* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium ethanolate In ethanol at 20 - 76℃; for 3.16667 h;
(200 g, 616 mmol) and absolute EtOH (1 L). At temperature <20°C, a freshly prepared NaOEt (253 mL, 677 mmol, 21percent in EtOH) wasadded over 10 min. The reaction mixture was heated to reflux (76 °C)and a suspension was formed. After 3 h, GC analysis showed full conversionof the pentaerythritol. The reaction mixture was cooled to r.t. and the solid material was removed by filtration. The filtrate was partitionedbetween MTBE (400 mL) and H2O (550 mL). The aqueousphase was extracted with MTBE (250 mL). The combined organicphases were washed successively with H2O (250 mL) and brine (150mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was distilled with a short path distillation setup (56 °C/0.1 mbar) and130 g (85percent) of 5b was collected as an almost colorless oil.1H NMR (CDCl3, 400 MHz): δ = 4.44 (s, 4 H), 3.86 (s, 4 H).
Reference：
[1] Synthesis (Germany), 2017, vol. 49, # 11, p. 2394 - 2401
[2] Journal of Organometallic Chemistry, 2007, vol. 692, # 24, p. 5395 - 5402
[3] Proceedings of the Koninklijke Nederlandse Akademie van Wetenschappen, Series B: Physical Sciences, 1939, vol. 42, p. 778[4] Chem. Zentralbl., 1940, vol. 111, # I, p. 2458
[5] Kogyo Kagaku Zasshi, 1958, vol. 61, p. 904,906[6] Chem.Abstr., 1961, p. 18696
[7] Organic Process Research and Development, 2016, vol. 20, # 3, p. 675 - 682
2
[ 1522-92-5 ]
[ 174-79-8 ]
[ 2402-83-7 ]
[ 22633-44-9 ]
Reference：
[1] Environmental Science and Technology, 2005, vol. 39, # 2, p. 505 - 512
3
[ 1522-92-5 ]
[ 174-79-8 ]
[ 2402-83-7 ]
[ 22633-44-9 ]
Reference：
[1] Environmental Science and Technology, 2005, vol. 39, # 2, p. 505 - 512
4
[ 115-77-5 ]
[ 64-19-7 ]
[ 3296-90-0 ]
[ 1522-92-5 ]
[ 3580-97-0 ]
Yield
Reaction Conditions
Operation in experiment
49%
With sulfuric acid; hydrogen bromide In water for 10 h; Heating
A 2-l Erlenmeyer flask was charged withpentaerythritol (136 g, 1 mol), 48percent hydrobromic acid (680 ml,1006.4 g, 6 mol), acetic acid (100 ml, 105.1 g, 1.75 mol),and then sulfuric acid (250 ml, 458.5 g, 4.5 mol) was carefully added while stirring the reaction mixture. The obtainedsolution was refluxed for 10 h. After that, the reactionmixture was cooled to 15°. The bottom (organic) layerwas separated by using a separatory funnel, and the top(aqueous) layer was extracted with chloroform (3×200 ml).The extracts were combined with the organic phase, theobtained solution was washed with water (3×75 ml). Theorganic phase was dried over anhydrous K2CO3 (20 g) forseveral hours. Then the chloroform solution wasevaporated, providing a brown liquid (275.4 g) with thefollowing composition (according to 1 NMR spectrum):3-bromo-2,2-bis(bromomethyl)propan-1-ol (3a), 3-bromo-2,2-bis(bromomethyl)propyl acetate (3b), 2,2-bis(bromomethyl)-1,3-propanediol (4a), 3-bromo-2-(bromomethyl)-2-(hydroxymethyl)propyl acetate (4b).3-Bromo-2,2-bis(bromomethyl)propan-1-ol (3a). Yield134.7 g (48.9percent). 