(R)-4-Cyclohexyl-2,3-butadien-1-ol

(R)-4-Cyclohexyl-2,3-butadien-1-ol


B. (R)-4-Cyclohexyl-2,3-butadien-1-ol ((R)-3). The crude product (R)-2 prepared above (20.80 g) is dissolved in 200 mL of THF  in a 500-mL round-bottomed flask that contains a magnetic stir bar and is equipped with a solid addition funnel. The flask is placed in an ice-water bath and stirred while open to the atmosphere. To this solution is added TBAF·3H₂O (32.0 g, 101 mmol) (Note 7) in one portion via a solid addition funnel. After the addition is complete, the ice-water bath is removed and the resulting mixture is allowed to stir at room temperature. After 2 h, the reaction is complete as monitored by TLC . The reaction mixture is poured into ice water (150 mL) in a 1-L beaker followed by addition of diethyl ether (300 mL). The mixture is transferred to a separatory funnel, the organic layer is separated, and the aqueous layer is extracted with ethyl ether (3 x 50 mL). The combined organic layer is washed with brine (100 mL) and dried over anhydrous Na₂SO₄ (15 g). After evaporation (15 mmHg with a water bath of 30 °C), the residue is purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 20:1 → 15:1) (Note 16) to afford 9.42 g of (R)-3 (62% combined yield over steps A and B) (Notes 17 and 18) as a light yellow liquid with 99% ee 



The enantiomeric excess was determined by chiral HPLC (conditions: Chiralcel AS-H column, eluent: hexane/i-PrOH = 98/2, flow rate: 0.7 mL/min). The peaks were visualized at 214 nm with retention times of 17.2 (major isomer) and 20.3 min (minor isomer). Enantioenriched (R)-4-cyclohexyl-2,3-butadien-1-ol ((R)-3) exhibits the following characteristics: 

[a]_D²⁸ = - 97.1 (c = 1.01, CHCl₃); 

¹H NMR pdf(500 MHz, CDCl₃) δ: 1.00-1.32 (m, 5 H), 1.62-1.77 (m, 6 H), 1.98-2.05 (m, 1 H), 4.10 (s, 2 H), 5.27-5.38 (m, 2 H);

¹³C NMR pdf(125 MHz, CDCl₃) δ: 25.8, 25.9, 32.8, 32.9, 36.9, 60.7, 92.4, 99.4, 202.0; MS (EI) m/z (%): 152 (M⁺, 0.70), 55 (100);

 IR (neat): v = 3331, 2924, 2851, 1961, 1448, 1302, 1258, 1214, 1062, 1012 cm^-1; 


HRMS calcd for C ₁₀H₁₆O [M⁺]: 152.1201, found: 152.1198.

16. The column (diameter = 80 mm) was packed with 390 g of silica gel (10-40 mm): a mixture of 4.0 L of petroleum ether (60-90 °C) and 0.2 L of ethyl acetate was first used as the eluent (~400 mL for each fraction); then a mixture of 3.8 L of petroleum ether (60-90 °C) and 0.25 L of ethyl acetate was used (~100 mL for each fraction). After evaporation of the solvents, 9.42 g of the product (R)-3 was obtained as a light yellow liquid.

17. The purity of the product (R)-4-cyclohexyl-2,3-butadien-1-ol ((R)-3) is 99% as determined by GC; GC conditions: hp-5 (30 m x 0.32 mm x 0.25 mm); oven: 50 °C for 2 min, then 20 °C/min, 250 °C for 10 min; inject: 320 °C; FID: 320 °C; split: 80:1; N ₂: 20 mL/min.

