: 0.01mol%H 3PO 4/ water, buffer B: 0.01mol%H 3PO 4/ CH 3CN; Under 10% buffer B 1 minute, 8 minutes inside gradients were from 10% buffer B to 90% buffer B, and inside gradient was from 90% buffer B to 10% buffer B in 4 minutes.
(d) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 2500mmDynamax 8uM C-18 post is equipped with; Flow velocity 18mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients kept 30 minutes under 100% buffer B from 30% buffer B to 100% buffer B.
(e) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 2500mmDynamax 8uM C-18 post is equipped with; Flow velocity 18mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients are from 50% buffer B to 60% buffer B, and inside gradient from 60% to 100% in 32 minutes.
(f) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mm Microsorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients kept 30 minutes for 100% time at 100%B from 30% buffer B to 100% buffer B.
(g) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mmMicrosorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients kept 7 minutes for 100% time at 100%B from 50% buffer B to 100% buffer B.
(h) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mmMicrosorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 30 minutes inside gradients kept 7 minutes for 100% time at 100%B from 10% buffer B to 100% buffer B.
(i) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 4.6 * 100mmMicrosorb 5uM C-8 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 5 minutes inside gradients kept 1.5 minutes for 100% time at 100%B from 10% buffer B to 100% buffer B.
(j) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mm Microsorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 30 minutes inside gradients kept 7 minutes for 100% time at 100%B from 20% buffer B to 100% buffer B.Table 3.2-imino--1, the 3-oxazolidine
Figure A9981646403101
(a) Hewlett Packard 1100 HPLC of Finnigan LCQ MS detector and 2 * 300mm Phenomenex 3uM C-18 post are equipped with; Flow velocity 1.0mL/min; Buffer A: 0.02%TFA/2%CH 3CN/ water, buffer B: 0.018%TFA/98%CH 3CN/ water; Under 100% buffer A, kept 1 minute, inside gradient was from 100% buffer A to 100% buffer B in 3 minutes, kept 1 minute under 100% buffer B, 0.5 minute inside gradient kept 1.5 minutes under 100% buffer A from 100% buffer B to 100% buffer A.
(b) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 4 * 100mmDynamax 3uM C-18 post is equipped with; Flow velocity 1.5mL/min; Buffer A: 0.5%TFA/ water, buffer B: 0.5%TFA/CH 3CN; 10 minutes inside gradients kept 5 minutes under 100% buffer B from 100% buffer A to 100% buffer B.
(c) Hewlett Packard 1090 HPLC of UV detector (210nM) and 4 * 125mm Nucleosil 3uM C-18 post are equipped with; Flow velocity 2.0mL/min; Buffer A: 0.01mol%H 3PO 4/ water, buffer B: 0.01mol%H 3PO 4/ CH 3CN; Under 10% buffer B 1 minute, 8 minutes inside gradients were from 10 buffer B to 90% buffer B, and inside gradient was from 90% buffer B to 10% buffer B in 4 minutes.
(d) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 2500mmDynamax 8uM C-18 post is equipped with; Flow velocity 18mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients kept 30 minutes under 100% buffer B from 30% buffer B to 100% buffer B.
(e) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 2500mmDynamax 8uM C-18 post is equipped with; Flow velocity 18mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients are from 50% buffer B to 60% buffer B, and inside gradient from 60% to 100% in 32 minutes.
(f) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mmMicrosorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients kept 30 minutes for 100% time at 100%B from 30% buffer B to 100% buffer B.
(g) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mm Microsorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients kept 7 minutes for 100% time at 100%B from 50% buffer B to 100% buffer B.
(h) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mm Microsorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 30 minutes inside gradients kept 7 minutes for 100% time at 100%B from 10% buffer B to 100% buffer B.
(i) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 4.6 * 100mmMicrosorb 5uM C-8 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 5 minutes inside gradients kept 1.5 minutes for 100% time at 100%B from 10% buffer B to 100% buffer B.
(j) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mmMicrosorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 30 minutes inside gradients kept 7 minutes for 100% time at 100%B from 20% buffer B to 100% buffer B.Table 4. additional embodiments
Figure A9981646403121
(a) Hewlett Packard 1100 HPLC of Finnigan LCQ MS detector and 2 * 300mm Phenomenex 3uM C-18 post are equipped with; Flow velocity 1.0mL/min; Buffer A: 0.02%TFA/2%CH 3CN/ water, buffer B: 0.018%TFA/98%CH 3CN/ water; Under 100% buffer A, kept 1 minute, inside gradient was from 100% buffer A to 100% buffer B in 3 minutes, kept 1 minute under 100% buffer B, 0.5 minute inside gradient kept 1.5 minutes under 100% buffer A from 100% buffer B to 100% buffer A.
(b) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 4 * 100mm Dynamax 3uM C-18 post is equipped with; Flow velocity 1.5mL/min; Buffer A: 0.5%TFA/ water, buffer B: 0.5%TFA/CH 3CN; 10 minutes inside gradients kept 5 minutes under 100% buffer B from 100% buffer A to 100% buffer B.