1H NMR spectrum (DMSO-d6), δ, ppm(J, Hz): 3.41 (2, d, J = 5.0, 2OH); 3.49 (6, s, CH2Br);5.26 (1H, t, J = 5.0, OH).3-Bromo-2,2-bis(bromomethyl)propyl acetate (3b).Yield 101.9 g (37.0percent). 1H NMR spectrum (DMSO-d6),δ, ppm: 2.06 (3, s, OC(O)CH3); 3.57 (6, s, CH2Br); 4.06(2, s, CH2OC(O)CH3).2,2-Bis(bromomethyl)-1,3-propanediol (4a). Yield6.3 g (2.3percent). 1H NMR spectrum (DMSO-d6), δ, ppm(J, Hz): 3.41 (4, d, J = 5.0, 2OH); 3.44 (4, s, CH2Br);4.84 (1H, t, J = 5.0, OH).3-Bromo-2-(bromomethyl)-2-(hydroxymethyl)propylacetate (4b). Yield 32.5 g (11.8percent). 1H NMR spectrum(DMSO-d6), δ, ppm (J, Hz): 2.03 (3, s, OC(O)CH3); 3.40(2H, d, J = 4.1, CH2OH); 3.50 (4, s, CH2Br); 3.98 (2, s,CH2OC(O)CH3); 5.10 (1H, t, J = 4.6, OH). 13C NMRspectrum (CDCl3), δ, ppm: 171.22; 170.15; 63.95; 63.78;63.32; 62.33; 61.82; 44.50; 44.23; 42.67; 42.31; 34.83;34.51; 34.09; 33.53; 20.78 (for mixture 3a,b and 4a,b).The yield calculated for the target compounds 3a and 3bwas 236.6 g (69.2percent).
Reference：
[1] Chemistry of Heterocyclic Compounds, 2017, vol. 53, # 6-7, p. 811 - 821[2] Khim. Geterotsikl. Soedin., 2017, vol. 53, # 6-7, p. 811 - 821,11
5
[ 115-77-5 ]
[ 3296-90-0 ]
[ 1522-92-5 ]
Reference：
[1] Chemische Berichte, 1928, vol. 61, p. 542
6
[ 115-77-5 ]
[ 10035-10-6 ]
[ 3296-90-0 ]
[ 1522-92-5 ]
Reference：
[1] Chemische Berichte, 1928, vol. 61, p. 542
7
[ 115-77-5 ]
[ 1522-92-5 ]
Reference：
[1] Mendeleev Communications, 2009, vol. 19, # 2, p. 62 - 63
[2] Journal of Organometallic Chemistry, 2007, vol. 692, # 24, p. 5395 - 5402
[3] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2303 - 2311
[4] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8103 - 8113
[5] Journal of Organic Chemistry, 2004, vol. 69, # 11, p. 3986 - 3989
[6] Justus Liebigs Annalen der Chemie, 1893, vol. 276, p. 61
[7] Proceedings of the Koninklijke Nederlandse Akademie van Wetenschappen, Series B: Physical Sciences, 1939, vol. 42, p. 778[8] Chem. Zentralbl., 1940, vol. 111, # I, p. 2458
[9] Natuurw.Tijdsch., 1940, vol. 22, p. 266[10] Chem. Zentralbl., 1941, vol. 112, # I, p. 1944
[11] Bulletin de la Societe Chimique de France, 1964, p. 1268 - 1275
[12] Patent: CN105037087, 2017, B, . Location in patent: Paragraph 0022; 0023; 0024; 0025; 0026; 0027-0037
8
[ 115-77-5 ]
[ 64-19-7 ]
[ 3296-90-0 ]
[ 1522-92-5 ]
[ 3580-97-0 ]
Yield
Reaction Conditions
Operation in experiment
49%
With sulfuric acid; hydrogen bromide In water for 10 h; Heating
A 2-l Erlenmeyer flask was charged withpentaerythritol (136 g, 1 mol), 48percent hydrobromic acid (680 ml,1006.4 g, 6 mol), acetic acid (100 ml, 105.1 g, 1.75 mol),and then sulfuric acid (250 ml, 458.5 g, 4.5 mol) was carefully added while stirring the reaction mixture. The obtainedsolution was refluxed for 10 h. After that, the reactionmixture was cooled to 15°. The bottom (organic) layerwas separated by using a separatory funnel, and the top(aqueous) layer was extracted with chloroform (3×200 ml).The extracts were combined with the organic phase, theobtained solution was washed with water (3×75 ml). Theorganic phase was dried over anhydrous K2CO3 (20 g) forseveral hours. Then the chloroform solution wasevaporated, providing a brown liquid (275.4 g) with thefollowing composition (according to 1 NMR spectrum):3-bromo-2,2-bis(bromomethyl)propan-1-ol (3a), 3-bromo-2,2-bis(bromomethyl)propyl acetate (3b), 2,2-bis(bromomethyl)-1,3-propanediol (4a), 3-bromo-2-(bromomethyl)-2-(hydroxymethyl)propyl acetate (4b).3-Bromo-2,2-bis(bromomethyl)propan-1-ol (3a). Yield134.7 g (48.9percent). 