18. The yield was calculated based on (S)-α,α-diphenylprolinol since it is the limiting reagent (1 equiv).

19. A second full-scale run provided 9.82 g (65%) for the two steps.

20. Determination of the enantiomeric excess of the product (R)-4-cyclohexyl-2,3-butadien-1-ol ((R)-3) required the synthesis of the corresponding racemic 4-cyclohexyl-2,3-butadien-1-ol (±)-3 (Scheme 1)

To a flame-dried Schlenk tube that contained a stir bar were added CuBr (7.4 mg, 0.05 mmol) and activated 4 Å molecular sieves (301.7 mg). Toluene (2 mL), tert-butyldimethyl(2-propynyloxy)silane 1 (170.5 mg, 1.0 mmol),cyclohexanecarboxaldehyde (124.0 mg, 1.1 mmol) and pyrrolidine (78.3 mg, 1.1 mmol) were then added sequentially under an argon atmosphere. The solution was then stirred at 25 °C until completion of the reaction as monitored by TLC (12 h). The crude reaction mixture was filtrated through a short pad of silica gel eluted with ether (20 mL). After evaporation, the crude product was used in the next step without further treatment. To another Schlenk tube that contained a stir bar were added anhydrous ground ZnI₂ (147.0 mg, 0.45 mmol) and NaI (75.2 mg, 0.5 mmol). 

The Schlenk tube was heated with a heating gun under vacuum (1 mmHg) for about 1 min, and the flask was refilled with argon. The above crude product was then dissolved in toluene (5 mL) and transferred to the Schlenk tube via a syringe under argon atmosphere. The Schlenk tube was then equipped with a condenser and placed in a pre-heated oil bath at 110 °C with stirring. After 6 h, the reaction was judged as complete by TLC, after which the crude reaction mixture was filtrated through a short pad of silica gel (diameter: 30 mm, height: 20 mm) with ether (20 mL) as the eluent. After evaporation, the crude product was then dissolved in THF (3 mL) and treated at 0 °C with TBAF·3H₂O (316 mg, 1.0 mmol). The resulting mixture was allowed to warm to room temperature naturally with stirring. After 2 h, the reaction was complete, as determined by TLC, and H₂O (10 mL) and ether (10 mL) were then added. The organic layer was separated and the aqueous layer was extracted with ether (3 x 10 mL). The combined organic layer was dried over anhydrous Na₂SO₄. After filtration and evaporation, the residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to afford 4-cyclohexyl-2,3-butadien-1-ol (±)-3 (113.0 mg, 74%) as a liquid.

Acebutolol

Acebutolol

N-(3-Acetyl-4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl)butanamide

3′-acetyl-4′-(2-hydroxy-3-(isopropylamino)propoxy)butyranilide

(±)-acebutolol

Acetobutolol; Sectral; Prent; Neptal; Acebutololum; Acebutololo; (+-)-Acebutolol; dl-Acebutolol; Acebrutololum

Molecular Formula: C18H28N2O4   Molecular Weight: 336.42592

CAS Registry Number: 37517-30-9

CAS Name: N-[3-Acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]phenyl]butanamide

Additional Names: 3¢-acetyl-4¢-[2-hydroxy-3-(isopropylamino)propoxy]butyranilide; 1-(2-acetyl-4-n-butyramidophenoxy)-2-hydroxy-3-isopropylaminopropane; 5¢-butyramido-2¢-(2-hydroxy-3-isopropylaminopropoxy)acetophenone

Percent Composition: C 64.26%, H 8.39%, N 8.33%, O 19.02%

Melting point: mp 119-123°

Derivative Type: Hydrochloride

CAS Registry Number: 34381-68-5

Manufacturers’ Codes: M & B 17803A; IL-17803A

Trademarks: Acecor (SPA); Acetanol (RPR); Neptal (Procter & Gamble); Prent (Bayer); Sectral (RPR)

Molecular Formula: C18H28N2O4.HCl

Molecular Weight: 372.89

Percent Composition: C 57.98%, H 7.84%, N 7.51%, O 17.16%, Cl 9.51%

Properties: Crystals from anhydr methanol-anhydr diethyl ether, mp 141-143°. Freely sol in water. Soly at room temperature (mg/ml): water 200; ethanol 70.

Melting point: mp 141-143°

Therap-Cat: Antihypertensive; antianginal; antiarrhythmic (class II).

Acebutolol (trade names Sectral, Prent) is a beta blocker for the treatment of hypertension and arrhythmias.

A cardioselective beta-adrenergic antagonist with little effect on the bronchial receptors. The drug has stabilizing and quinidine-like effects on cardiac rhythm as well as weak inherent sympathomimetic action.