(c) Hewlett Packard 1090 HPLC of UV detector (210nM) and 4 * 125mm Nucleosil 3uM C-18 post are equipped with; Flow velocity 2.0mL/min; Buffer A: 0.01mol%H 3PO 4/ water, buffer B: 0.01mol%H 3PO 4/ CH 3CN; Under 10% buffer B 1 minute, 8 minutes inside gradients were from 10% buffer B to 90% buffer B, and inside gradient was from 90% buffer B to 10% buffer B in 4 minutes.
(d) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 2500mm Dynamax 8uM C-18 post is equipped with; Flow velocity 18mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients kept 30 minutes under 100% buffer B from 30% buffer B to 100% buffer B.
(e) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 2500mm Dynamax 8uM C-18 post is equipped with; Flow velocity 18mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients are from 50% buffer B to 60% buffer B, and inside gradient from 60% to 100% in 32 minutes.
(f) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mm Microsorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients kept 30 minutes for 100% time at 100%B from 30% buffer B to 100% buffer B.
(g) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mm Microsorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 25 minutes inside gradients kept 7 minutes for 100% time at 100%B from 50% buffer B to 100% buffer B.
(h) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mm Microsorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 30 minutes inside gradients kept 7 minutes for 100% time at 100%B from 10% buffer B to 100% buffer B.
(i) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 4.6 * 100mm Microsorb 5uM C-8 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 5 minutes inside gradients kept 1.5 minutes for 100% time at 100%B from 10% buffer B to 100% buffer B.
(j) the Ranin Dynamax HPLC of UV-DII dual wavelength detector (254 and 220nm) and 21 * 2500mm Microsorb 5uM C-18 post is equipped with; Flow velocity 20mL/min; Buffer A: 0.1%TFA/99.9% water, buffer B: 0.1%TFA/99.9%CH 3CN; 30 minutes inside gradients kept 7 minutes for 100% time at 100%B from 20% buffer B to 100% buffer B.The biology scheme
According to the method for following discloses, can the given compound of conventionally test be incorporated into the activity of PgR.This method is used to measure the progesterone of The compounds of this invention in conjunction with activity.PgR is in conjunction with test
Binding buffer liquid (the 100mL that on ice-water bath, adds the test-compound that contains multiple concentration in the refrigerative silication glass test tube; 50mM Tris, pH 7.4, the 10mM molybdic acid, 2mMEDTA, 150mM NaCl, 5% glycerine, 1%DMSO), T47D cytosol (solution of 100 μ L, it provides the combination of 4000cpm at least) and 3The H-progesterone (50 μ L, 10nM, NET-381).Under 4 ℃,, and handle with gac (Mixture of Activated Carbon of 0.5% the 0.05% dextran bag quilt of 250 μ L, it has used binding buffer liquid washed twice) with this mixture incubation 16 hours.Under 4 ℃, with the mixture incubation that generates 10 minutes.Under 4 ℃, with test tube centrifugal (with following 20 minutes of 2800xg).Supernatant liquor is transferred in the flicker phial that contains scintillation solution (4mL).Measure remaining with Packard 1900TR β counter 3The H-progesterone.Test each time comprises following control group: 1) sum up and set up (not containing compound), 2 jointly) non-specific binding group (containing the 400nM progesterone) and 3) positive controls (containing 2nM progesterone or known inhibitor).
Under the compound concentration of 200nM, find that The compounds of this invention causes more than or equal to 30% 3The H-progesterone is to PgR bonded inhibiting rate.Under the compound concentration of 200nM, The compounds of this invention is listed in the table 5 in conjunction with the field of activity in the test at PgR.The inhibition activity of table 5. embodiment compound
Under 200nM, cause the compound (registration item No.) of 30-59% inhibiting rate Under 200nM, cause the compound (registration item No.) of 60-79% inhibiting rate Under 200nM, cause the compound (registration item No.) of 80-100% inhibiting rate
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By with those reagents and/or the operational condition used among general description of the present invention or specifically described reagent and/or the alternative embodiment formerly of operational condition, can equally successfully repeat embodiment formerly.
Consider that from the angle of specification sheets of the present invention disclosed herein or enforcement other embodiment of the present invention will be conspicuous for a person skilled in the art.This specification sheets and embodiment only plan explanation as an example, and consistent with the indicated scope and spirit of the present invention of following claims.