1H NMR spectrum (DMSO-d6), δ, ppm(J, Hz): 3.41 (2, d, J = 5.0, 2OH); 3.49 (6, s, CH2Br);5.26 (1H, t, J = 5.0, OH).3-Bromo-2,2-bis(bromomethyl)propyl acetate (3b).Yield 101.9 g (37.0percent). 1H NMR spectrum (DMSO-d6),δ, ppm: 2.06 (3, s, OC(O)CH3); 3.57 (6, s, CH2Br); 4.06(2, s, CH2OC(O)CH3).2,2-Bis(bromomethyl)-1,3-propanediol (4a). Yield6.3 g (2.3percent). 1H NMR spectrum (DMSO-d6), δ, ppm(J, Hz): 3.41 (4, d, J = 5.0, 2OH); 3.44 (4, s, CH2Br);4.84 (1H, t, J = 5.0, OH).3-Bromo-2-(bromomethyl)-2-(hydroxymethyl)propylacetate (4b). Yield 32.5 g (11.8percent). 1H NMR spectrum(DMSO-d6), δ, ppm (J, Hz): 2.03 (3, s, OC(O)CH3); 3.40(2H, d, J = 4.1, CH2OH); 3.50 (4, s, CH2Br); 3.98 (2, s,CH2OC(O)CH3); 5.10 (1H, t, J = 4.6, OH). 13C NMRspectrum (CDCl3), δ, ppm: 171.22; 170.15; 63.95; 63.78;63.32; 62.33; 61.82; 44.50; 44.23; 42.67; 42.31; 34.83;34.51; 34.09; 33.53; 20.78 (for mixture 3a,b and 4a,b).The yield calculated for the target compounds 3a and 3bwas 236.6 g (69.2percent).
Reference：
[1] Chemistry of Heterocyclic Compounds, 2017, vol. 53, # 6-7, p. 811 - 821[2] Khim. Geterotsikl. Soedin., 2017, vol. 53, # 6-7, p. 811 - 821,11
9
[ 3296-90-0 ]
[ 1522-92-5 ]
Reference：
[1] Chemische Berichte, 1958, vol. 91, p. 938,941
[2] Monatshefte fuer Chemie, 1965, vol. 96, p. 147 - 158
10
[ 115-77-5 ]
[ 3229-00-3 ]
[ 1522-92-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1893, vol. 276, p. 61
[2] Chemische Berichte, 1928, vol. 61, p. 542
11
[ 115-77-5 ]
[ 3296-90-0 ]
[ 1522-92-5 ]
Reference：
[1] Chemische Berichte, 1928, vol. 61, p. 542
12
[ 115-77-5 ]
[ 10035-10-6 ]
[ 3296-90-0 ]
[ 1522-92-5 ]
Reference：
[1] Chemische Berichte, 1928, vol. 61, p. 542
13
[ 115-77-5 ]
[ 10035-10-6 ]
[ 3229-00-3 ]
[ 1522-92-5 ]
Reference：
[1] Chemische Berichte, 1928, vol. 61, p. 542
With potassium hydroxide In ethanol for 90 h; Reflux
2.2 Preparation of N-tosyl-2-oxa-6-azaspiro[3.3]heptane (5) To a solution of KOH (179 g, 3.2 mol) and p-tosylamide (205 g, 1.2 mol) in 1500 mL ethanol, 3-bromo-2,2-bis(bromomethyl)propan-1-ol (324 g, 1.0 mol) was added at room temperature and the reaction mixture was heated to reflux for 90 h. The solvent was removed by evaporation, 2000 mL 1 M KOH was added and the white suspension was left to stir for another 2 h at room temperature. The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral. The filter cake was dried under high vacuum to give N-tosyl-2-oxa-6-azaspiro[3.3]heptane (5, 192 g, yield 76percent) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.69 (d, 2H, J = 8.4 Hz), 7.47 (d, 2H, J = 8.4 Hz), 4.42 (s, 4H), 3.85 (s, 4H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.4, 130.9, 130.2, 128.5, 79.1, 59.5, 37.3, 21.3.