View current batch: S401001..http://www.selleckchem.com/products/acebutolol-hcl.html

Purity=99.93% COA

NMR

HPLC

Datasheet

MSDS

http://www.allfordrugs.com/2014/09/05/acebutolol-for-the-management-of-hypertension-and-ventricular-premature-beats-in-adults/

21′α-Cyanoanhydrovinblastine

Some derivatives ) are known as being intermediates in the preparation of anti-tumor medicaments such as vinblastine, vincristine and vinorelbine.

R=CH3, vinblastine

R=CHO, vincristine

n=2, anhydrovinblastine

n=1, vinorelbine

The remarkable anti-tumor properties of these complex natural molecules, extracted from the Madagascar periwinkle, Carantheus roseus, are known and they are already used in anti-cancer treatment. Vinblastine and vincristine are “spindle poisons” which oppose the formation of the mitotic spindle during cellular division, thus preventing cellular proliferation.

Vincristine and vinblastine are active agents in the treatment of leukemia, lymphosarcoma and solid tumors. Vinblastine is also used in the treatment of Hodgkin’s disease.

Vinorelbine is currently used in the treatment of the most widespread form of cancer of the lungs, that is lung cancer of non-small cells. It is also used in the treatment of metastasic cancers of the breast.

The methods currently used for preparing vinblastine and vincristine involve extraction of these molecules from plants. The plants have to be crushed and dried before these substances can be extracted. The extraction process is long and costly, given that the extract obtained is very complex, containing at least 200 different alkaloids. The yields are also very low; 5 to 10 g of vinoblastine are obtained per ton of dried plant material, and 0.5 to 1 g of vincristine per ton of dried plant material.

Many research groups have thus tried to achieve synthesis of these molecules by using more efficient procedures which enable better yields and which make use of derivatives with interesting anti-tumor properties but which are endowed with lower levels of toxicity.

just an animation

The patent FI 882 755, filed by the HUATAN-MAKI Oy Company, relates to the formation of vinblastine and vincristine by irradiation of catharanthine and of vindoline with UV radiation in an acidic aqueous solution, under an atmosphere of oxygen or an inert gas. The yields obtained in these reactions are extremely low.

Furthermore, other processes are known which make use of anhydrovinblastine which is an intermediate in the synthesis of vinblastine, vincristine and also of vinorelbine.

Anhydrovinblastine is thus a key chemical intermediate which enables access to all alkaloids of the vinblastine type. This intermediate is synthesised by coupling catharanthine and vindoline.

The latter two alkaloids are also extracted from the Madagascar periwinkle but, in contrast to vincristine and vinblastine, they represent the main constituents of the extract obtained. In fact, 400 g of catharanthine per ton of dried plant material and 800 g of vindoline per ton of dried plant material are obtained.

The preparation of anhydrovinblastine by coupling catharanthine and vindoline is therefore a favoured route for synthesising this intermediate product.

There are several methods for preparing anhydrovinblastine from catharanthine and vindoline.

The patent FR 2 296 418 filed by ANVAR describes a process during the course of which the N-oxide of catharanthine is coupled to vindoline in the presence of trifluoroacetic anhydride.

When this process is performed at ambient temperature only the inactive 16′-R epimer of anhydrovinblastine is obtained. The naturally occurring active 16′-S epimer is obtained as the major product when this reaction is performed at a temperature which is at least 50° C. lower and under an inert gas. Nevertheless, even at low temperature, 10% of the 16′-R epimer of anhydrovinblastine is still produced.

This process has several disadvantages. The operating conditions are extremely restrictive due to the use of anhydrous solvents, the low temperature and the atmosphere of inert gas. The product obtained has to be subjected to a purification procedure due to the presence of 10% of the 16′-R epimer of anhydrovinblastine. The yield of isolated anhydrovinblastine is low, of the order of 35%.

A second process, suggested by VUKOVIC et al. in the review “Tetrahedron” (1998, volume 44, pages 325-331) describes a coupling reaction between catharanthine and vindoline initiated by ferric ions. Catharanthine is also oxidised in this reaction. The yield of anhydrovinblastine is of the order of 69% when the reaction is performed under an atmosphere of inert gas. However, this process has the major disadvantage that it leads to many secondary products. These are impurities resulting from further oxidation of the dimeric alkaloids formed, whatever the chosen operating conditions. This makes the purification stage difficult and delicate.