Claims (9)

1. a compound and pharmacy acceptable salt thereof with following formula Wherein R is
The aryl of 6-14 carbon; Or
3-10 carbon and contain the heteroatomic heteroaryl that 1-3 is selected from N, O and S, condition is that R is not cumarone or thionaphthene; R 1For
The alkyl of 1-10 carbon;
3-12 carbon and contain 1-3 the ring cycloalkyl;
4-7 carbon and contain 1-3 ring and the individual heteroatomic Heterocyclylalkyl that is selected from N, O and S of 1-3;
The alkenyl of 2-10 carbon;
5-12 carbon and contain 1-3 the ring cycloalkenyl group; Or
The alkynyl of 3-10 carbon; R 2, R 3And R 4Independently be selected from
H；
The alkyl of 1-10 carbon;
The cycloalkyl of 3-12 carbon;
The alkenyl of 2-10 carbon;
The cycloalkenyl group of 5-12 carbon;
The aryl of 6-13 carbon;
3-9 carbon and contain the heteroatomic heteroaryl that 1-3 is selected from N, O and S;
CO 2R 5Wherein
R 5Be the alkyl of 1-4 carbon, the haloalkyl of a 1-4 carbon, the cycloalkyl of a 3-6 carbon or the halogenated cycloalkyl of 3-6 carbon;
Halogen; With
=O, the expression radicals R 2, R 3And R 4In two; X is O or S (O) yWherein
Y is 0,1 or 2; N is 2,3,4 or 5; P is non-H substituent R 2, R 3And R 4Sum; T is the substituting group that is selected from following group
The alkyl of 1-4 carbon;
The alkoxyl group of 1-4 carbon;
The aryl of 6-10 carbon;
CO 2H；
CO 2R 5；
The alkenyl of 2-4 carbon;
The alkynyl of 2-4 carbon;
C(O)C 6H 5；
C (O) N (R 6) (R 7); Wherein
R 6Alkyl for H or 1-5 carbon; With
R 7Alkyl for H or 1-5 carbon;
S (O) Y 'R 8Wherein
Y ' is 1 or 2; With
R 8Alkyl for 1-5 carbon;
SO 2F；
CHO；
OH；
NO 2；
CN；
Halogen;
OCF 3；
The N-oxide compound;
O-C (R 9) 2-O; This oxygen is connected in the ortho position on the R;
And wherein
R 9Alkyl for H, a halogen or 1-4 carbon;
C (O) NHC (O), this carbon is connected in the ortho position on the R; With
C (O) C 6H 4, this carbonyl carbon and carbonyl adjacent ring carbon are connected in the ortho position on the R; T is 1-5;
Condition be when substituting group part T be the alkyl of 1-4 carbon, the alkoxyl group of a 1-4 carbon, aryl, the CO of a 6-10 carbon 2R 5, the alkenyl of a 2-4 carbon, the alkynyl of a 2-4 carbon, C (O) C 6H 5, C (O) N (R 6) (R 7), S (O) Y 'R 8, O-C (R 9) 2-O or C (O) C 6H 4The time, T is optional so can have the secondary substituting group that is selected from following group, comprising: alkoxyl group, the CO of the alkyl of 1-4 carbon, a 1-4 carbon 2R 5, CO 2H, C (O) N (R 6) (R 7), CHO, OH, NO 2, CN, halogen, S (O) yR 8Or=O, described secondary substituent number is 1 or 2 except that halogen, it can use at most can reach the perhalogeno level; G is the substituting group that is selected from following group:
Halogen;
OH；
OR 5；
=O represents two substituting group G;
The alkyl of 1-4 carbon;
The alkenyl of 1-4 carbon;
The cycloalkyl of 3-7 carbon;
3-5 carbon and 1-3 heteroatomic Heterocyclylalkyl that is selected from N, O and S;
The cycloalkenyl group of 5-7 carbon;
4-6 carbon and 1-3 heteroatomic heterocycloalkenyl that is selected from N, O and S;
CO 2R 5；
C(O)N(R 6)(R 7)；
The aryl of 6-10 carbon;
3-9 carbon and 1-3 heteroatomic heteroaryl that is selected from N, O and S;
NO 2；
CN；
S(O) yR 8；
SO 3R 8With
SO 2N (R 6) (R 7); G is 0-4, and except that halogen, it can use at most can reach the perhalogeno level;
Condition is when substituting group G is the heterocycloalkenyl of the cycloalkenyl group of Heterocyclylalkyl, a 5-7 carbon of cycloalkyl, a 3-5 carbon of alkenyl, a 3-7 carbon of alkyl, a 1-4 carbon of 1-4 carbon or 4-6 carbon, G chooses the secondary substituting group that can have the halogen that can reach the perhalogeno level at most wantonly so, and when substituting group G is aryl or heteroaryl, G can choose wantonly and have the alkyl that independently is selected from 1-4 carbon and the secondary substituting group of halogen so, described secondary substituent number can reach 3 at most to moieties, and can reach the perhalogeno level at most to halogen; Q is the substituting group that is selected from following group
The alkyl of 1-4 carbon;
The haloalkyl of 1-4 carbon;
The cycloalkyl of 3-8 carbon;
The alkoxyl group of 1-8 carbon;
The alkenyl of 2-5 carbon;
The cycloalkenyl group of 5-8 carbon;
The aryl of 6-10 carbon;
3-9 carbon and contain the heteroatomic heteroaryl that 1-3 is selected from N, O and S;
CO 2R 5；
=O represents two substituting group Q;
OH；
Halogen;
N(R 6)(R 7)；
S(O) yR 8；
SO 3R 8With
SO 2N (R 6) (R 7); Q is 0-4