69%
With potassium hydroxide In ethanol for 45 h; Reflux
Step 1 6-(Toluene-4-sulfonyl)-2-oxa-6-azaspiro[3.3]heptane Procedure: To a solution of KOH (4.98 g, 0.089 mol) and 4-methylbenzenesulfonamide (5.7 g, 0.033 mol) in 90 ml of ethanol, 3-bromo-2,2-bis(bromomethyl)propan-1-ol (9 g, 0.0277 mol) was added at room temperature and the reaction mixture was heated to reflux for 45 h. The solvent was removed by evaporation, 75 ml of 1 M KOH were added and the white suspension was left to stir for another 2 h at room temperature. The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral. The filter cake was dried under high vacuum to give 4.87 g 6-toluene-4-sulfonyl-2-oxa-6-azaspiro[3.3]heptane (69percent) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.70-7.68 (m, 2H), 7.36-7.34 (m, 2H), 4.58 (s, 4H), 3.90 (s, 4H), 2.45 (s, 3H).
64%
With potassium hydroxide In ethanol at 90℃; for 72 h; Inert atmosphere
Intermediate 1 : 2,6-Diaza-spiro[3.31heptane-2-carboxylic acid tert-butyl ester, oxalic acid salt.6-(Toluene-4-sulfonyl)-2-oxa-6-aza-spiror3.31heptane. To a solution of tribromopentaerythitol (17.886 g, 55 mmol) and p-toluenesulfonamide (11.301 g, 66 mmol) in EtOH (200 ml_) was added KOH (9.875 g, 176 mmol). The reaction vessel was purged with N2 and heated to reflux (90 0C) for three days. The solvent was evaporated in vacuo and the product precipitated by stirring in 1 M KOH (100 ml_) for 2 h. The crude solid was purified (FCC) to give 6-(toluene-4-sulfonyl)-2-oxa-6-aza- spiro[3.3]heptane as a white solid (8.939 g, 64percent). MS (ESI+): calcd for Ci2Hi5NO3S m/z 253.08, found 254.1 (M+H)+. 1H NMR (CDCI3): 7.71 (d, J = 8.2, 2H), 7.37 (d, J = 8.4, 2H), 4.58 (s, 4H), 3.91 (s, 4H).
63%
With potassium hydroxide In ethanol; water for 2 h; Reflux
To a solution of 3-bromo-2,2-bis(bromomethyl)propanol (127) (3.25 g, 10 mmol) and potassium hydroxide (1.12 g, 20 mmol, in 10 mL water ) in EtOH (20 mL) were added toluene-4-sulfonamide (3.76 g, 22 mmol). The reaction mixture was refluxed for 2 h, evaporated to remove EtOH then diluted with EAOAc (20 mL), washed with H20 (20 mL). The organic layer was washed with brine (20 mL), dried over Na2S04, and filtered, evaporated to give the product to give 6-(toluene-4-sulfonyl)-2-oxa-6-aza-spiro[3.3]heptane (128) (1.6 g, 6.3 mmol, yield: 63percent).ESI-MS (M+l): 128 calc. for C7H13N
59%
With potassium hydroxide In ethanol at 25 - 100℃; for 48 h;
To a solution of p-toluenesulfonamide (57 g, 330 mmol) and potassium hydroxide (49.8 g, 890 mmol) in ethanol (1000 mL) was added 3-bromo-2,2-bis(bromomethyl)propan-1-ol (90 g, 270 mmol) at 25°C then the reaction mixture was stirred at 100°C for 48 h. The mixture was concentrated under reduced pressure, and the crude material was poured into solution of potassium hydroxide (75 mL) and stirred for 2 h, to afford filter cake (3) (10 g, 59percent) as a white solid.LC-MS (ESI) m/z = 254 [M+H].