An improved process was suggested in the patent U.S. Pat. No. 5,037,977 and this increases the yield of anhydrovinblastine to 89%. However, this improvement is described only for very small amounts of reagents and its extension to the industrial scale seems to be difficult. In any case, these processes based on ferric ions lead in all cases to many secondary products due to the fact that these ions are responsible for parasitic reactions.

A third process described by GUNIC et al. in “Journal of the Chemical Society Chemical Communications” (1993), volume 19, pages 1496-1497, and by Tabakovic et al. in “Journal of Organic Chemistry” (1997), volume 62, pages 947-953, describes a coupling reaction between catharanthine and vindoline as a result of anodic oxidation of catharanthine. However, this process also suffers from disadvantages which, on the one hand, are due to the requirement for an inert atmosphere and, on the other hand, are connected with the nature of the electrochemical process itself, involving wear of the electrodes, difficulty in controlling the reproducibility and the cost of electrolytes. And, as in all the preceding methods, the anhydrovinblastine is contaminated with about 10% of the 16′-R epimer of anhydrovinblastine.

http://www.google.com/patents/US6365735

EXAMPLE 11 Preparation of 21′α-Cyanoanhydrovinblastine

0.537 mmol of catharanthine hydrochloride (200 mg), 0.537 mmol of vindoline (245 mg) and 0.054 mmol of dimethyl viologen (14 mg) and 0.028 mmol of triphenylpyrilium hydrogen sulfate (11 mg) are added to 50 ml of 0.1 N sulfuric acid. The entire mixture is irradiated with light of wavelength λ>400 nm in a Pyrex irradiation flask, under an atmosphere of oxygen. The reaction is terminated after 2 h 30 min of irradiation.

The aqueous phase is then saturated with lithium tetrafluoroborate and then extracted with dichloromethane. A solution of 15 ml of dichloromethane containing 100 μl (1.34 mmol, 2 eq.) of trimethylsilyl cyanide, TMSCN, is then added to the reaction medium. The organic phase is washed with a solution of 0.1 M sodium carbonate, dried and evaporated under reduced pressure at 20° C.

The only product in the residue (403 mg, 0.509 mmol, 95%) is recrystallised from absolute isopropanol. 340 mg of white crystals of 21′α-cyanoanhydrovinblastine (0.430 mmol; yield: 80%) are recovered.

C47H55N5O8

M.pt. 212° C. (iPrOH) IR film 3450, 2950, 2220, 1740, 1610 cm−1; MS M/z (relative intensity) 818 (MH+, 3), 122 (100), 108 (21);

NMR 1H (500 MHz, CDCl3) 9.78 (s, 1H, OH), 8.04 (s, 1H, Na′H), 7.51 (1H, H-9′), 7.16 (1H, H-11′), 7.13 (1H, H-12′), 7.12 (1H, H-10′), 6.63 (s, 1H, H-9), 6.13 (s, 1H, H-12), 5.85 (m, 1H, H-14), 5.47 (s, 1H, Hα-17), 5.54 (m, 1H, H-15′), 5.30 (m 1H, H-15), 4.18 (1H, H62-2), 3.60 (s, 3H, C16′—COOCH3), 3.38 (1H, H62-3), 3.35 (1H, Hβ-3′), 3.31 (1H, Hβ-5), 3.25 (1H, Hβ-6′), 3.24 (m, 1H, Hβ-5′), 3.15 (1H, Hβ-17′), 3.14 (m, 1H, Hα-5′), 3.12 (1H, Hα-6′), 2.82 (1H, Hα-3), 2.72 (s, 3H, NaCH3), 2.66 (s, 1H, Hα-21), 2.62 (1H, Hα-3′), 2.46 (1H, Hα-5), 2.40 (1H, Hα-17′), 2.20 (1H, Hβ-5), 2.11 (s, 3H, CH3—COO), 2.11 (1H, H-19′), 2.03 (1H, H-19′), 1.80 (1H, Hα-6), 1.80 (1H, H-19), 1.35 (1H, H-19), 1.21 (m, 1H, H-14′), 1.04 (3H, H-18′), 0.81 (3H, H-18).