Condition is when substituting group Q is aryl or heteroaryl, Q is optional so can have the alkyl that independently is selected from 1-4 carbon and the secondary substituting group of halogen, described secondary substituent number can reach 3 at most to moieties, and can reach the perhalogeno level at most to halogen; With other condition be: a) (Q) qR 1, (Q) qR 2, (Q) qR 3(Q) qR 4In two can connect, and form with the atom that they connected and to contain 0-2 and be selected from the heteroatomic 3-8 unit's spiral shell of N, O and S or the non-aromatic ring of non-spiral shell; B) when n=2 or 3, R 2, R 3And R 4In at least one is not H; C) work as n=2, and during X=O, if t=1, T is selected from above substituting group T clauses and subclauses so, except that alkyl, and 1, the 4-position of 3-oxazolidine ring must have a substituting group; D) work as n=3, and during X=O, if t is equal to or greater than 1, at least one T is selected from above substituting group T clauses and subclauses so, except that alkyl and alkoxyl group; E) when n=2 or 3, and when X=O or S, R so 1, R 2, R 3And R 4In non-hydrogen atom add up at least 5; F) work as n=2, X=O, 1, the 4-bit strip of 3-oxazolidine ring has a carbonyl, and R is when its 2-position and 4-bit strip have halogen, and the 5-bit strip of R has H so; G) when n=2 and X=O, only when the 5-of described ring bit strip has at least one non-H substituting group, 1, the 4-position of 3-oxazolidine ring can have a carbonyl; H) work as n=2, X=S (O) yThe time, the 4-bit strip of 1,3-thiazoles alkane ring has a carbonyl, R 1The methyl that be to replace, and G is when being phenyl, so described phenyl has secondary substituting group; I) work as n=4, X=S and G are CO 2R 5The time, R so 5Contain at least two carbon.
2. a compound and pharmacy acceptable salt thereof with following formula Wherein R is
Phenyl; Or
Pyridyl; R 1For
The alkyl of 1-10 carbon;
3-12 carbon and contain 1-3 the ring cycloalkyl;
The alkenyl of 2-10 carbon;
5-12 carbon and contain 1-3 the ring cycloalkenyl group; Or
The alkynyl of 3-10 carbon; R 2, R 3And R 4Independently be selected from
H；
The alkyl of 1-10 carbon;
The cycloalkyl of 3-12 carbon;
The alkenyl of 2-10 carbon;
The cycloalkenyl group of 5-12 carbon; With
=O, the expression radicals R 2, R 3And R 4In two; X is O or S (O) yWherein
Y is 0,1 or 2; N is 2 or 3; P is non-H substituent R 2, R 3And R 4Sum; T is the substituting group that is selected from following group
The alkyl of 1-4 carbon;
The alkoxyl group of 1-4 carbon;
The alkenyl of 2-4 carbon;
The alkynyl of 2-4 carbon;
NO 2；
CN; With
Halogen; T is 1-5;
Condition is that T is optional so can have the secondary substituting group that is selected from following group when substituting group part T is the alkynyl of the alkenyl of alkoxyl group, a 2-4 carbon of alkyl, a 1-4 carbon of 1-4 carbon or 2-4 carbon;
The alkyl of 1-4 carbon;
The alkoxyl group of 1-4 carbon;
CO 2R 5Wherein
R 5Be the alkyl of 1-4 carbon, the haloalkyl of a 1-4 carbon, the cycloalkyl of a 3-6 carbon or the halogenated cycloalkyl of 3-6 carbon;
CO 2H；
C (O) N (R 6) (R 7); Wherein
R 6Alkyl for H or 1-5 carbon; With
R 7Alkyl for H or 1-5 carbon;
CHO；
OH；
NO 2；
CN；
Halogen;
S (O) yR 8Wherein
R 8Alkyl for 1-5 carbon; With
=O represents two secondary substituting groups;
Described secondary substituent number is 1 or 2 except that halogen, and it can use at most can reach the perhalogeno level; G is the substituting group that is selected from following group
Halogen;
OR 5；
The alkyl of 1-4 carbon;
The alkenyl of 1-4 carbon;
The cycloalkyl of 3-7 carbon;
The cycloalkenyl group of 5-7 carbon;
The aryl of 6-10 carbon; With
CN; G is 0-4, and except that halogen, it can use at most can reach the perhalogeno level;
Condition is when substituting group G is the cycloalkenyl group of the cycloalkyl of alkenyl, a 3-7 carbon of alkyl, a 1-4 carbon of 1-4 carbon or 5-7 carbon, G chooses the secondary substituting group that can have the halogen that can reach the perhalogeno level at most wantonly so, and when substituting group G is aryl, G can choose wantonly and have the alkyl that independently is selected from 1-4 carbon and the secondary substituting group of halogen so, described secondary substituent number can reach 3 at most to moieties, and can reach the perhalogeno level at most to halogen; Q is the substituting group that is selected from following group:
The alkyl of 1-4 carbon;
The haloalkyl of 1-4 carbon;
The cycloalkyl of 3-8 carbon;
The alkoxyl group of 1-8 carbon;
The alkenyl of 2-5 carbon;
The cycloalkenyl group of 5-8 carbon;
CO 2R 5；
=O represents two substituting group Q;
OH；
Halogen;
N (R 6) (R 7); With
S (O) yR 8Q is 0-4;