58%
With potassium hydroxide In ethanol at 20℃; for 92 h; Reflux
To a solution of KOH (33.2g, 0.59mol) and p-tosylamide (37.9g,0.22mol) in 600ml ethano., 3- Bromo-2,2-bis(bromomethyl)propan- l -ol (154; 60. l g, 0. 19mol) was added at room temperature and the reaction mixture was heated to refluxed for 90h. The solvent was removed by evaporation, 500 ml 1 M KOH was added and the white suspension was left to stir for another 2 hours at room temperature. The mixture was filtered and the white fi lter cake was rinsed with water until the washing water was neutral. The filter cake was dried under high vacuum to give 6-tosyl-2-oxa-6-azaspiro[3.3]heptane (155; 30.55 g of product containing 10 molpercent of tosylamide as a white solid). The overall yield of pure 6-tosyl-2-oxa-6-azaspiro[3.3]heptane was calculated to be (155; 27.4 g, 58percent). MS (ESI) calcd for C 12H 15NO3S 253.3.
58%
With potassium hydroxide In ethanol for 90 h; Reflux
To a solution of KOH (33.2 g, 0.59 mol) and p-tosylamide (37.9 g, 0.22 mol) in 600 mL ethanol, 3-Bromo-2,2-bis(bromomethyl)propan-1-ol(60.1 g, 0.19 mol) was added at room temp and the reaction mixture was heated to reflux for 90 h. The solvent was removed by evaporation, 500 mL 1M KOH was added and the white suspension was left to stir for another 2 h at room temp. The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral. The filter cake was dried under high vacuum to give 30.55 g of product containing 10 molpercent of tosylamide as a white solid. The overall yield of pure 6-tosyl-2-oxa-6-azaspiro[3.3]heptane was calculated to be 27.4 g (58percent). MS (ESI) calcd for C12H15N03S: 253.3
58%
With potassium hydroxide In ethanol at 20℃; for 92 h; Reflux
To a solution of KOH (33.2 g, 0.59 mol) and p-tosylamide (37.9 g, 0.22 mol) in 600 mL ethanol, 3-Bromo-2,2-bis(bromomethyl)propan-1-ol(60.1 g, 0.19 mol) was added at room temp and the reaction mixture was heated to reflux for 90 h. The solvent was removed by evaporation, 500 mL 1M KOH was added and the white suspension was left to stir for another 2 h at room temp. The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral. The filter cake was dried under high vacuum to give 30.55 g of product containing 10 molpercent of tosylamide as a white solid. The overall yield of pure 6-tosyl-2-oxa-6-azaspiro[3.3]heptane was calculated to be 27.4 g (58percent). MS (ESI) calcd for C12H15NO3S: 253.3.
57.7%
With potassium hydroxide In ethanol at 90℃; for 48 h; Inert atmosphere
To a solution of benzenesulfonamide (8) (5.81 g, 36.9 mmol) in 500 mL of EtOH, 3-bromo-2,2-bis(bromomethyl)propan-1-ol (9) (10 g, 30.8 mmol), KOH (5.53 g, 99 mmol) was added and heated to reflux at 90 °C for 48 h. The solvent was evaporated and 100 mL of 1 M KOH was added and the resultant white suspension was stirred for another 2 h at RT. The mixture was filtered and the residue was rinsed with water until the filtrate was neutral. The filter cake was dried under high vacuum to give crude product (4.5 g). Yield: 57.7percent; off-white solid; 1H NMR (300 MHz, DMSO-d6) δ (ppm): 7.69 (d, J = 8 Hz, 2H, Ar-H), 7.49 (d, J = 8.1 Hz, 2H, Ar-H), 4.42 (s, 4H, 2CH2, spiro morpholine), 3.84 (s, 4H, 2CH2, spiro morpholine), 2.42 (s, 3H, CH3); LC-MS (ESI +ve) m/z 254 [M+H]+; HPLC purity: 99.79percent.