NMR 13C (125 MHz, CDCl3) 174.69 (C16′—COOCH3), 171.74 (C16—COOCH3), 171.03130.01 (C15), 129.34 (C8′), 129.16 (C15′), 124.63 (C14), 123.48 (C9), 123.24 (C8), 122.49 (C11′), 121.00 (C10), 119.21 (C10′), 119.21 (CN), 118.35 (C9′), 115.65 (C7′), 110.64 (C11—OCH3), 55.40 (C16′), 53.30 (C7), 52.46 (C16′—COOCH3), 52.30 (C16—COOCH3), 52.26 (C5′), 50.50 (C5), 50.41 (C5), 44.86 (C6), 44.48 (C3′), 42.76 (C20), 38.32 (Na—CH3), 34.00 (C17′), 33.28 (C14′), 30.92 (C19), 28.63 (C8′), 25.92 (C19′), 21.19 (CH3—COO), 11.86 (C18′), 8.50 (C18).

Patent Citations

Cited Patent	Filing date	Publication date	Applicant	Title
US4737586	Apr 29, 1986	Apr 12, 1988	Agence Nationale De Valorisation De La Recherche	Process for the preparation of bis-indolic compounds
US5037977	Aug 8, 1989	Aug 6, 1991	Mitsui Petrochemical Industries Ltd.	Reacting catharanthine with vindoline in presence of ferric ions, inactivating iron with ligand, reducing
DE3801450A1	Jan 20, 1988	Aug 18, 1988	Univ British Columbia	Verfahren fuer die synthese von vinblastin und vincristin
DE3826412A1	Aug 3, 1988	Feb 16, 1989	Univ British Columbia	Verfahren fuer die synthese von vinblastin und vincristin
WO1989012056A1	Jun 9, 1989	Dec 14, 1989	Huhtamaeki Oy	Process for the preparation of dimeric catharanthus alkaloids

Non-Patent Citations

Reference
1		E. Gunic et al., “Electrochemical Synthesis of Anhydrovinblastine“, J. Chem. Soc., Chem. Commun., 1993, pp. 1496-1497.
2		I. Tabakovic et al., “Anodic Fragmentation of Catharanthine and Coupling with Vindoline. Formation of Anhydrovinblastine“, J. Org. Chem., 1997, vol. 62, pp 947-953.
3		J. Vucovik et al., “Production of 3′,4′-anhydrovinblastine: a Unique Chemical Synthesis“, Pergamon Journals Ltd., 1988, vol. 44, pp. 325-331.
4		Richard J. Sundberg et al.; “Mechanistic aspects of the formation of anhydrovinblastine by Potier-Polonovski oxidative coupling of catharanthine and vindoline. Spectroscopic observation and chemical reactions of intermediates” Tetrahedron., vol. 48, No. 2,-Jan. 10, 1992; pp. 277-296, XP002083507 Oxford GB-the whole document.
5		Richard J. Sundberg et al.; “Oxidative fragmentation of catharanthine by dichlorodicyanoquinone“; Journal of Organic Chemistry,-Mar. 1, 1991; pp. 1689-1692, XP002083508 Easton US -the whole document.
6		Richard J. Sundberg et al.; “Photoactivated C16-C21 fragmentation of catharanthine” Tetrahedron Letters, vol. 32, No. 26, Jun. 24, 1992, pp. 3035-3038 XP002083509 Oxford GB-the whole document.
7		Richard J. Sundberg et al.; “Mechanistic aspects of the formation of anhydrovinblastine by Potier-Polonovski oxidative coupling of catharanthine and vindoline. Spectroscopic observation and chemical reactions of intermediates” Tetrahedron., vol. 48, No. 2,—Jan. 10, 1992; pp. 277-296, XP002083507 Oxford GB—the whole document.
8		Richard J. Sundberg et al.; “Oxidative fragmentation of catharanthine by dichlorodicyanoquinone“; Journal of Organic Chemistry,—Mar. 1, 1991; pp. 1689-1692, XP002083508 Easton US —the whole document.
9		Richard J. Sundberg et al.; “Photoactivated C16-C21 fragmentation of catharanthine” Tetrahedron Letters, vol. 32, No. 26, Jun. 24, 1992, pp. 3035-3038 XP002083509 Oxford GB—the whole document.

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 ANTHONY MELVIN CRASTO