And other condition is: a) (Q) qR 1, (Q) qR 2, (Q) qR 3(Q) qR 4In two can connect, and form with the atom that they connected and to contain 0-2 and be selected from the heteroatomic 3-8 unit's spiral shell of N, O and S or the non-aromatic ring of non-spiral shell; B) when n=2 or 3, R 2, R 3And R 4In at least one is not H; C) work as n=2, and during X=O, if t=1, T is selected from above substituting group T clauses and subclauses so, except that alkyl, and 1, the 4-position of 3-oxazolidine ring must have a substituting group; D) work as n=3, and during X=O, if t is equal to or greater than 1, at least one T is selected from above substituting group T clauses and subclauses so, except that alkyl and alkoxyl group; E) when n=2 or 3, and when X=O or S, R so 1, R 2, R 3And R 4In non-hydrogen atom add up at least 5; F) work as n=2, X=O, 1, the 4-bit strip of 3-oxazolidine ring has a carbonyl, and R is when its 2-position and 4-bit strip have halogen, and the 5-bit strip of R has H so; G) when n=2 and X=O, only when the 5-of described ring bit strip has at least one non-H substituting group, 1, the 4-position of 3-oxazolidine ring can have a carbonyl; H) work as n=2, X=S (O) yThe time, the 4-bit strip of 1,3-thiazoles alkane ring has a carbonyl, R 1The methyl that be to replace, and G is when being phenyl, so described phenyl has secondary substituting group.
3. a compound and pharmacy acceptable salt thereof with following formula Wherein R is
Phenyl; Or
Pyridyl; R 1For
The alkyl of 1-10 carbon;
3-12 carbon and contain 1-3 the ring cycloalkyl;
The alkenyl of 2-10 carbon; Or
5-12 carbon and contain 1-3 the ring cycloalkenyl group; R 2, R 3And R 4Independently be selected from
H；
The alkyl of 1-10 carbon;
The cycloalkyl of 3-12 carbon;
The alkenyl of 2-10 carbon; With
The cycloalkenyl group of 5-12 carbon; X is O or S (O) yWherein
Y is 0,1 or 2; N is 2 or 3; P is non-H substituent R 2, R 3And R 4Sum; T is the substituting group that is selected from following group
The alkyl of 1-4 carbon;
The alkenyl of 2-4 carbon;
NO 2；
CN; With
Halogen; T is 1-5;
Condition is when substituting group part T is the alkenyl of the alkyl of 1-4 carbon or 2-4 carbon, and T is optional so can have the secondary substituting group that is selected from following group:
The alkyl of 1-4 carbon;
The alkoxyl group of 1-4 carbon;
CO 2R 5Wherein
R 5Be the alkyl of 1-4 carbon, the haloalkyl of a 1-4 carbon, the cycloalkyl of a 3-6 carbon or the halogenated cycloalkyl of 3-6 carbon;
CO 2H；
C (O) N (R 6) (R 7); Wherein
R 6Alkyl for H or 1-5 carbon; With
R 7Alkyl for H or 1-5 carbon;
CHO；
OH；
NO 2；
CN；
Halogen;
S (O) yR 8Wherein
R 8Alkyl for 1-5 carbon; With
＝O；
Described secondary substituent number is 1 or 2 except that halogen, and it can use at most can reach the perhalogeno level; G is the substituting group that is selected from following group
Halogen;
The alkyl of 1-4 carbon;
The alkenyl of 1-4 carbon;
The cycloalkyl of 3-7 carbon;
The cycloalkenyl group of 5-7 carbon; With
The aryl of 6-10 carbon; G is 0-4, and except that halogen, it can use at most can reach the perhalogeno level;
Condition is when substituting group G is the cycloalkenyl group of the cycloalkyl of alkenyl, a 3-7 carbon of alkyl, a 1-4 carbon of 1-4 carbon or 5-7 carbon, G chooses the secondary substituting group that can have the halogen that can reach the perhalogeno level at most wantonly so, and when substituting group G is aryl, G can choose wantonly and have the alkyl that independently is selected from 1-4 carbon and the secondary substituting group of halogen so, described secondary substituent number can reach 3 at most to moieties, and can reach the perhalogeno level at most to halogen; Q is the substituting group that is selected from following group
The alkyl of 1-4 carbon;
The haloalkyl of 1-4 carbon;
The cycloalkyl of 3-8 carbon;
The alkoxyl group of 1-8 carbon;
The alkenyl of 2-5 carbon;
The cycloalkenyl group of 5-8 carbon; With
Halogen; Q is 0-4;
And other condition is: a) (Q) qR 1, (Q) qR 2, (Q) qR 3(Q) qR 4In two can connect, and form with the atom that they connected and to contain 0-2 and be selected from the heteroatomic 3-8 unit's spiral shell of N, O and S or the non-aromatic ring of non-spiral shell; B) when n=2 or 3, R 2, R 3And R 4In at least one is not H; C) work as n=2, and during X=O, if t=1, T is selected from above substituting group T clauses and subclauses so, except that alkyl, and 1, the 4-position of 3-oxazolidine ring must have a substituting group; D) work as n=3, and during X=O, if t is equal to or greater than 1, at least one T is selected from above substituting group T clauses and subclauses so, except that alkyl; E) when n=2 or 3, and when X=O or S, R so 1, R 2, R 3And R 4In non-hydrogen atom add up at least 5.