Reference：
[1] Fitoterapia, 2014, vol. 92, p. 111 - 115
[2] Patent: US2012/252777, 2012, A1, . Location in patent: Page/Page column 83
[3] Patent: WO2010/141817, 2010, A1, . Location in patent: Page/Page column 29
[4] Patent: WO2011/143365, 2011, A1, . Location in patent: Page/Page column 192
[5] Patent: WO2017/15106, 2017, A1, . Location in patent: Page/Page column 40; 42; 138
[6] Angewandte Chemie - International Edition, 2008, vol. 47, # 24, p. 4512 - 4515
[7] Patent: WO2011/59839, 2011, A1, . Location in patent: Page/Page column 142-143
[8] Patent: WO2013/59587, 2013, A1, . Location in patent: Page/Page column 211; 212
[9] Patent: EP2768509, 2017, B1, . Location in patent: Paragraph 0877; 0878
[10] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 475 - 487
[11] ACS Combinatorial Science, 2017, vol. 20, # 6, p. 335 - 343
[12] Chemical Communications, 2018, vol. 54, # 11, p. 1303 - 1306
16
[ 1522-92-5 ]
[ 1159599-99-1 ]
Reference：
[1] Fitoterapia, 2014, vol. 92, p. 111 - 115
[2] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 475 - 487
[3] Patent: WO2017/15106, 2017, A1,
[4] Synthesis (Germany), 2017, vol. 49, # 11, p. 2394 - 2401
With sodium ethanolate; In ethanol; at 20 - 76℃; for 3.16667h;
(200 g, 616 mmol) and absolute EtOH (1 L). At temperature <20C, a freshly prepared NaOEt (253 mL, 677 mmol, 21% in EtOH) wasadded over 10 min. The reaction mixture was heated to reflux (76 C)and a suspension was formed. After 3 h, GC analysis showed full conversionof the pentaerythritol. The reaction mixture was cooled to r.t. and the solid material was removed by filtration. The filtrate was partitionedbetween MTBE (400 mL) and H2O (550 mL). The aqueousphase was extracted with MTBE (250 mL). The combined organicphases were washed successively with H2O (250 mL) and brine (150mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was distilled with a short path distillation setup (56 C/0.1 mbar) and130 g (85%) of 5b was collected as an almost colorless oil.1H NMR (CDCl3, 400 MHz): delta = 4.44 (s, 4 H), 3.86 (s, 4 H).
With magnesium chloride; trichlorophosphate In 1,1,2,2-tetrachloroethylene
4 EXAMPLE 4
EXAMPLE 4 Following the procedures outlined in Example 1, 150 g of 3-bromo-2,2 bis(bromomethyl)propyl alcohol, 3 g anhydrous magnesium chloride and 25 g phosphorus oxychloride were mixed in 300 ml tetrachloroethylene in a flask. The contents were heated at reflux temperature for 21 hours. Following the described cooling, filtering and drying, a dry white product of 130 g of tris(3-bromo-2,2 bis(bromomethyl)propyl) phosphate was obtained, making an 83 percent yield based on the tribromoneopentyl alcohol.
To a solution of EtOH (500 mL) and 3-bromo-2,2-bis(bromomethyl)propan-1-ol (14.00 g, 43.1 mmol) was added 4-methylbenzenesulfonamide (16.23 g, 95 mmol) at 25 C. and the reaction mixture was refluxed for 20 h. The solvent was removed by evaporation and to this was added 100 mL of an 8% NaOH solution. The suspension was stirred for another 2 hours, filtered and the yellow filter cake was rinsed with water and dried overnight through air to give 6-tosyl-2-oxa-6-azaspiro[3.3]heptane (9.05 g, 35.7 mmol, 83% yield) as a light yellow solid. LCMS retention time 0.72 min [Method A]. MS m/z: 254.3 (M+H).
76%
With potassium hydroxide; In ethanol; for 90h;Reflux;
2.2 Preparation of N-tosyl-2-oxa-6-azaspiro[3.3]heptane (5) To a solution of KOH (179 g, 3.2 mol) and p-tosylamide (205 g, 1.2 mol) in 1500 mL ethanol, 3-bromo-2,2-bis(bromomethyl)propan-1-ol (324 g, 1.0 mol) was added at room temperature and the reaction mixture was heated to reflux for 90 h. The solvent was removed by evaporation, 2000 mL 1 M KOH was added and the white suspension was left to stir for another 2 h at room temperature. The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral. The filter cake was dried under high vacuum to give N-tosyl-2-oxa-6-azaspiro[3.3]heptane (5, 192 g, yield 76%) as a white solid. 1H NMR (400 MHz, CDCl3): delta 7.69 (d, 2H, J = 8.4 Hz), 7.47 (d, 2H, J = 8.4 Hz), 4.42 (s, 4H), 3.85 (s, 4H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) delta 144.4, 130.9, 130.2, 128.5, 79.1, 59.5, 37.3, 21.3.
69%
With potassium hydroxide; In ethanol; for 45h;Reflux;
Step 1 6-(Toluene-4-sulfonyl)-2-oxa-6-azaspiro[3.3]heptane Procedure: To a solution of KOH (4.98 g, 0.089 mol) and 4-methylbenzenesulfonamide (5.7 g, 0.033 mol) in 90 ml of ethanol, 3-bromo-2,2-bis(bromomethyl)propan-1-ol (9 g, 0.0277 mol) was added at room temperature and the reaction mixture was heated to reflux for 45 h. The solvent was removed by evaporation, 75 ml of 1 M KOH were added and the white suspension was left to stir for another 2 h at room temperature. The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral. The filter cake was dried under high vacuum to give 4.87 g 6-toluene-4-sulfonyl-2-oxa-6-azaspiro[3.3]heptane (69%) as a white solid. 1H NMR (300 MHz, CDCl3) delta 7.70-7.68 (m, 2H), 7.36-7.34 (m, 2H), 4.58 (s, 4H), 3.90 (s, 4H), 2.45 (s, 3H).
64%
With potassium hydroxide; In ethanol; at 90℃; for 72h;Inert atmosphere;
Intermediate 1 : 2,6-Diaza-spiro[3.31heptane-2-carboxylic acid tert-butyl ester, oxalic acid salt.6-(Toluene-4-sulfonyl)-2-oxa-6-aza-spiror3.31heptane. To a solution of tribromopentaerythitol (17.886 g, 55 mmol) and p-toluenesulfonamide (11.301 g, 66 mmol) in EtOH (200 ml_) was added KOH (9.875 g, 176 mmol). The reaction vessel was purged with N2 and heated to reflux (90 0C) for three days. The solvent was evaporated in vacuo and the product precipitated by stirring in 1 M KOH (100 ml_) for 2 h. The crude solid was purified (FCC) to give 6-(toluene-4-sulfonyl)-2-oxa-6-aza- spiro[3.3]heptane as a white solid (8.939 g, 64%). MS (ESI+): calcd for Ci2Hi5NO3S m/z 253.08, found 254.1 (M+H)+. 1H NMR (CDCI3): 7.71 (d, J = 8.2, 2H), 7.37 (d, J = 8.4, 2H), 4.58 (s, 4H), 3.91 (s, 4H).
63%
With potassium hydroxide; In ethanol; water; for 2h;Reflux;
To a solution of 3-bromo-2,2-bis(bromomethyl)propanol (127) (3.25 g, 10 mmol) and potassium hydroxide (1.12 g, 20 mmol, in 10 mL water ) in EtOH (20 mL) were added toluene-4-sulfonamide (3.76 g, 22 mmol). The reaction mixture was refluxed for 2 h, evaporated to remove EtOH then diluted with EAOAc (20 mL), washed with H20 (20 mL). The organic layer was washed with brine (20 mL), dried over Na2S04, and filtered, evaporated to give the product to give 6-(toluene-4-sulfonyl)-2-oxa-6-aza-spiro[3.3]heptane (128) (1.6 g, 6.3 mmol, yield: 63%).ESI-MS (M+l): 128 calc. for C7H13N
59%
With potassium hydroxide; In ethanol; at 25 - 100℃; for 48h;
To a solution of p-toluenesulfonamide (57 g, 330 mmol) and potassium hydroxide (49.8 g, 890 mmol) in ethanol (1000 mL) was added 3-bromo-2,2-bis(bromomethyl)propan-1-ol (90 g, 270 mmol) at 25C then the reaction mixture was stirred at 100C for 48 h. The mixture was concentrated under reduced pressure, and the crude material was poured into solution of potassium hydroxide (75 mL) and stirred for 2 h, to afford filter cake (3) (10 g, 59%) as a white solid.LC-MS (ESI) m/z = 254 [M+H].