4. the compound of claim 1 is selected from: (4S)-and 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-sec.-propyl-1,3-thiazoles alkane; (4S)-and 2-(2-methyl-4-nitrophenyl imino-)-3,4-diisobutyl-1,3-thiazoles alkane; (4S)-2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-(trifluoromethyl)-1,3-thiazoles alkane; (4S)-2-(2-methyl-4-nitrophenyl imino-)-3-cyclopentyl-4-isobutyl--1,3-thiazoles alkane; (4S)-2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-sec.-propyl-1,3-thiazoles alkane; (4S)-2-(2-methyl-4-nitrophenyl imino-)-3-cyclopentyl-4-sec.-propyl-1,3-thiazoles alkane; (4R)-and 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4-sec.-propyl tetrahydrochysene-2H-1, the 3-thiazine; (4S)-2-(4-nitro-1-naphthyl imino-)-3-cyclopentyl-4-((1R)-1-hydroxyethyl)-1,3-thiazoles alkane; 2-(4-cyano group-2-aminomethyl phenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane; 2-(4-cyano group-2-ethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.2-(4-cyano-phenyl-imino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane; 2-(4-cyano group-2-aminomethyl phenyl imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane; 2-(4-cyano group-2,3-3,5-dimethylphenyl imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane; 2-(4-cyano group-2-aminomethyl phenyl imino-)-1-(1-ethyl-1-propyl group)-3-thia-1-azaspiro [4.4] nonane; 2-(4-cyano group-1-naphthyl imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane; 2-(2-methyl-4-nitrophenyl imino-)-1-(third-2-alkene-1-yl)-3-thia-1-azaspiro [4.4] nonane; 2-(2-methyl-4-nitrophenyl imino-)-1-sec.-propyl-3-thia-1-azaspiro [4.4] nonane; 2-(2-methyl-4-nitrophenyl imino-)-1-isobutyl--3-thia-1-azaspiro [4.4] nonane; 2-(2-methyl-4-nitrophenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane; 2-(3-methyl-4-nitrophenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane; 2-(2-methyl-4-nitrophenyl imino-)-1-cyclohexyl-3-thia-1-azaspiro [4.4] nonane; 2-(2,3-dimethyl-4-nitrophenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane; And 2-(4-cyano group-2,3-3,5-dimethylphenyl imino-)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.
5. the compound of claim 1 is selected from: 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--1,3-thiazoles alkane-4-ketone; 2-(3-methyl-4-nitrophenyl imino-)-3-isobutyl--1,3-thiazoles alkane-4-ketone; 2-(2-methyl-4-nitrophenyl imino-)-3-benzyl-1,3-thiazoles alkane-4-ketone; 2-(3-methyl-4-nitrophenyl imino-)-3-benzyl-1,3-thiazoles alkane-4-ketone; 2-(2-methyl-4-nitrophenyl imino-)-3-(2-methyl-1-butene base)-1,3-thiazoles alkane-4-ketone; 2-(3-methyl-4-nitrophenyl imino-)-3-(2-methyl-1-butene base)-1,3-thiazoles alkane-4-ketone; 2-(2-methyl-4-nitrophenyl imino-)-3-(1-cyclohexyl-1-ethyl)-1,3-thiazoles alkane-4-ketone; 2-(3-methyl-4-nitrophenyl imino-)-3-(1-cyclohexyl-1-ethyl)-1,3-thiazoles alkane-4-ketone; 2-(2-methyl-4-nitrophenyl imino-)-3-(2-ethyl-1-butyl)-1,3-thiazoles alkane-4-ketone; 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--5-methylene radical-1,3-thiazoles alkane-4-ketone; And 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--5-methyl isophthalic acid, the 3-thiazolidin-4-one.
6. the compound of claim 1 is selected from: 2-(2-methyl-4-nitrophenyl imino-)-3-isobutyl--4,4-dimethyl-1,3-oxazolidine; 1-cyclopentyl-2-(4-cyano group-2-ethylphenyl imino-)-3-oxa--1-azaspiro [4.4] nonane; 1-cyclopentyl-2-(2-methyl-4-nitrophenyl imino-)-3-oxa--1-azaspiro [4.4] nonane; With 1-cyclohexyl-2-(2-methyl-4-nitrophenyl imino-)-3-oxa--1-azaspiro [4.4] nonane.
7. medicinal compositions, it comprises claim 1,2,3,4,5 or 6 compound and pharmaceutically acceptable carrier.
8. one kind by the mammiferous method of the compounds for treating that gives described Mammals significant quantity, is used for: A1) strengthen the bone forming of bone debilitating disease, be used for the treatment of or prevention of osteoporosis reduces or osteoporosis; A2) strengthen union of fracture; B1) as women's anti-early pregnancy drug; B2) the prevention uterine endometrium is implanted; B3) induced labor; B4) the treatment corpus luteum lacks; B5) strengthen the identification of gestation and keeping; B6) to antipregnancy preeclampsia, eclampsia and premature labor; B7) treatment infertility comprises promoting spermatogeny, induce acrosomal reaction, make oocyte maturation or making the Oocyte in Vitro fertilization; C1) treatment dysmenorrhoea; C2) treatment dysfunction temper palace is hemorrhage; C3) treatment ovarian hyperandrogenism; C4) treatment ovary aldosteronism; C5) alleviate premenstrual syndrome and alleviation premenstrual tension; C6) alleviation is obstacle through moving ahead; C7) the treatment climacteric disturbances comprises menopause transformation, emotional change, sleep disordered and vagina drying; C8) strengthen women's property susceptibility and the male sex's property susceptibility; C9) treatment postmenopause urine incontinence; C10) improve sensation and motor function; C11) improve short-term memory; C12) alleviate postpartum depression; C13) treatment reproduction atrophy; C14) the prevention of postoperative adhesion forms; C15) regulate the uterus immunologic function; C16) prevention myocardial infarction; D1) Hormone Replacement Therapy; E1) the treatment cancer comprises mammary cancer, uterus carcinoma, ovarian cancer and carcinoma of endometrium; E2) treatment endometriosis; E3) treatment fibroma uteri; F1) treatment hirsutism; F2) suppress natural on-off cycles of hair growth; G1) as the activity of male contraceptive pill; G2) as the activity of aborticide; And H1) promote mylin to repair;
Wherein said compound has following general formula Wherein R is
The aryl of 6-14 carbon; Or
3-10 carbon and contain the heteroatomic heteroaryl that 1-3 is selected from N, O and S, condition is that R is not cumarone or thionaphthene; R 1For
The alkyl of 1-10 carbon;
3-12 carbon and contain 1-3 the ring cycloalkyl;
4-7 carbon and contain 1-3 ring and the individual heteroatomic Heterocyclylalkyl that is selected from N, O and S of 1-3;
The aryl of 6-10 carbon;
3-9 carbon and contain 1-3 ring and contain the heteroatomic heteroaryl that 1-3 is selected from N, O and S;
The alkenyl of 2-10 carbon;
5-12 carbon and contain 1-3 the ring cycloalkenyl group; Or
The alkynyl of 3-10 carbon; R 2, R 3And R 4Independently be selected from
H；
The alkyl of 1-10 carbon;
The cycloalkyl of 3-12 carbon;
The alkenyl of 2-10 carbon;
The cycloalkenyl group of 5-12 carbon;
The aryl of 6-13 carbon;
3-9 carbon and contain the heteroatomic heteroaryl that 1-3 is selected from N, O and S;
CO 2R 5Wherein
R 5Be the alkyl of 1-4 carbon, the haloalkyl of a 1-4 carbon, the cycloalkyl of a 3-6 carbon or the halogenated cycloalkyl of 3-6 carbon;
Halogen; With
=O, the expression radicals R 2, R 3And R 4In two; X is O or S (O) yWherein
Y is 0,1 or 2; N is 2,3,4 or 5; P is non-H substituent R 2, R 3And R 4Sum; The number of two keys in the s representative ring, and be 0,1 or 2; T is the substituting group that is selected from following group
The alkyl of 1-4 carbon;
The alkoxyl group of 1-4 carbon;
The aryl of 6-10 carbon;
CO 2H；
CO 2R 5；
The alkenyl of 2-4 carbon;
The alkynyl of 2-4 carbon;
C(O)C 6H 5；
C (O) N (R 6) (R 7); Wherein
R 6Alkyl for H or 1-5 carbon; With
R 7Alkyl for H or 1-5 carbon;
S (O) Y 'R 8Wherein
Y ' is 1 or 2; With
R 8Alkyl for 1-5 carbon;
SO 2F；
CHO；
OH；
NO 2；
CN；
Halogen;
OCF 3；
The N-oxide compound;