58%
With potassium hydroxide; In ethanol; at 20℃; for 92h;Reflux;
To a solution of KOH (33.2g, 0.59mol) and p-tosylamide (37.9g,0.22mol) in 600ml ethano., 3- Bromo-2,2-bis(bromomethyl)propan- l -ol (154; 60. l g, 0. 19mol) was added at room temperature and the reaction mixture was heated to refluxed for 90h. The solvent was removed by evaporation, 500 ml 1 M KOH was added and the white suspension was left to stir for another 2 hours at room temperature. The mixture was filtered and the white fi lter cake was rinsed with water until the washing water was neutral. The filter cake was dried under high vacuum to give 6-tosyl-2-oxa-6-azaspiro[3.3]heptane (155; 30.55 g of product containing 10 mol% of tosylamide as a white solid). The overall yield of pure 6-tosyl-2-oxa-6-azaspiro[3.3]heptane was calculated to be (155; 27.4 g, 58%). MS (ESI) calcd for C 12H 15NO3S 253.3.
58%
With potassium hydroxide; In ethanol; for 90h;Reflux;
To a solution of KOH (33.2 g, 0.59 mol) and p-tosylamide (37.9 g, 0.22 mol) in 600 mL ethanol, 3-Bromo-2,2-bis(bromomethyl)propan-1-ol(60.1 g, 0.19 mol) was added at room temp and the reaction mixture was heated to reflux for 90 h. The solvent was removed by evaporation, 500 mL 1M KOH was added and the white suspension was left to stir for another 2 h at room temp. The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral. The filter cake was dried under high vacuum to give 30.55 g of product containing 10 mol% of tosylamide as a white solid. The overall yield of pure 6-tosyl-2-oxa-6-azaspiro[3.3]heptane was calculated to be 27.4 g (58%). MS (ESI) calcd for C12H15N03S: 253.3
58%
With potassium hydroxide; In ethanol; at 20℃; for 92h;Reflux;
To a solution of KOH (33.2 g, 0.59 mol) and p-tosylamide (37.9 g, 0.22 mol) in 600 mL ethanol, 3-Bromo-2,2-bis(bromomethyl)propan-1-ol(60.1 g, 0.19 mol) was added at room temp and the reaction mixture was heated to reflux for 90 h. The solvent was removed by evaporation, 500 mL 1M KOH was added and the white suspension was left to stir for another 2 h at room temp. The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral. The filter cake was dried under high vacuum to give 30.55 g of product containing 10 mol% of tosylamide as a white solid. The overall yield of pure 6-tosyl-2-oxa-6-azaspiro[3.3]heptane was calculated to be 27.4 g (58%). MS (ESI) calcd for C12H15NO3S: 253.3.
57.7%
With potassium hydroxide; In ethanol; at 90℃; for 48h;Inert atmosphere;
To a solution of benzenesulfonamide (8) (5.81 g, 36.9 mmol) in 500 mL of EtOH, 3-bromo-2,2-bis(bromomethyl)propan-1-ol (9) (10 g, 30.8 mmol), KOH (5.53 g, 99 mmol) was added and heated to reflux at 90 C for 48 h. The solvent was evaporated and 100 mL of 1 M KOH was added and the resultant white suspension was stirred for another 2 h at RT. The mixture was filtered and the residue was rinsed with water until the filtrate was neutral. The filter cake was dried under high vacuum to give crude product (4.5 g). Yield: 57.7%; off-white solid; 1H NMR (300 MHz, DMSO-d6) delta (ppm): 7.69 (d, J = 8 Hz, 2H, Ar-H), 7.49 (d, J = 8.1 Hz, 2H, Ar-H), 4.42 (s, 4H, 2CH2, spiro morpholine), 3.84 (s, 4H, 2CH2, spiro morpholine), 2.42 (s, 3H, CH3); LC-MS (ESI +ve) m/z 254 [M+H]+; HPLC purity: 99.79%.
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