O-C (R 9) 2-O; This oxygen is connected in the ortho position on the R;
And wherein
R 9Alkyl for H, a halogen or 1-4 carbon;
C (O) NHC (O), this carbon is connected in the ortho position on the R; With
C (O) C 6H 4This carbonyl carbon and carbonyl adjacent ring carbon are connected in the ortho position on the R; T is 1-5;
Condition be when substituting group part T be the alkyl of 1-4 carbon, the alkoxyl group of a 1-4 carbon, aryl, the CO of a 6-10 carbon 2R 5, the alkenyl of a 2-4 carbon, the alkynyl of a 2-4 carbon, C (O) C 6H 5, C (O) N (R 6) (R 7), S (O) Y 'R 8, O-C (R 9) 2-O or C (O) C 6H 4The time, T is optional so can have the secondary substituting group that is selected from following group, comprising: the alkyl of 1-4 carbon, the alkoxyl group of 1-4 carbon, CO 2R 5, CO 2H, C (O) N (R 6) (R 7), CHO, OH, NO 2, CN, halogen, S (O) yR 8Or=O, described secondary substituent number is 1 or 2 except that halogen, it can use at most can reach the perhalogeno level; G is the substituting group that is selected from following group
Halogen;
OH；
OR 5；
=O represents two substituting group G;
The alkyl of 1-4 carbon;
The alkenyl of 1-4 carbon;
The cycloalkyl of 3-7 carbon;
3-5 carbon and 1-3 heteroatomic Heterocyclylalkyl that is selected from N, O and S;
The cycloalkenyl group of 5-7 carbon;
4-6 carbon and 1-3 heteroatomic heterocycloalkenyl that is selected from N, O and S;
CO 2R 5；
C(O)N(R 6)(R 7)；
The aryl of 6-10 carbon;
3-9 carbon and 1-3 heteroatomic heteroaryl that is selected from N, O and S;
NO 2；
CN；
S(O) yR 8；
SO 3R 8With
SO 2N (R 6) (R 7); G is 0-4, and except that halogen, it can use at most can reach the perhalogeno level;
Condition is when substituting group G is the heterocycloalkenyl of the cycloalkenyl group of Heterocyclylalkyl, a 5-7 carbon of cycloalkyl, a 3-5 carbon of alkenyl, a 3-7 carbon of alkyl, a 1-4 carbon of 1-4 carbon or 4-6 carbon, G chooses the secondary substituting group that can have the halogen that can reach the perhalogeno level at most wantonly so, and when substituting group G is aryl or heteroaryl, G can choose wantonly and have the alkyl that independently is selected from 1-4 carbon and the secondary substituting group of halogen so, described secondary substituent number can reach 3 at most to moieties, and can reach the perhalogeno level at most to halogen; Q is the substituting group that is selected from following group
The alkyl of 1-4 carbon;
The haloalkyl of 1-4 carbon;
The cycloalkyl of 3-8 carbon;
The alkoxyl group of 1-8 carbon;
The alkenyl of 2-5 carbon;
The cycloalkenyl group of 5-8 carbon;
The aryl of 6-10 carbon;
3-9 carbon and contain the heteroatomic heteroaryl that 1-3 is selected from N, O and S;
CO 2R 5；
=O represents two substituting group Q;
OH；
Halogen;
N(R 6)(R 7)；
S(O) yR 8；
SO 3R 8With
SO 2N (R 6) (R 7); Q is 0-4
Condition is when substituting group Q is aryl or heteroaryl, Q is optional so can have the alkyl that independently is selected from 1-4 carbon and the secondary substituting group of halogen, described secondary substituent number can reach 3 at most to moieties, and can reach the perhalogeno level at most to halogen; With other condition be (Q) qR 1, (Q) qR 2, (Q) qR 3(Q) qR 4In two can connect, and form with the atom that they connected and to contain 0-2 and be selected from the heteroatomic 3-8 unit's spiral shell of N, O and S or the non-aromatic ring of non-spiral shell; And pharmacy acceptable salt.
9. the method for claim 8, wherein said Mammals are human.
CN99816464A 1999-01-14 1999-12-14 Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents Pending CN1337955A (en)

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CN103382158B (en) * 2013-07-29 2015-11-18 张家港市大伟助剂有限公司 A kind of preparation method of 2-clopentylamino ethanol
CN114507143A (en) * 2022-02-26 2022-05-17 江苏壹药新材料有限公司 Synthesis method of 2-ethyl-1-fluoro-4-nitrobenzene
CN114671828A (en) * 2022-04-28 2022-06-28 蔚林新材料科技股份有限公司 Preparation method of 3-methyl-2-thiazolethione
CN114671828B (en) * 2022-04-28 2024-05-31 蔚林新材料科技股份有限公司 Preparation method of 3-methyl-2-thiazole thioketone
CN115925559A (en) * 2022-11-11 2023-04-07 上海泰坦科技股份有限公司 Preparation method of 1-amino-1-cyclopentyl methanol

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